title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Remission rates at post-measurement (three months after admission). | Anorexia Nervosa, Bulimia Nervosa | Note: AN = Anorexia Nervosa. BN = Bulimia Nervosa, Amb. = Ambulatory. | PMC10313003 | |
Discussion | anxiety, weight gain, psychiatric, comorbid disorder, AN, reduction, depressive symptoms | REMISSION, PATHOLOGY | Few empirical data examine the implementation of guideline-oriented CBT for EDs and associated outcomes in routine clinical care. In the present study, findings for full-time treatment (e.g., hospitalization) were contrasted with findings for ambulatory treatment. Across settings, patient characteristics and treatment intensity were quite heterogeneous. Due to these differences, direct comparisons of treatment outcomes between settings are not indicated and results should not be interpreted as superiority of one treatment setting over another. Generally, the present study showed that a substantial number of patients with AN and BN displayed symptomatic improvements on several indicators of mental health within three months of treatment admission, although recovery rates remained quite low.Among women with AN receiving full-time treatment, substantial improvements were observed in body weight, depressive symptoms, symptoms of anxiety, and somatic symptoms, while improvements in ED pathology were moderate. It should be noted that, particularly for this group, the range of the number of psychotherapeutic sessions received was remarkably broad, indicating strong variations in treatment intensity. Results showed that, for women with AN, reduction in ED pathology was directly related to the number of psychotherapeutic sessions received, while weight gain was associated with higher AN severity (i.e., more severe underweight). Although nearly one fifth of patients with AN was considered partially remitted after three months of full-time treatment, the recovery rate (i.e., full remission of symptoms) was very low (3.1%). In line with this, a multi-centre study of short-term outcomes of inpatient treatment (e.g. hospitalization) similarly reported large increases in BMI and improvements in physical health, but the majority of patients remained in an underweight BMI range and continued to display clinical levels of ED symptoms at discharge [For women with BN receiving full-time treatment, large improvements in self-reported ED pathology and somatic symptoms were observed as well as moderate improvements in depressive symptoms and symptoms of anxiety. In line with this, research indicates that nearly half of patients with severe BN showed clinically significant symptom changes after hospitalization [Several differences between the full-time setting and the ambulatory setting are noteworthy. First, as expected, patient characteristics differed between settings. Patients with AN receiving full-time treatment were younger, had a lower BMI, and more often a severe or extreme form of AN compared to ambulatory AN patients. Patients with BN receiving full-time treatment more often reported the use of psychopharmateucis, were more often diagnosed with a comorbid disorder, and more often displayed an extreme form of BN compared to ambulatory BN patients. These findings indicate that ED severity and psychiatric comorbidity are somewhat more severe among patients who voluntarily admitted to full-time treatment compared to ambulatory treatment. Yet, it is noteworthy that approximately half of all full-time AN patients displayed a mild or moderate severity form (average BMI of full-time AN patients was 16.7). This finding indicates that, in clinical practice, hospitalization of patients with AN often occurs for reasons other than very low body weight (i.e., severe form of AN).Furthermore, treatment intensity differed largely between settings as well as treatment institutions. Full-time patients with AN received on average 65 psychotherapeutic sessions within three months after admission and full-time patients with BN received on average 38 psychotherapeutic sessions. It should be noted, that the range of the number of sessions differed largely, especially among AN patients. In this context, it should be noted that one treatment institution adminstered a highly intensive AN treatment program (including 2–5 individual sessions per day plus daily group sessions, resulting in an average of 130 psychotherapeutic sessions for AN patients in this treatment institution), thereby strongly increasing the average number of psychotherapeutic sessions for full-time AN patients in the present study. In line with this, previous studies have already noted a large variability in treatment programs and outcomes [The present study has several limtations. First of all, generalizability of the present findings may be limited by several factors including small sample size of subgroups, specific sample characteristics of study participants, or specific characteristics of cooperating treatment institutions. It should be acknowledged that both patients and institutions do not represent the general population. Furthermore, the present study only examined a few potential covariates. It is possible that additional patient or treatment characteristics may be associated with treatment setting as well as symptom course. In addition, the present study does not include a control group. Therefore, it cannot disentangle symptomatic improvements attributable to the treatment and naturally occurring fluctuations in symptoms. Furthermore, the short-term outcomes reported in the present study should be distinguished from long-term outcomes. As treatments may still be ongoing, remission rates after treatment termination will probably be higher. Therefore, comparisons to the remission rates of clinical trials, which typically report remission rates after treatment termination, are not feasible. Finally, it should be noted that the response rate of therapists, who provided information regarding treatment characteristics, was relatively low (67%). The strengths of the present study include the application of a thorough diagnostical procedure and well-validated measures among ED patients in nine different treatment facilities in Germany and Switzerland. It is one of the few studies evaluating outcomes of guideline-oriented ED treatment in routine clinical care.In conclusion, the present study showed considerable symptomatic improvements among patients with AN and BN in routine clinical care. Among women with AN, full-time treatment was associated with substantial improvements in body weight, ED pathology, depressive symptoms, symptoms of anxiety, and somatic symptoms. Among women with BN, full-time treatment and ambulatory treatment were associated with considerable improvements on all measured variables, but with different treatment dosages. Results also show that full recovery of EDs is typically not achieved within three months of treatment initiation and requires prolonged treatment duration, even after initial symptomatic improvements during intensive hospitalization. Generally, results also show that treatment intensity and treatment outcomes are quite diverse, indicating the possibility for increasing effectiveness in the treatment of EDs in routine clinical care. | PMC10313003 |
Supporting information | PMC10313003 | |||
ED treatments in routine clinical care. | (SAV)Click here for additional data file. | PMC10313003 | ||
Purpose | To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda | PMC10806046 | ||
Methods | MERCURY-3 was a 6-month prospective, double–masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. | PMC10806046 | ||
Results | Overall, 430 patients were randomized (NET/LAT, | PMC10806046 | ||
Conclusions | OAG | Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT. | PMC10806046 | |
Supplementary information | The online version contains supplementary material available at 10.1007/s00417-023-06192-0. | PMC10806046 | ||
Keywords | PMC10806046 | |||
Introduction | toxicity, open-angle glaucoma, OAG, glaucoma | OCULAR HYPERTENSION, OPEN-ANGLE GLAUCOMA, PGA, GLAUCOMA, INTRAOCULAR PRESSURE | Controlling intraocular pressure (IOP), the key modifiable risk factor of conversion of ocular hypertension (OHT) to glaucoma and progression of open-angle glaucoma (OAG), remains the cornerstone of glaucoma management [IOP is determined by aqueous humour (AH) production and AH drainage through trabecular (conventional) outflow to the episcleral veins, and uveoscleral (unconventional) outflow to the orbital venous system. Trabecular outflow is significantly influenced by the episcleral venous pressure (EVP) [Topical fixed-dose combination (FDC) formulations for lowering IOP have been increasingly used worldwide because they offer a convenient mode of administration that could potentially improve adherence, and may help to reduce toxicity related to cumulative preservative exposure if a patient is receiving more than one active topical ingredient [Rho-kinase (ROCK) signalling has been identified in the TM and is an important regulator of trabecular outflow [ROCK inhibitors are the first new class of drugs for glaucoma since the mid-1990s, and their unique mechanism of action represents an opportunity to evolve OAG/OHT treatment as a monotherapy or in combination with other drug classes with complementary mechanisms [The commercially available novel FDC of netarsudil and latanoprost, a commonly used PGA which increases uveoscleral outflow, has been developed to optimize complementary IOP-lowering mechanisms [Here, we present the first large-scale randomized prospective investigation of the efficacy and safety of netarsudil/latanoprost 0.02%/0.005% (NET/LAT; Roclanda | PMC10806046 |
Methods | PMC10806046 | |||
Study design and patients | ocular disease, inflammation, Diabetic Retinopathy, ocular infection, ocular trauma, keratitis, psychiatric, coma, occludable, glaucoma, Glaucoma, blepharitis, ocular hypotensive, angle-closure glaucoma, hypersensitivity, pseudoexfoliation | SYSTEMIC DISEASE, DIABETIC RETINOPATHY, DRY EYE, KERATITIS, BLEPHARITIS, COMA, CONJUNCTIVITIS, GLAUCOMA, ANGLE-CLOSURE GLAUCOMA, HYPERSENSITIVITY, GLAUCOMA, HERPES SIMPLEX | MERCURY-3 (NCT03284853) was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Participants were evaluated at one of 58 clinical sites in 11 European countries (Supplementary Table The study was conducted in accordance with the Declaration of Helsinki, US FDA law, EU Clinical Trials Directive 2001/20/ED and in compliance with international guidelines (ICHGCP E6R2). Local and national regulatory requirements were followed as appropriate, and participants gave informed, written consent prior to entering the study.Eligible participants were aged ≥ 18 years and had a diagnosis of OAG or OHT in both eyes that was insufficiently controlled by their existing treatment (medicated IOP ≥ 17 mmHg in at least one eye and < 28 mmHg in both eyes at screening). To qualify for the study, patients had to have been taking the same IOP-lowering medication for 30 days prior to screening. Between screening and the first treatment visit, a washout period was required (4 weeks for PGAs and β-adrenoceptor antagonists; 2 weeks for adrenergic agonists [including α-agonists such as brimonidine and apraclonidine]; and 5 days for muscarinic agonists [e.g., pilocarpine] and carbonic anhydrase inhibitors). Lid scrubs (which may have been used prior to, but not after, screening) and lubricating drops for dry eye (unrestricted use) were permitted.The best-corrected visual acuity requirement was + 1.0 logarithm of the minimum angle resolvable (logMAR) or better by Early Treatment Diabetic Retinopathy Study (ETDRS) criteria in each eye (equivalent to 20/200 or better Snellen visual acuity in each eye). Before starting the masked study medication, the patients needed, as appropriate, a negative pregnancy test and/or willingness to use highly effective contraception during the study.Treatment-naïve patients were excluded, as were those who were participating in any investigational study within 30 days prior to screening and those considered vulnerable (such as minors or adults under legal protection) or unable to express their consent (e.g., hospitalized persons in coma), persons deprived of liberty (prisoners from jails), or persons subject to psychiatric care. Ophthalmic exclusion criteria were as follows: clinically significant ocular disease; pseudoexfoliation or pigment dispersion glaucoma; a history of angle-closure glaucoma or eyes with complete or partial angle closure, and occludable anterior chamber angle (Shaffer grade < 2); previous laser peripheral iridotomy and/or an IOP ≥ 36.0 mmHg (unmedicated) in either eye. Medication-based exclusion criteria were: current (immediately prior to screening visit) treatment with BIM/TIM; use of more than two ocular hypotensive medications within 30 days of screening; and known hypersensitivity or contraindication to any component of the study medications or fluorescein. Any use of any topical steroid medication on the face or in, or around, the eyes was not permitted during the study, and use of steroid at screening was an exclusion criterion. Patients with prior insufficient IOP response/treatment failure (i.e., IOP did not reach the target range) with BIM/TIM ophthalmic solution were excluded. Glaucoma intraocular surgery (including laser treatments) as well as refractive surgery or ocular trauma in the six months prior to screening, and any other ocular surgery within three months prior to screening were also exclusion criteria.Further exclusion criteria were a mean central corneal thickness > 620 µm at screening; any abnormality preventing reliable Goldmann applanation tonometry in either eye; recent or current evidence of ocular infection or inflammation, clinically significant blepharitis, conjunctivitis, herpes simplex, and/or keratitis. Patients were excluded if laboratory tests identified clinically significant abnormalities or previously unknown systemic disease deemed likely to interfere with the study. The use of any systemic medication, including corticosteroid use, with a possible effect on IOP was also an exclusion criterion. | PMC10806046 |
Endpoints | SECONDARY | The primary objective of this study was to establish non-inferiority (a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3) for NET/LAT relative to BIM/TIM, and the primary efficacy outcome was a comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h at Week 2, Week 6, and Month 3. Diurnal values were a mean of measurements taken during the day. Outcome comparisons of the study drugs were expressed as mean values and assessment of each time point was undertaken for the following secondary efficacy endpoints: diurnal IOP; change from diurnally adjusted baseline IOP at each study time point; change from baseline in mean diurnal IOP; percent change from diurnally adjusted baseline IOP; percentage change from baseline in mean diurnal IOP; and the percentage of patients achieving a pre-specified mean, mean change, and percentage mean change in diurnal IOP levels. | PMC10806046 | |
Procedures | hyperemia, petechiae, conjunctival blood vessels | ADVERSE EVENTS, HYPEREMIA, CORNEA, PETECHIAE, LENS, SUBCONJUNCTIVAL HEMORRHAGE, CONJUNCTIVA | Once enrolled, participants were randomly assigned 1:1 to either NET/LAT or comparator BIM/TIM, both administered as one drop, once daily (QD) in both eyes in the evening between 20:00 and 22:00 h. Treatment continued with either NET/LAT or BIM/TIM for approximately 180 days (the safety endpoint). IOP measurements were taken at 08:00, 10:00, and 16:00 h at baseline and at Week 2 (Day 15), Week 6 (Day 43), and Month 3 (Day 90) using Goldmann applanation tonometry. One eye was termed the 'study' eye and the other the 'fellow eye'. The study eye was the eye with the higher IOP at 08:00 h on Visit 3; if both eyes had the same IOP at this visit, then the right eye was determined the study eye. Only the IOP values measured in the study eye were evaluated for efficacy. In each patient, both eyes received the study medication.At each study visit, assessments were conducted for some or all of the following: systemic safety (heart rate, blood pressure and clinical laboratory evaluations, including hematology and clinical chemistry), pregnancy testing (for women of childbearing potential), ETDRS corrected visual acuity, objective findings of biomicroscopic evaluations (i.e., anterior segment evaluations including evaluation of cornea, conjunctiva, lids and lens), cup-to-disc ratio measurements, dilated ophthalmoscopic examination, quality of life assessments (NEI VFQ-25 and SF-36), and ocular symptoms and adverse events (AEs). Visual field testing was performed at screening, Month 3, and Month 6. For participants who discontinued treatment, every possible effort was made to conduct a final visit that included all study visit examinations at Month 6. Biomicroscopic grading of conjunctival hyperemia was performed on a standardized, 4-point scale: 0 = none (normal; appears white with a small number of conjunctival blood vessels easily observed); 1 = mild (prominent pinkish-red colour of both the bulbar and palpebral conjunctiva); 2 = moderate (bright, scarlet red colour of the bulbar and palpebral conjunctiva); 3 = severe (“beefy red” with petechiae; dark red bulbar and palpebral conjunctiva with evidence of subconjunctival hemorrhage) [ | PMC10806046 |
Statistical methods | Two efficacy analysis sets were defined for statistical purposes, the intention-to-treat (ITT) population, which was used for all endpoints, and a per protocol (PP) set, which included participants without major protocol violations that were likely to seriously influence the primary outcome of the study as judged by a masked evaluation prior to the unmasking of the study treatment. Clinical non-inferiority for the experimental drug could be applied if the upper limit of the 95% confidence intervals (CI) around the difference was ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at the majority of time points (at least five of nine) through Month 3. Each time point within each visit was modelled separately. Assuming no difference between NET/LAT and BIM/TIM, a two-tailed alpha of 0.05 (two-sided 95% CI) at each of the nine time points, a common SD of 3.5 mmHg, and a correlation between time points of 0.6 or less, 200 (ITT) participants per arm were necessary to have 85% power to show clinical non-inferiority (as defined above) for the primary endpoint. A randomization code for allocating the treatments was prepared by an independent biostatistician (Statistics & Data Corporation, Tempe, AZ and Waltham, MA, USA) who was not involved in the day-to-day conduct of the study. Study medication was provided in identical packaging to preserve masking.To evaluate the primary outcome, a linear model was employed with IOP at the given visit and time point as the response, baseline IOP as a covariate, and treatment as a main effect factor at each time point at each visit. Markov Chain Monte Carlo (MCMC) multiple imputation techniques were used to impute missing data.All patients who received at least one dose of treatment were included in the safety analysis population, and assessments took place until study completion or discontinuation. | PMC10806046 | ||
Results | PMC10806046 | |||
Primary efficacy endpoint | Ocular hypotensive | At the upper limit of the 95% CI difference, IOP ≤ 1.5 mmHg was achieved at all nine time points and ≤ 1.0 mmHg at the majority (six out of nine) of time points from Week 2 through Month 3 (Fig. Ocular hypotensive efficacy assessed by mean IOP at Week 2, Week 6 and Month 3. * | PMC10806046 | |
Secondary efficacy endpoints | INTRAOCULAR PRESSURE, PGA | The analysis for the primary efficacy endpoint was repeated on the PP population; the threshold for clinical non-inferiority was met at eight out of nine time points. Non-inferiority could not be confirmed overall for this population, because the upper bound 95% CI was 1.55 at the Week 6 08:00 time point. The mean IOP change at each of the pre-specified time points demonstrated clinical non-inferiority of NET/LAT relative to BIM/TIM using observed values (Fig. Actual mean IOP change at the pre-specified timepoints. *p < 0.005. Analysis performed in ITT set. FDC, fixed-dose combination; IOP, intraocular pressure; ITT, intention-to-treat; SD, standard deviationPercentage of patients reaching pre-specified categorical treatment targets at Month 3: mean diurnal IOP (mmHg). Analysis performed in ITT set. Baseline diurnal mean IOP: NET/LAT, 25.05 mmHg (SD ± 3.405); BIM/TIM, 24.81 mmHg (SD ± 3.256). N, number of patients randomized; n, number of patients with data included at this time point; FDC, fixed-dose combination; IOP, intraocular pressure; ITT, intention-to-treatPercentage of patients reaching pre-specified categorical treatment targets at Month 3: percentage reduction from baseline in mean diurnal IOP. Analysis performed in ITT set. N, number of patients randomized; n, number of patients with data included at this time point. FDC, fixed-dose combination; IOP, intraocular pressure; ITT, intention-to-treatThe range of mean diurnal IOPs during the study period was 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups, respectively; no statistically significant differences were observed in the ITT analysis population. Mean change from diurnally adjusted baseline IOP at each study time point and at each study visit were calculated and no statistically significant differences were observed for the majority of endpoints. Mean diurnal IOP in the study eye at baseline was similar in both treatment groups: 25.1 mmHg for NET/LAT and 24.8 mmHg for BIM/TIM. Similar mean changes from diurnal baseline were observed at Month 3 for NET/LAT (– 9.4 mmHg) and BIM/TIM (–9.7 mmHg). No significant differences were observed in mean percent change in diurnal IOP from baseline for NET/LAT (–36.7%) and BIM/TIM (–38.6%) at Month 3 (Mean percent change from diurnally adjusted baseline IOP was similar for NET/LAT (–35.0% to –38.3%) compared to BIM/TIM (–34.8% to –40.2%) from Week 2 to Month 6; the majority of time points demonstrated no statistically significant difference between treatment groups. The efficacy profile for both treatment groups with or without prior PGA therapy is shown in Supplementary Fig. | PMC10806046 | |
Discussion | hyperemia, glaucoma, OAG, conjunctival hyperemia, TEAE, TM dysfunction | CORNEA VERTICILLATA, DISEASE PROGRESSION, HYPEREMIA, PGA, GLAUCOMA, EVENTS | This 6-month prospective, double–masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study compared, for the first time, the efficacy and safety of NET/LAT and BIM/TIM in patients with OAG and OHT. For the primary efficacy analysis, NET/LAT FDC demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) from Week 2 through Month 3, the primary efficacy endpoint of the study.The percentages of participants achieving a pre-specified mean, mean change, and percent mean change in diurnal IOP levels were similar in the two treatment groups throughout the study period. There were only two time points at which a statistically significant difference in mean IOP was observed: 08:00 at Week 6 and Month 3 in favour of BIM/TIM. A similar trend with regard to differences at specific time points has been observed in a previous work comparing once-daily netarsudil with twice-daily timolol [In clinical practice, the differences of < 1.0 mmHg (0.9 mmHg and 0.7 mmHg observed at 08:00 at Week 6 and Month 3) are unlikely to be clinically meaningful.Treatment groups were broadly similar in baseline characteristics, although a between-group disparity was observed in prior use of PGA therapy. Despite more participants recording prior PGA use in the NET/LAT arm, and despite high intra-cohort variability in length of this PGA use, prior PGA exposure was not associated with meaningful differences in efficacy or treatment discontinuation.Overall, no serious treatment-related AEs were observed, and AEs were mostly mild or moderate in severity in both treatment groups. The safety profile was consistent with previous MERCURY analyses [Although incidences of conjunctival hyperemia were significantly higher in the NET/LAT arm, the mean conjunctival hyperemia severity score was below 1 (mild) at all time points in both treatment arms and the majority of patients experiencing conjunctival hyperemia continued the study medication. Conjunctival hyperemia events reported in the NET/LAT arm (33.0%) were considerably lower than those reported in the earlier MERCURY-1 (53.4%) and MERCURY-2 (54.5%) studies conducted in the USA [Conjunctival hyperemia in NET/LAT users can be explained by the vasodilatory effects of both components of the FDC, the ROCK inhibitor and the PGA. Latanoprost has previously been associated with an increased incidence of conjunctival hyperemia compared with timolol [Real-world experience with NET/LAT can provide context to the conjunctival hyperemia observations in the MERCURY trials. A recent study found that incidence of conjunctival hyperemia in routine practice was lower (32.9%) than in the randomized controlled clinical trials (53.4% to 63.0%) [Cornea verticillata was only reported in the NET/LAT arm. This TEAE has been reported in the previous MERCURY Phase 3 studies where incidences were asymptomatic and had no impact on patient visual acuity [The observation of a reduced central corneal thickness in the NET/LAT arm was consistent with previous findings that suggest an additive effect of netarsudil and latanoprost, with the change (mean –6.4 µm in the MERCURY-2 Despite the prospective, randomized, multicenter design of this study, it has limitations. The strict inclusion and exclusion criteria may have resulted in a study population that is not fully representative of real-world patients. As ever, controlled trial data should be complemented by clinic-based observational research. Stringent trial processes were challenging to follow for some investigators, resulting in a relatively high proportion of patients affected by protocol deviations. To account for the possibility that these deviations may have impacted on findings, a PP population was analyzed, and the findings were consistent with those of the ITT population; however, the PP group was not statistically powered to determine significance and so conclusions reached using this population must remain speculative. Because disease progression is common in treated patients, a longer-term study that could provide insight into the effects of NET/LAT on progression of glaucoma would be valuable and welcome.In conclusion, the MERCURY studies show, overall, that NET/LAT offers a compelling, alternative FDC treatment option for OAG and OHT. The current MERCURY-3 study presents the first European NET/LAT study clinical data, derived from a large-scale, head-to-head comparison with BIM/TIM. By combining the ROCK inhibitor netarsudil (which increases conventional outflow by targeting TM dysfunction) with latanoprost (which increases unconventional outflow), this study demonstrates that NET/LAT FDC effectively lowers IOP to a similar degree to that of BIM/TIM. | PMC10806046 |
Acknowledgements | Valéria | POLAND, EYE, RETINA | The authors, Aerie Pharmaceuticals Ireland Ltd and Santen SA wish to acknowledge the contribution of the MERCURY-3 Study Group: Austria: Ewald Lindner (Department of Ophthalmology, Medical University Graz, Graz, Austria), Ana Prinz (Hanusch Hospital, Vienna, Austria); Czech Republic: Jitka Svačinová (University Hospital Brno, Brno, Czech Republic); France: Dominique Bremond-Gignac (University Hospital Necker Enfants Malades, APHP, Paris, France; INSERM Unit UMRS1138, Paris Sorbonne Cité University, Paris, France), Philippe Denis (Hôpital de la Croix-Rousse, Lyon, France), Muriel Poli (Clinique de la Sauvegarde, Rhône, France), Bertrand Vabres; Germany: Alexandra Anton, Katrin Lorenz (Johannes Gutenberg-University, Mainz, Germany), Andreas Bayer, Ulrich Thelen (Universitäts-Augenklinik, Münster, Germany); Hungary: György Bátor (Markusovszky University Teaching Hospital, Szombathely, Hungary), Ilona Elek (Bugat Pal Hospital, Gyongyos, Heves, Hungary), Gábor Holló, Péter Kóthy (Semmelweis University, Budapest, Hungary), Valéria Nagy (University of Debrecen, Debrecen, Hungary), András Seres (Budapest Retina Associates, Budapest, Hungary), Edit Tóth-Molnár, Balázs Varsányi (Ganglion Medical Center, Pécs, Hungary); Italy: Francesco Bandello (Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy), Michele Figus (University of Pisa, Pisa, Italy), Paolo Frezzotti, Stefano Gandolfi, Giorgio Marchini (Eye Clinic, Borgo Roma Hospital, AOUI, Italy; University of Verona, Italy), Teresa Rolle (AOU Città della Salute e della Scienza, Torino, Italy), Luca Rossetti (ASST Santi Paolo e Carlo, University of Milan, Milan, Italy), Gemma Caterina Maria Rossi (Ophthamic Clinic of the University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy), Giovanni Staurenghi, Daniele Tognetto (Eye Clinic- Maggiore Hospital University of Trieste, Trieste, Italy), Carlo Enrico Traverso (Clinica Oculistica, Di.N.O.G.M.I., Ospedale Policlinico San Martino IRCCS—Genova, Italy); Latvia: Kristine Baumane (Riga East University Hospital, Riga, Latvia), Signe Ozolina (Signes Ozolinas Doctor Practice in Ophthalmology, Jelgava, Latvia), Alina Suhorukova; Poland: Marek Rekas ( Military Institute of Medicine, Warsaw, Poland), Zofia Nawrocka (née Michalewska; Ophthalmic Clinic Jasne Blonia, Lodz, Poland), Ewa Mrukwa-Kominek (Medical University of Silesia, Katowice, Poland), Kornel Gibiński (University Clinical Center of the Medical University of Silesia, Katowice, Poland); Spain: Juan Ibañez Alperte (Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain), Javier Antonio (Montero Moreno, Hospital Universitario Rio Hortega, Valladolid, Spain), Javier Benitez-del-Castillo (Hospital Universitario de Jerez, Jerez [Cádiz], Spain), María Isabel Canut Jordana, Rafael Giménez Gómez (Hospital Universitario Reina Sofía de Córdoba, Córdoba, Spain), Amadeu Carceller Guillamet (Hospital QuironSalud Barcelona, Barcelona, Spain), Aitor Lanzagorta-Aresti (Fisabio Oftalmologia Medica, Valencia, Spain), Vicente Polo Llorens (Hospital Universitario Miguel Servet, Zaragoza, Spain), Alfonso Antón López (Institut Catala de Retina, Barcelona, Spain), José Antonio Saavedra Pazos (Centro de Ojos de La Coruña, A Coruña, Spain), Beatriz Ponte-Zuñiga (Hospital Universitario Virgen Macarena, Sevilla, Spain), Nuria Mendieta Rasos (Hospital de l'Esperança, Parc de Salut Mar, Barcelona, Spain); UK: Mohammed Abu-Bakra (Queen Mary Hospital, King's College Hospital NHS Foundation Trust, Sidcup, United Kingdom), Georgas Athanasios (Northwest Anglia NHS Foundation Trust, Huntingdon, United Kingdom), Graham Auger (Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom), Rupert R A Bourne (Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom), Jonathan Clarke, M Francesca Cordeiro, (Western Eye Hospital, London, United Kingdom), James F Kirwan (Portsmouth Hospitals NHS Trust, Cosham, (United Kingdom), Gerassimos Lascaratos (King’s College Hospital, London, United Kingdom), Dan Nguyen (Mid-Cheshire Hospitals NHS Foundation Trust, Crewe, United Kingdom), Manjula Kumarasamy, Nicholas Wride (Sunderland Eye Infirmary City Hospitals Sunderland NHS Foundation Trust, Sunderland, United Kingdom). | PMC10806046 |
Author contributions | All authors contributed to the study conception and design. Material preparation and data collection were performed by all authors. All authors recruited and saw patients involved in this study. Data analysis was performed by Santen SA and Aerie Pharmaceuticals Ireland Ltd; all authors interpreted the study data. The first draft of the manuscript was written by Ingeborg Stalmans and Gábor Holló, with support from Colin Griffin, and all authors commented on pre-final versions of the manuscript. All authors read and approved the final manuscript. | PMC10806046 | ||
Funding | This study was funded by Aerie Pharmaceuticals Ireland Ltd. The sponsor funded, designed, and conducted the study, including data collection, management, and interpretation. Additional data management and interpretation was performed by Santen SA, with the support of Jérôme Wojcik (Data2time Sàrl, funded by Santen SA). Medical writing and editorial assistance in the development of this manuscript was provided by Dr Colin Griffin (Griffin Scientific Ltd, UK), funded by Santen SA. | PMC10806046 | ||
Declarations | PMC10806046 | |||
Ethical approval | Independent Ethics Committee (IEC) or Institutional Review Board (IRB). The clinical study protocol, protocol amendments, materials used to recruit subjects, informed consent forms (ICFs) and materials to document consent, and any other appropriate study-related documents were reviewed and approved by IECs and Competent Ethics Committees (CECs) before initiations of the study at each study center. | PMC10806046 | ||
Ethical conduct of the study | ICH | This study was conducted in accordance with the accepted version of the Declaration of Helsinki, United States Food and Drug Administration (FDA) Law, the European Union (EU) Clinical Trials Directive 2001/20/EC, in compliance with International Council for Harmonization (ICH) good clinical practice (GCP) E6 R2 guidelines, and according to the appropriate regulatory requirements in the countries where the study was conducted. | PMC10806046 | |
Informed consent | Informed consent was obtained from all individual participants included in the study. | PMC10806046 | ||
Conflict of interest | JIB | IS reports financial support from Aerie Pharmaceuticals Ireland Ltd during the conduct of this study; and grants and personal fees from Théa and Santen, personal fees from Eye-D Pharma, Allergan-Abbvie, Horus and Alcon, and is a co-founder and shareholder of, and consultant for, MONA, outside the submitted work.KSL reports grants and lecture fees from Santen during the conduct of the study.FO reports grants and personal fees from Santen and Abbvie outside the submitted work.MF reports personal fees and non-financial support from Santen outside the submitted work.JIB reports personal fees from Glaukos, Zeiss and Santen, and personal fees and non-financial support from Esteve, outside the submitted work.AH reports personal fees from Aerie Pharmaceuticals Ireland Ltd during the conduct of this study, and personal fees from Théa and Santen outside the submitted work.GL has nothing to disclose.CS reports personal fees from Abbvie, Horus, Glaukos, Théa, Alcon, Santen, Nicox and Johnson & Johnson outside the submitted work.BV reports grants from Aerie Pharmaceuticals Ireland Ltd during the conduct of this study and grants from Santen outside the submitted work.TZ has nothing to disclose.GH reports personal fees from Santen outside the submitted work. | PMC10806046 | |
References | PMC10806046 | |||
Introduction | The American Society of Anesthesiologists published recommendations on the timing of elective surgery for patients who have recently recovered from COVID-19. | PMC10051067 | ||
Methods | infection, death | REGRESSION, INFECTION, THROMBOEMBOLIC EVENT, CARDIAC EVENTS | This cohort study was a target trial emulation with pseudorandomization to control (without recent infection) vs 2 mutually exclusive exposures (most recent infection in preoperative days 1-30 or 31-60). Eligible patients underwent major surgery from January 1 to September 30, 2021 (Alpha and Delta strain prevalence). All participants were encouraged to receive vaccination, and policy was to test preoperatively using reverse transcription–polymerase chain reaction. No oral outpatient therapies were in use. The Veterans Affairs Boston institutional review board approved this study and approved a waiver of informed consent, as the risk to participants was considered minimal. The Time zero for pseudorandomization was preoperative day 60. A propensity score model and stabilized inverse probability of treatment weighting balanced characteristics across exposure groups. Propensity score covariates were factors known at time zero that would be associated with exposure and were considered balanced if standardized mean differences were less than 0.2. We did not assess infection severity.The end point was death, cardiac events, central nervous system outcomes, respiratory outcomes, surgical infection, or thromboembolic events within 30 days after surgery. Weighted logistic regression estimated the odds ratio (OR) of any outcome as a function of exposure group, perioperative factors (because they were not known at time zero), and any propensity score covariates unbalanced after weighting. The eMethods in | PMC10051067 |
Results | A total of 29 093 patients (mean [SD] age, 66.1 [11.4] years; 90.0% men; 67.5% White patients) underwent surgery at 123 hospitals ( | PMC10051067 | ||
Baseline Characteristics of Surgical Patients Stratified by Prior COVID-19 Infection | Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); NA, not applicable; SMD, standardized mean difference.SI conversion factor: To convert albumin to grams per liter, multiply by 10.0.The “prior” in the column headings is relative to the date of surgery.Factors known at time zero that would be associated with exposure and were considered balanced if SMDs were less than 0.2.COVID-19 vaccine status is on day 60 prior to surgery.Includes Montana, Wyoming, Louisiana, Texas, Missouri, Colorado, Arkansas, Oklahoma, and Utah. | PMC10051067 | ||
Weighted Logistic Regression for Outcome of Any Adverse Postoperative Outcome | thromboembolic | INFECTIOUS DISEASES, EMERGENCY | Any adverse postoperative outcome consists of 30-day mortality, cardiac outcomes, central nervous system outcomes, respiratory outcomes, infectious diseases outcomes, or thromboembolic outcomes.Emergency surgery, anesthesia, operative duration, and surgical specialty were included as postrandomization confounders; surgical specialty was omitted. | PMC10051067 |
Discussion | HAND INFECTION, COVID-19 INFECTION | These findings suggest that recent COVID-19 infection was not associated with risk of adverse postoperative outcomes, regardless of timing within the previous 60 days. A recent study found surgery within 8 weeks after a positive COVID-19 test result was associated with higher 90-day mortality vs matched controls.Study strengths include a national surgical registry and reliable assessment of vaccination and infection. The target trial emulation was chosen to reduce certain biases. | PMC10051067 | |
References |
eMethods.
Click here for additional data file.
Data Sharing Statement
Click here for additional data file. | PMC10051067 | ||
Abstract | PMC10698808 | |||
Introduction | Optimizing HIV prevention may require structured approaches for providing client‐centred choices as well as community‐based entry points and delivery. We evaluated the effect of a dynamic choice model for HIV prevention, delivered by community health workers (CHWs) with clinician support, on the use of biomedical prevention among persons at risk of HIV in rural East Africa. | PMC10698808 | ||
Methods | We conducted a cluster randomized trial among persons (≥15 years) with current or anticipated HIV risk in 16 villages in Uganda and Kenya (SEARCH; NCT04810650). The intervention was a client‐centred HIV prevention model, including (1) structured client choice of product (pre‐exposure prophylaxis [PrEP] or post‐exposure prophylaxis [PEP]), service location (clinic or out‐of‐clinic) and HIV testing modality (self‐test or rapid test), with the ability to switch over time; (2) a structured assessment of patient barriers and development of a personalized support plan; and (3) phone access to a clinician 24/7. The intervention was delivered by CHWs and supported by clinicians who oversaw PrEP and PEP initiation and monitoring. Participants in control villages were referred to local health facilities for HIV prevention services, delivered by Ministry of Health staff. The primary outcome was biomedical prevention coverage: a proportion of 48‐week follow‐up with self‐reported PrEP or PEP use. | PMC10698808 | ||
Results | MAY | From May to July 2021, we enrolled 429 people (212 intervention; 217 control): 57% women and 35% aged 15–24 years. Among intervention participants, 58% chose PrEP and 58% chose PEP at least once over follow‐up; self‐testing increased from 52% (baseline) to 71% (week 48); ≥98% chose out‐of‐facility service delivery. Among 413 (96%) participants with the primary outcome ascertained, average biomedical prevention coverage was 28.0% in the intervention versus 0.5% in the control: a difference of 27.5% (95% CI: 23.0–31.9%, | PMC10698808 | |
Conclusions | A client‐centred dynamic choice HIV prevention intervention, including the option to switch between products and CHW‐based delivery in the community, increased biomedical prevention coverage by 27.5%. However, substantial person‐time at risk of HIV remained uncovered.Clinical Trial Number: NCT04810650 | PMC10698808 | ||
INTRODUCTION | Pre‐exposure prophylaxis (PrEP) and post‐exposure prophylaxis (PEP) are highly effective for HIV prevention [Delivery models that provide structured client‐centred choices, including the option to switch between biomedical prevention options (PrEP or PEP) over time, may help overcome these barriers. Several studies of hypothetical choices have been conducted to understand HIV prevention options that people at risk of HIV might prefer [Community‐based screening and prevention delivery offers an opportunity to provide client‐centred choices to persons who face barriers to accessing care at a health facility. However, community‐based delivery must leverage existing infrastructure to be scalable and sustainable. community health workers (CHWs) in Kenya and Uganda currently provide a range of primary healthcare services, including health promotion, management of common childhood illnesses, and follow‐up of expectant mothers and children aged ⩽5 years [We conducted a cluster randomized trial to test the hypothesis that a multi‐component intervention, offering structured client choices for HIV prevention product (PrEP or PEP), service location and testing, and delivered by CHWs with the support of clinicians would increase biomedical prevention coverage compared to referral for HIV prevention services at local health facilities. | PMC10698808 | ||
METHODS | PMC10698808 | |||
Setting and participants | MAY | Between May 2021 and August 2022, we conducted a cluster randomized study in 16 villages located in rural settings with high HIV prevalence in Southwestern Uganda (Ndeija) and Western Kenya (Homa Bay and Migori). We chose a cluster randomized trial design because the intervention was delivered in the village by CHWs, precluding individual randomization. Village inclusion criteria were location in a non‐adjacent geopolitical unit (i.e. a community with 9000–11,000 persons), served by a health facility providing antiretroviral therapy (ART), PrEP and PEP services, and with a community leader committed to study participation. Communities with ongoing HIV prevention interventions beyond country guidelines, in urban settings, and without a health centre providing ART, PrEP and PEP were excluded.Residents of the 16 villages were eligible for participation if they were aged ≥15 years, HIV negative by country‐standard HIV testing algorithm and reporting current or anticipated HIV risk. HIV risk was assessed using in‐country Ministry of Health (MoH) screening instrument for PrEP initiation and two general questions regarding self‐assessed risk of HIV acquisition currently or in the next 3 months. | PMC10698808 | |
Study design and procedures | LBB, malaria | MALARIA | Prior to randomization, study villages were pair‐matched within community on village size, number of CHWs and proximity to a trading centre or highway. Randomization was conducted at a meeting of community leaders, where representatives from each matched pair selected and opened sealed envelopes to reveal the trial arm. Community leaders, CHWs, study staff and participants were not blinded to the randomization arm, but the study statistician (LBB) was blinded until trial completion.In both intervention and control villages, an existing CHW who could speak English and conduct data collection using a phone app was selected for trial participation. In both arms, the selected CHW received training on routine HIV prevention, including key messaging about HIV testing, PrEP and PEP. For each CHW, 20 households under their care and with at least one person aged 15–39 years were randomly selected for study participation.In all villages, CHWs conducted mobilization about study activities, including announcements at religious gatherings and community meetings. During enrolment, CHWs introduced study staff to the household head who provided verbal consent for household participation and general information about their household: number of members, their relationship to the household head and their age. Members of consenting households who were aged ≥15 years then provided individual written informed consent and were screened for eligibility (HIV negative by country‐standard testing algorithm, and with current or anticipated HIV risk).In villages randomized to the control arm, participants reporting risk for HIV were referred to local health facilities for routine HIV prevention services. These services included confirmatory screening by an MoH health worker using standard tools, routine provision of PrEP or PEP if eligible and provision of HIV self‐test kits if requested and available. In villages randomized to the intervention, CHWs delivered the dynamic choice HIV prevention (DCP) model with clinician support, as detailed below. CHWs in both arms continued their existing MoH duties, such as the distribution of malaria bed nets and activities related to maternal‐child health. Table Baseline characteristics of study participants, by arm and overallAmong participants reporting a primary partner.Among participants reporting their primary partner is with HIV. | PMC10698808 |
Study intervention | AIDS | Building on our experience offering PrEP and PEP in rural Kenya and Uganda [CONSORT diagram.Prior to the study launch and every 6 months, both CHWs and clinicians received training on client‐centred care, including a framework for structured assessment of barriers and personalization of actions in response. Additionally, both CHWs and clinicians were trained on the DCP intervention and delivery, including structured choices by clients on HIV prevention services. CHWs were also trained on HIV testing, provided with job aids on HIV testing, and had monthly support supervision visits conducted by study laboratory personnel. Finally, external quality assurance and proficiency for HIV testing were performed with MoH panels, achieving 100% accuracy at both baseline and 6 months into the trial.Intervention visits occurred at baseline and at weeks 4, 12, 24, 36 and 48 of follow‐up. Prior to study visits, additional mobilization was conducted by CHWs. At each visit, CHWs offered participants structured choices for HIV prevention services (Figure The DCP intervention was delivered by existing CHWs, leveraging their local knowledge and established relationships in the villages they serve. CHW delivery was overseen by clinicians, who supported rapid HIV testing and risk assessment, oversaw PrEP and PEP initiation, prescribed medications, facilitated switches between PrEP and PEP, responded to phone queries and facilitated refresher training for CHWs. | PMC10698808 | |
Study measures | In both arms, baseline demographics, HIV risk factors, and prior PrEP and PEP use were assessed at enrolment. For endpoint ascertainment at 24 and 48 weeks of follow‐up in both arms, CHWs and research staff conducted community‐based rapid HIV testing and HIV RNA testing (Gene Xpert, Cepheid) and administered a structured survey on PrEP and PEP use (i.e. pill ingestion) and HIV risk over the past 6 months. Specifically, for each month, participants were asked to retrospectively, self‐report general HIV risk, any risk due to sex with a partner with HIV or unknown status, any use of PrEP pills and any use of PEP. | PMC10698808 | ||
Outcomes | SECONDARY | The primary study outcome was biomedical prevention coverage, defined as the number of months during which a participant reported taking any PrEP or PEP pills divided by the number of months assessed. Biomedical prevention coverage during periods of self‐reported HIV risk was a pre‐specified secondary endpoint, compared between arms. We additionally report on HIV seroconversions, defined as any reactive HIV self‐test or HIV rapid test (per national testing algorithm) with confirmatory HIV RNA testing. | PMC10698808 | |
Statistical analysis | SECONDARY | Accounting for the pair‐matched cluster randomized design [Primary and secondary outcomes were compared between arms with targeted minimum loss‐based estimation, accounting for the dependence of outcomes within clusters and adaptively adjusting for baseline covariates to maximize precision, while preserving Type‐I error control [Within the intervention arm, we also summarized visit coverage and dynamic choice of the intervention components, including prevention product (PrEP, PEP, condoms only or none), location choice (out‐of‐clinic or clinic) and HIV testing (rapid or self‐testing) at baseline, week 24 and week 48. | PMC10698808 | |
Ethical approval | The Makerere University School of Medicine Research and Ethics Committee, the Uganda National Council for Science and Technology, the Kenya Scientific and Ethics Review Unit, the National Commission for Science, Technology and Innovation, and the University of California San Francisco Committee on Human Research reviewed and approved the study protocol. All participants provided written informed consent prior to study participation. | PMC10698808 | ||
RESULTS | MAY | From May to August 2021, we enrolled 429 people (212 intervention; 217 control) in 16 villages in Southwestern Uganda and Western Kenya (Figure | PMC10698808 | |
Intervention implementation | At scheduled visits, at least 80% of 212 intervention participants were seen by CHWs and offered the DCP package. Choice varied over time (Figure Choice of intervention components over time. (a) Choice of prevention product. (b) Choice of HIV testing modality. (c) Choice of visit location.Restricted to participants offered DCP at baseline, week 24 and week 48. (Plots including all intervention participants are given in Figure | PMC10698808 | ||
Primary and secondary outcomes | The primary endpoint of biomedical prevention coverage, the proportion of follow‐up with self‐reported PrEP or PEP use, was ascertained in 413/429 (96%) participants: 202/212 (95%) of intervention participants and 211/217 (97%) of control participants. Average biomedical prevention coverage was 28.0% (95% CI: 23.5–32.4%) among intervention participants and 0.5% (95% CI: 0–1.0%) among control participants corresponding to an absolute increase of 27.5% (95% CI: 23.0–31.9%; The intervention significantly improved prevention coverage across key subgroups (Figure Effects on self‐reported use of biomedical prevention, overall and by subgroups.Effect estimates in terms of the difference in average biomedical prevention coverage between intervention and control arms.Self‐reported HIV risk and use of biomedical prevention varied by arm and by time, as shown in Figure Heatmaps of self‐reported HIV risk and use of biomedical prevention, by arm over time.
Effects on self‐reported use of biomedical prevention during periods of self‐reported HIV risk, overall and by subgroups.
Over the 48‐week follow‐up, two participants seroconverted. Both were in the intervention arm, and both were 24‐year‐old females. One had a partner of unknown status, and the other was in a polygamous marriage. Both chose PEP pill‐in‐pocket, but did not start PEP after unprotected sexual encounters. | PMC10698808 | ||
DISCUSSION | fatigue, HIV self‐testing | In this cluster randomized trial, CHWs, supported by clinicians, delivered a community‐based, client‐centred dynamic choice model for prevention (DCP) to persons at risk of HIV acquisition. The DCP intervention provided clients with structured choices between biomedical prevention products (PrEP or PEP), service locations (clinic or out‐of‐clinic) and HIV testing options (self‐test or rapid test) as well as the ability to switch over time. A key innovation was bringing HIV prevention services into the community by leveraging existing CHWs. The intervention increased biomedical HIV prevention coverage by 27.5% overall and 35.7% during periods of self‐reported risk. Prevention coverage was <1% in the control, highlighting that offering PrEP or PEP does not equate to uptake.Client preferences for HIV prevention have previously been explored in discrete choice experiments, providing insights on HIV self‐testing was more popular than rapid testing in this study, and participant selection of self‐testing increased over time, highlighting the importance of this option in the community setting. Self‐testing has been widely accepted to be a safe alternative to rapid testing [Our study increases the evidence of the potential for CHWs to extend HIV prevention services into the community. Previous literature has demonstrated the value of CHWs in improving other aspects of HIV care, specifically behavioural change counselling, health education, ART adherence counselling and defaulter tracing [Prior studies have shown the effectiveness of CHWs in intervention delivery is impacted by various factors, including task‐specific training and capacity building [Delivery of the DCP intervention by existing CHWs is potentially scalable, but additional research is necessary to understand effectiveness and implementation in routine practice. Since CHWs did not previously conduct HIV testing or PrEP/PEP delivery, clinician oversight was needed to ensure participant safety and intervention fidelity. In routine programmes, supervision will be required to ensure the safe delivery of HIV prevention services by CHWs but may not be as intensive as implemented in this pilot. We aim to address these and other open questions in a follow‐up, population‐level, community‐randomized trial (NCT05768763).While the community‐based DCP intervention substantially increased biomedical prevention coverage, a significant proportion of time at risk remained uncovered. This could be explained, in part, by several barriers to taking PrEP within the household setting, including stigma and fatigue associated with daily pill taking. In addition, some participants were not comfortable disclosing their HIV risk status to CHWs and tensions within the household setting prohibited some from choosing oral PrEP or PEP. We provided location choice to address these barriers. In addition, the emergence of new biomedical products such as long‐acting injectable Cabotegravir could help to counter many of these barriers and further increase biomedical prevention coverage.Our study has several limitations. First, we piloted a multi‐component intervention, which makes it challenging to parse out individual component effects. However, our results show both risk and choice change over time, suggesting the limitations of a one‐size‐fits‐all intervention and the importance of client‐centred service models. Open questions remain about the impact of each component of the intervention, as well as about its scale‐up. In particular, while choice was a core feature of our DCP model, our intervention also included other services (e.g. structured assessment of barriers). These other services, together with client‐centred choice, likely contributed to improvements in biomedical coverage, overall and during periods of risk. Ongoing qualitative and implementation science studies will help elucidate the specific impact of choice, and our follow‐up trial aims to assess scale‐up, implementation and impact of DCP at the population level. Second, our assessment of biomedical prevention coverage was by self‐report of any use of PrEP or PEP. As a result, covered time may have been over‐estimated; however, given the magnitude of the estimated effects, it is unlikely that bias due to self‐report or the survey limitations accounts for all, or even the majority, of the increases in biomedical coverage, seen overall and across key subgroups. Furthermore, 76% of participants reporting recent PrEP or PEP use had detectable tenofovir levels in their hair ( | PMC10698808 | |
CONCLUSIONS | In this cluster randomized trial, a CHW‐led, community‐based HIV prevention intervention that provided client‐centred dynamic choices in biomedical product, HIV testing and service location increased biomedical prevention coverage, both overall and during periods of risk, compared to community‐based referral for HIV prevention services at local health facilities. However, substantial time at risk of HIV remained uncovered, highlighting the need for additional interventions. | PMC10698808 | ||
COMPETING INTERESTS | DVH reports non‐financial support from ViiV Healthcare. All other authors declare no competing interests. | PMC10698808 | ||
AUTHORS’ CONTRIBUTIONS | LBB | ERK, JA, HS, EB, MN, GA, JK, CA, HNA, NS, AO, JL, EWM, GC, MRK, DVH, MLP and LBB conceptualized and designed the study. All authors participated in study operations or data collection. EWM, JP, JS and LBB performed the data analyses with input from ERK, JA, HS, EB, MN, GA, JK, CA, HNA, NS, AO, JL, GC, MCB, MRK, DVH and MLP. ERK, DVH, MLP and LBB drafted the manuscript with input from the other authors. All authors reviewed and approved the final manuscript. | PMC10698808 | |
FUNDING | INFECTIOUS DISEASES, LUNG, ALLERGY, BLOOD, HEART | Research reported in this manuscript was supported by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Mental Health (NIMH) and co‐funded under award number U01AI150510. | PMC10698808 | |
DISCLAIMER | The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. | PMC10698808 | ||
Supporting information |
Click here for additional data file. | PMC10698808 | ||
ACKNOWLEDGEMENTS | The SEARCH study gratefully acknowledges the Kenya Ministry of Health, Uganda Ministry of Health, our research teams and administrative teams in San Francisco, Kenya and Uganda, collaborators and advisory boards, and especially all communities and participants involved. We also thank Catherine Koss, Monica Ghandi, Hana Rivera Garza, Anindita Chattopadhyay and Karen Kuncze of the Hair Analytical Laboratory at the University of California, San Francisco for their work on analysing tenofovir concentrations in hair samples provided by participants. | PMC10698808 | ||
DATA AVAILABILITY STATEMENT | A complete de‐identified patient dataset sufficient to reproduce the study findings will be made available approximately 1 year after completion of the ongoing trial (NCT04810650), following approval of a concept sheet summarizing the analyses to be performed. Further inquiries can be directed to the SEARCH Scientific Committee at | PMC10698808 | ||
REFERENCES | PMC10698808 | |||
Background | Dyspnea, CAD, angina | CORONARY ARTERY DISEASE, CAD | Dyspnea is a frequent symptom in patients with stable coronary artery disease (CAD) and is recognized as a possible angina equivalent. | PMC10449717 |
Objectives | CAD, dyspnea, angina pectoris | CAD | This study was to assess the impact of percutaneous coronary intervention (PCI) on dyspnea, quality of life, and angina pectoris in patients with stable CAD. | PMC10449717 |
Methods | CAD, Seattle Angina, dyspnea, angina pectoris | REGRESSION, CAD | The prospective, multi-center PLA-pCi-EBO-pilot trial included 144 patients with symptomatic stable CAD and successful PCI. The prespecified endpoints angina pectoris (Seattle Angina Questionnaire–SAQ) and dyspnea (NYHA scale) were assessed 6 months after PCI. Predictors for symptomatic improvement were assessed with uni- and multivariable logistic regression analyses. | PMC10449717 |
Results | dyspnea | Patients with concomitant dyspnea had worse SAQ physical limitation scores at baseline (49.5 ± 21.0 vs 58.9 ± 22.0, | PMC10449717 | |
Conclusion | CAD, dyspnea | CAD | PCI effectively reduced dyspnea, which is a frequent and demanding symptom in patients with CAD. The German Clinical Trials Register registration number is DRKS0001752 ( | PMC10449717 |
Graphical abstract | PMC10449717 | |||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00392-022-02107-x. | PMC10449717 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10449717 | ||
Introduction | Dyspnea, CAD, dyspnea, angina pectoris | DISEASE, CORONARY ARTERY DISEASE, CAD, LEFT MAIN CORONARY ARTERY DISEASE | Coronary artery disease (CAD) is an often debilitating disease and the symptomatic burden, including angina pectoris and dyspnea, can be accompanied by starkly impaired quality of life [The EXCEL trial found that dyspnea was present in 73% of patients with left main coronary artery disease [Dyspnea often is multi-factorial in nature and causes are manifold, including numerous organ systems [Large gaps of knowledge remain regarding the extent and relevance of dyspnea as a symptom of stable CAD on total symptom burden and quality of life and its susceptibility for PCI as a common treatment strategy. We therefore analyzed the burden of dyspnea in a well-characterized patient cohort presenting with stable CAD who received PCI with special regard to changes in dyspnea 6 months after PCI. We first aimed at identifying the relevance of concomitant dyspnea on the symptomatic prognosis after PCI. Patients were classified as “concomitant dyspnea” when dyspnea did occur together with angina pectoris. We then tried to evaluate the effect of PCI on total dyspnea for which we used the NYHA classification. A NYHA class of ≥ 2 was considered symptomatic dyspnea. | PMC10449717 |
Methods | PMC10449717 | |||
Study population | CCS angina, dyspnea, impaired vision, chest pain, anemia, CAD, valvular disease, angina pectoris | PULMONARY DISEASE, ANEMIA, CONCOMITANT DISEASE, CAD | This study was designed as a prospective randomized and controlled trial to investigate the effect of visual demonstration of successful PCI on quality of life and angina pectoris in patients with symptomatic stable CAD. The details of the study design have been published previously [Between April 2019 and September 2020, consecutive symptomatic patients undergoing PCI at five academic centers and large community hospitals in Germany were screened for eligibility. Main inclusion criteria were as follows: age ≥ 18 years, symptomatic CAD, CCS angina score ≥ 2, angina pectoris frequency ≥ 2/week, and successful implantation of ≥ 1 coronary artery stent, i.e., complete revascularization of the culprit lesion. Main exclusion criteria were as follows: concomitant disease that could cause dyspnea or chest pain (i.e., left ventricular ejection fraction < 35%; anemia; severe pulmonary disease; severe valvular disease); conditions that prevented sufficient understanding of the visual demonstration and explanation of the angiographic results (language barrier; impaired vision or hearing; dementia).The study complied with the Declaration of Helsinki. Each study site obtained approval by the local ethics committee (Reference number 19-1261-101) and all patients provided written informed consent for participation. The German Clinical Trials Register registration number is DRKS00017524. | PMC10449717 |
Symptomatic evaluation of angina pectoris and dyspnea | Dyspnea, angina pectoris | Patient-reported angina pectoris symptom burden was evaluated using the SAQ [Dyspnea was determined according to the NYHA classification pre PCI, and 6 months after PCI [Patients with missing data in one of the endpoints were excluded from the respective analysis. As there was no difference between the intervention and control group regarding angina pectoris [ | PMC10449717 | |
Statistical analysis | CAD, dyspnea | REGRESSION, CAD | For the present analyses, patients of the randomized controlled trial were first divided into those with “concomitant dyspnea” and those without “concomitant dyspnea.” Categorical data are presented as absolute (As it can be difficult to clearly distinguish dyspnea of cardiac origin from dyspnea due to other comorbidities in patients with stable CAD, we then analyzed the study cohort according to the NYHA class of dyspnea. NYHA class I was considered “no dyspnea” and classes II to IV were labelled “symptomatic dyspnea.” To assess the effect of PCI on overall dyspnea, we presented the number of initially symptomatic patients (NYHA class II–IV at baseline) who changed in NYHA class from baseline to the 6-month follow-up. Then, predictors for an improvement of ≥ 1 NYHA class were assessed by univariable logistic regression analyses. Thus, we excluded patients without initial dyspnea because these patients could not further improve after PCI.As choosing variables for a multivariable logistic regression model is ambiguous, we calculated two different models. Model 1 includes all variables with Statistical significance was defined as | PMC10449717 |
Results | PMC10449717 | |||
Differences in angina symptoms and quality of life in patients with and without concomitant dyspnea | ±, Angina pectoris, dyspnea | Angina pectoris symptom burden was evaluated using the SAQ subscales. At baseline, patients with concomitant dyspnea had a worse physical limitation score (49.5 ± 21.0 vs 58.9 ± 22.0, Differences in angina symptoms and quality of life in patients presenting with and without dyspnea. PCI led to a marked relief in symptomatic burden. Patients who presented with concomitant dyspnea had significant less improvement. Presented are mean (± 95% confidence interval) values for SAQ subscales at baseline and 6 months after PCI for patients presenting with (red) and without (gray) dyspnea. p-values are two-sided Student’s | PMC10449717 | |
Discussion | PMC10449717 | |||
Worse symptomatic outcome after PCI in patients presenting with dyspnea | dyspnea, angina, Dyspnea, CAD, angina pectoris, COPD, obstructive pulmonary disease | COPD, PULMONARY DISEASE, OBSTRUCTIVE PULMONARY DISEASE, CAD | Dyspnea and angina pectoris correlate in patients with stable CAD. It is, however, not clear what the presence of dyspnea in addition to angina pectoris means for the symptomatic response after PCI. Patients who presented with concomitant dyspnea had a slightly higher body mass index (29 vs 27 kg/mChronic obstructive pulmonary disease (COPD) and CAD share smoking as a major risk factor and often occur in the same patients which may confound our findings as we did not specifically evaluate patients without known COPD for pulmonary disease. Jönsson et al. evaluated patients who were referred for further testing because of chest discomfort or dyspnea [Before PCI, patients with dyspnea experienced more physical limitation due to their CAD. Interestingly, the measure for quality of life did not differ between groups. There was no difference for angina stability or angina frequency. These findings suggest that there is no strong difference between patients who present with stable CAD and concomitant dyspnea or without dyspnea at baseline. However, it is striking that patients with initial dyspnea responded worse to PCI than patients without. Six months after PCI, patients with and without initial dyspnea have improved physical limitation, angina stability, angina frequency, and quality of life. However, patients with initial concomitant dyspnea have a higher angina frequency, more physical limitation, and lower quality of life. | PMC10449717 |
PCI effectively reduces dyspnea | Myocardial ischemia, CAD, dyspnea | MYOCARDIAL ISCHEMIA, CAD | Myocardial ischemia often manifests as dyspnea [Despite being a frequent and relevant symptom of CAD [The exclusion criteria that we employed limit the generalizability of our results to a specific patient population, i.e., patients with symptomatic CAD and without significant comorbidities. However, this group is numerically large and highly relevant in daily clinical practice. Our results provide valuable insights for these patients. | PMC10449717 |
Predictors for improvement of dyspnea | dyspnea, angina, microvascular dysfunction, atypical angina, diabetes | DIABETIC POLYNEUROPATHY, DISEASE, ATYPICAL ANGINA PECTORIS, PULMONARY DISEASE, DIABETES | We found that the presence of atypical angina pectoris symptoms increases, and that diabetes reduces the probability of less dyspnea 6 months after PCI. Data about predictors for changes of dyspnea after PCI are sparse. Qintar et al. investigated the effect of PCI in patients with chronic total occlusion on dyspnea [The finding that “atypical angina” is a predictor for better reduction of dyspnea is unexpected as clinical prejudice would conclude that these patients tend to be especially difficult to effectively treat. The prevalence of diabetes was similar in patients with typical or atypical angina pectoris; thus, diabetic polyneuropathy does not seem to be relevant in this context. We did not routinely assess microvascular dysfunction which could help differentiate the physiological differences between patients with typical and atypical angina. Furthermore, there was no difference in the percentage of patients with “atypical angina” between patients with and without concomitant dyspnea (14.4% vs 9.6%, There is a lack of studies aiming to identify clinical predictors for symptomatic improvement following PCI. However, this knowledge could substantially improve clinical practice by aiding in the selection of the best treatment strategy for each individual patient. In our sample, we found a negative association of diabetes with improved NYHA class after PCI, whereas atypical angina pectoris and a lower angina frequency showed a positive correlation. Equally important is the finding that many factors, which might be intuitively associated with symptomatic outcome, showed no significant relationship in our sample. These include for example age, body mass index, presence of multivessel disease, previous PCI, stent diameter, number of implanted stents, or pulmonary disease. Our findings thus add information to this field; however, further research is definitely warranted. | PMC10449717 |
Limitations | cardiac dyspnea, dyspnea | SECONDARY | This current analysis is a secondary analysis of a randomized controlled trial, which was not powered for the present analysis strategy; generalization is therefore limited. As there was no sham control for PCI, it is not possible to attribute all improvements in symptomatic outcome after PCI exclusively to the PCI. The clinical rating of concomitant cardiac dyspnea is complex in clinical practice and some patients might have been misclassified, but it was investigated carefully by experienced cardiologists in the most appropriate manner. We used the NYHA dyspnea scale to assess dyspnea which is a generally accepted and sufficiently good tool. However, general limitations regarding clinical scales in contrast to objectifiable physiological (e.g., echocardiography) or functional testing (e.g., 6-min walking test, treadmill exercise test) regarding inaccuracy and intra- as well as interpersonal variation do also apply to the NYHA dyspnea scale. | PMC10449717 |
Conclusions | dyspnea, angina, Dyspnea, CAD, angina pectoris | CAD | Dyspnea is often underappreciated in the context of stable CAD and data on the occurrence of dyspnea following PCI is scarce or totally lacking. We examined a very well-characterized patient cohort and found that dyspnea is a frequent and relevant symptom in patients with stable CAD. The majority of patients in our study initially presented with angina pectoris and dyspnea. We demonstrate that angina burden and quality of life of patients with concomitant dyspnea responded worse to PCI than in patients without. However, and most importantly, both angina pectoris and dyspnea can be treated effectively with PCI and symptom burden for both was significantly lower 6 months after PCI. These are important observations that should be taken into consideration when evaluating and treating patients with stable CAD and concomitant dyspnea. | PMC10449717 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 72 kb) | PMC10449717 | ||
Abbreviations | Angina, angina | Coronary artery diseaseCanadian cardiovascular society angina grading scaleChronic obstructive pulmonary diseasePercutaneous coronary interventionSeattle Angina Questionnaire | PMC10449717 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Doktor Robert Pfleger-Stiftung Bamberg, Germany. | PMC10449717 | ||
Data availability | The data underlying this article will be shared on reasonable request to the corresponding author. | PMC10449717 | ||
Declarations | PMC10449717 | |||
Conflict of interest | The authors have no conflict of interests to declare. | PMC10449717 | ||
References | PMC10449717 | |||
Introduction | colon cancer | COLON CANCER | Three nomograms for predicting the outcomes of early- and late-onset colon cancer (COCA) among patients not stratified by age were constructed using data in the Epidemiology and End Results (SEER) database (1975–2019). The accuracy of the nomogram was then assessed. | PMC10620318 |
Method | Clinical data of 6107 patients with COCA were obtained from the SEER database. The patients were randomly divided into training and validation cohorts in a ratio of 7:3. Univariate and multivariate COX analyses of factors that could independently impact the prognosis of COCA were performed, and the corresponding nomograms for early-onset and late-onset COCA were constructed. Calibration curves, ROC curves, and C-index were used to determine the predictive accuracy. The discriminatory ability of the nomograms to assess their clinical utility, which was compared with the TNM staging system of the 8th edition of AJCC, was verified using survival analysis. | PMC10620318 | ||
Result | colon cancer, Tumor | BRAIN METASTASIS, COLON CANCER, TUMOR | Tumor primary site, ethnicity, and serum carcinoembryonic antigen (CEA) level significantly impacted the prognosis of colon cancer. Race, brain metastasis, and CEA were independent factors for predicting COCA prognosis. C-index, ROC, and calibration curves demonstrated that the three nomograms were accurate and superior to the traditional TNM staging system. Among the three nomograms, the early-onset COCA nomogram had the highest predictive accuracy, followed by that of colon cancer not stratified by age. | PMC10620318 |
Conclusion | late-onset colon cancer | COLON CANCER | Three nomograms for patients not stratified by age, early-onset colon cancer, and late-onset colon cancer were constructed. The accuracies of the nomograms were good and were all superior to the conventional TNM staging system. The early- and late-onset COCA nomograms are useful for clinical management and individualized treatment of COCA patients at different ages. | PMC10620318 |
Keywords | PMC10620318 | |||
Introduction | obesity, tumor-node-metastasis, AJCC, CRC, cancer, malignant tumors, Early-onset, early-onset, Colorectal cancer, UICC, Cancer | OBESITY, CANCER, MALIGNANT TUMORS, COLORECTAL CANCER, PATHOGENESIS, CANCER | Colorectal cancer (CRC) is the fourth most fatal cancer globally, killing nearly 9 million people annually. In addition to an aging population and dietary habits, several factors, such as obesity, lack of physical activity, and smoking, increase the risk of CRC (Dekker et al. Early-onset COCA refers to COCA diagnosed at < 50 years of age. The incidence of early-onset COCA is increasing worldwide, and its pathogenesis is still unclear. Early-onset COCA has different clinical, pathological, and molecular features. Compared with late-onset COCA, which refers to COCA diagnosed at age > 50 years, early-onset COCA mostly occurs in the descending colon, is mostly diagnosed in the late stage, and is poorly differentiated. The risk factors of early-onset COCA are not the same as those of late-onset COCA (Zaborowski et al. The tumor-node-metastasis (TNM) staging system, proposed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), is the standard method for staging malignant tumors and is widely used to assess cancer prognosis (Hari et al. Nomograms have been applied in clinical studies related to prognosis and have gained wide acceptance (Song et al. | PMC10620318 |
Materials and methods | PMC10620318 | |||
Patients selection | This was a retrospective cohort study in which data were obtained from the surveillance, epidemiology, and final results database (Flow chart for selecting COCA patients included in the present study | PMC10620318 | ||
Clinical variables and outcomes | tumor, death | BRAIN METASTASIS, TUMOR, LUNG METASTASIS, BONE METASTASIS, LIVER METASTASIS | The clinical variables analyzed in this study include age, race, gender, tumor primary site, tumor size, TNM stage based on the 8th edition of AJCC guidelines, serum CEA level, nerve invasion, lymph node metastasis, liver metastasis, lung metastasis, bone metastasis, and brain metastasis. The primary outcome analyzed was the overall survival (OS), which refers to the time from diagnosis to death from any cause or the end of the follow-up period. | PMC10620318 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.