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2.1. Study Characteristics | drusen, ARDS | DRUSEN, ARDS | This is a double-blind, randomized controlled trial of parallel design, with 1:1 allocation. Inclusion criteria were AMD with persistent drusen, categorized according to ARDS categories 2 and 3, without GA or prior ocular surgery, and consent to participate. ARDS category 2 was defined as <63 µmin diameter or non-extensive intermediate drusen of 63–125 µm diameter, and ARDS category 3 as extensive intermediate large drusen ≥125 µm diameter [Patients who met the initial inclusion criteria were enrolled in the study. The participants were randomly assigned to the study or control group by computer randomization. The physician who registered the participants to the groups using serial numbers did not take further part in the study. | PMC10055796 |
2.2. Treatment Regime | BLIND | The participants were instructed to take one untagged pill daily for 12 months. Containers of pills were allocated by patient serial numbers, with the pharmacy blind to the content of the pills. Pills for the study group contained 400 mg of HCQ (plaquenil). Placebo pills for the control group contained calcium. Patients who did not comply with the treatment given, did not attend the follow-up examination or withdrew their consent were excluded from the analysis. | PMC10055796 | |
2.3. Follow-Up Time Line | toxicity, HCQ-induced retinal maculopathy, drusen | DRUSEN, ADVERSE EFFECT, ADVERSE EFFECTS, INTRAOCULAR PRESSURE | All the participants underwent a complete ophthalmic examination, including visual acuity (recorded as decimal score), intraocular pressure, anterior and posterior segment inspection and optical coherence tomography (OCT) for measuring central macular thickness. Since one of the first signs of macular toxicity of HCQ is a reduction of red light sensitivity, during the follow-ups, all participants underwent visual field testing conducted as macular visual fields of red/white. Macular fields were evaluated using the macular perimeter software in the Macular OCT HS-100 (Canon Inc, Tokyo, Japan). The number and volume of existing drusen were assessed by red-free fundus imaging. Participants were examined at 3, 6, 9, 12 and 24 months following the initiation of treatment. The follow-up was extended to 12 months following completion of treatment (up to two years after the beginning of the study), to ascertain the lack of HCQ-induced retinal maculopathy or another influence or adverse effect. All participants underwent extensive rheumatologic assessment and follow-ups, and any systemic adverse effects were also assessed. | PMC10055796 |
2.4. Evaluation of Drusen and Macular Appearance | drusen | DRUSEN | We used red-free images to evaluate the growth of new drusen or increased size of known drusen: Each participant underwent an initial red-free fundus snap-shot ( | PMC10055796 |
2.5. Clinical and Demographic Characteristics | drusen | DRUSEN | Demographic characteristics, visual acuity, retinal width, and initial and final follow-up drusen data were collected and analyzed. | PMC10055796 |
2.6. Statistical Analysis | For continuous variables, arithmetic means and standard deviations were calculated. For categorical variables, relative frequencies were calculated. The Mann–Whitney non-parametric test was applied to examine differences between the study groups for quantitative parameters; all the hypotheses were one-tail. Pearson chi-square and Fisher’s exact test were applied to examine correlations between the study and control groups of the categorical parameters. The sample size was determined by statistician consultation. A | PMC10055796 | ||
2.7. Sample Size | The sample size was calculated using a significance level of 5% and power of 80%, with an acceptable mean difference of 0.05 logMAR (half-line) [ | PMC10055796 | ||
3. Results | PMC10055796 | |||
3.1. Clinical and Demographic Characteristics | Of the 110 patients who enrolled in the study, 55 were randomized to the study group and 55 to the control group. Fourteen patients did not complete the trial due to loss of follow-up. Forty-six patients in the study group and fifty in the control group completed the study ( | PMC10055796 | ||
3.2. Visual Acuity | Visual acuity deterioration | Visual acuity deterioration at two-year follow-up compared to baseline was less in the study than in the control group (−0.03 ± 0.07 vs. −0.07 ± 0.07, | PMC10055796 | |
3.3. Central Macular Thickness | The difference between the study and control groups, in increased central macular thickness at two-year follow-up compared to baseline, was not statistically significant: 8.9 ± 21.6 and 13.2 ± 9.5, respectively, | PMC10055796 | ||
3.4. Drusen Number and Size | drusen, ARDS | DRUSEN, REGRESSION, ARDS | One year following the end of the treatment, the mean number of drusen per eye was lower in the study than the control group for ARDS type 2 (ARDS2) (8.1 vs. 12.3, The study and control groups showed similar proportions of eyes with regression of drusen size, as measured with macular OCT at the final examination, one year following the end of treatment. For ARDS2, these proportions for the respective groups were 3/46 (7%) vs. 4/50 (8%) eyes, | PMC10055796 |
3.5. Safety and Adverse Effects | scotoma | CHOROIDAL NEOVASCULARIZATION, ADVERSE EFFECTS, CORNEA | None of the participants showed HCQ toxicity manifested by cornea verticillata or changes in the red-to-white macular field of vision. Perimetric follow-up was performed by using the MP1 OCT and showed that none of the participants developed absolute or relative scotoma, and MP1 general-reduction-of-light threshold was not detected in any of the participants of the study group nor in the control group during the two-year follow-up.None of the participants in the study group developed GA or active choroidal neovascularization. None of the participants in the control group developed active AMD; however, one participant developed GA in both eyes. The trial ended, as planned, two years after commencement. None of the trial participants had any systemic adverse effects. | PMC10055796 |
4. Discussion | rheumatoid arthritis, AMD, dry, dry AMD, retinal thinning, systemic lupus erythematosus, long-term damage, drusen, detachments of basal linear or laminar deposits, retinal nerve insult, RPE, non-exudative, Drusen, retinal toxicity, HIT | RHEUMATOID ARTHRITIS, ADVERSE EFFECTS, DISEASE, SYSTEMIC LUPUS ERYTHEMATOSUS, RETINA, DRUSEN, ADVERSE EFFECTS, DRUSEN | The HIT study is the first study to address the effect of HCQ on the clinical and imaging characteristics of AMD. The main finding of this double-blind randomized controlled trial was less visual acuity deterioration at one-year follow-up among participants treated with HCQ than those treated with a placebo. Moreover, compared to the control group, the mean number of drusen per eye was lower for ARDS2 in the study group. For the study group, compared to the control group, the proportion of eyes with increased drusen growth was less, for both ARDS2 and ARDS3 drusen, and the total drusen growth was less. Drusen volume growth, as calculated by the area and height measured with macular OCT, was also more reduced in the study than the control group. None of the participants showed HCQ toxicity or adverse effects.Currently, no treatment can reverse AMD, due to the nature of retinal nerve insult. Thus, a preventive treatment could change the entire natural course of this disease. The HIT study examined the possibility that HCQ could be such an agent.Previous studies have examined means of preventing the development of AMD. Some studies focused on the correlation of retinal thinning or thickness with the development and progression of non-exudative (dry) AMD [Thus, if HCQ affects the development of drusen, it could stop the deterioration of the disease without long-term damage. The rationale of the current study emerged from the work of McGeer and Sibley, who showed that patients with rheumatoid arthritis who were treated with HCQ were relatively protected from the development of AMD [The retina is generally considered one of the most oxygen-consuming tissues in the human body, consuming even more oxygen per weight than the brain [Soft or large drusen may form, consequent to the formation of localized detachments of basal linear or laminar deposits; both these deposits reflect granular material collecting between the RPE and its basement membrane or outside the RPE's basement membrane [The demographic and pre-study clinical characteristics were similar for the study and control groups, reflecting good randomization. Comparing the final examination results (at two years from the beginning of the study, which was 12 months after treatment cessation), the mean number of new drusen formations was less in the study group, and fewer drusen grew in size. At the two-year follow-up, there was no difference in metamorphopsia between the groups. In both groups, the central macular was somewhat thicker at two-year follow-up, more so in the control group, though the difference between the groups was not statistically significant. At the final follow-up, the most significant difference between the groups was in visual acuity. Though visual acuity decreased in both groups, in the control group, this reduction was significantly greater than in the study group, yet only by 0.04 logMar.As drusen are considered to predispose to AMD, the main objective of this study was to show that HCQ treatment may reduce drusen production. Our study suggests that HCQ may have a protective effect against the development of inactive AMD (dry AMD), and also active AMD (wet AMD). We could not distinguish whether this effect is due to increased thickening of the retina outer band (RPE and Bruch’s membrane), as we suggested in our previous study [The precise mechanism underlying the anti-inflammatory and immunomodulatory effects of HCQ remains unknown, even though the drug is effective in treating several autoimmune and inflammatory illnesses, including systemic lupus erythematosus and rheumatoid arthritis. Due to its hydrophilic nature, HCQ can pass through cell membranes easily and accumulates in intracellular vesicles, including lysosomes, endosomes and autophagosomes. Raising the pH in these acidic vesicles precludes proper functioning of vesicular enzymes (such as proteases) [A main concern when treating patients with HCQ is retinal toxicity [Further studies are needed to explain the impact of HCQ on the retina and its protective effect against AMD development, whether due to thickening of the retinal outer band, an anti-inflammatory effect or something else. This study was composed of a single institute and comprised a relatively small number of participants. Treatment with HCQ and follow-up periods were relatively short. Adverse effects of a continuous therapy may first present only several years after initiation of treatment. | PMC10055796 |
Author Contributions | Conceptualization, J.P.; Methodology, J.P.; Validation, J.P. and Y.P.; Formal Analysis, J.P. and T.Y.; Investigation, J.P. and T.Y.; Data Curation, R.A. and D.P.; Writing–Original Draft Preparation, T.Y.; Writing–Review and Editing, R.A. and Y.P.; Visualization, D.P.; Supervision, J.P. All authors have read and agreed to the published version of the manuscript. | PMC10055796 | ||
Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Ziv Medical Center, Zefat, Israel (Zefat ZIV 061/11; 07.February.2013). | PMC10055796 | ||
Informed Consent Statement | Informed consent was obtained from all the participants. | PMC10055796 | ||
Data Availability Statement | This study was registered in the United States National Library of Medicine Clinical Trials Registry CLINICALTRAILS.GOV–Identifier number: NCT01541449. | PMC10055796 | ||
Conflicts of Interest | The authors declare no conflict of interest related to this work. | PMC10055796 | ||
References | Drusen, AMD, tumor necrosis | AGE-RELATED MACULAR DEGENERATION, TUMOR NECROSIS, RETINA, DRUSEN | The Beckman clinical classification of age-related macular degeneration (AMD) [Red-free fundus snap-shot. (Flow Diagram of the study’s participants. Of the 110 patients who enrolled in the study, 55 were randomized to the study group, and 55 to the control group. Fourteen patients did not complete the trial due to loss of follow-up. Forty-six patients in the study group and fifty in the control group completed the study.Suggested mechanisms of the anti-inflammatory and immunomodulatory effects of HCQ. 1. HCQ has a hydrophilic nature, can pass through cell membranes easily and accumulates in intracellular vesicles, including lysosomes, endosomes and autophagosomes. 2. Raising the pH in the acidic vesicles precludes proper functioning of vesicular enzymes. 3. HCQ prevents the presentation of peptides for major histocompatibility complex (MHC)-II, by interfering with the conversion of antigens to peptides in antigen-presenting cells. Hence, extracellular material may accumulate less under the retina. 4. HCQ prevents peptides from interacting with MHC-II in the loading compartment of acidic endosomes on MHC-II. 5. HCQ inhibits cytokine release by interfering with MHC-II-related autoantigen presentation to cluster of differentiation (CD) 4+ T-cells, via antigen-presenting cells. This prevents CD4+ T-cells from activating B-cells. HCQ causes autoreactive T-cells from undergoing apoptosis and obstructs B-cells from processing antigens. The result is impaired function and production of cytokines, including interleukin [IL]-1, IL-6, interferon-gamma, tumor necrosis factor and B-cell activating factor. 6. The binding of immune complexes to TLR7 and TLR9 results in the downstream stimulation of type-1 interferon transcription. Type-1 interferons trigger the generation of additional cytokines by activating T-cells, B-cells, natural killer cells, myeloid dendritic cells and monocytes. The binding of TLR7 and TLR9 to the immune complexes is directly inhibited by the accumulation of HCQ in endosomes that contain TLR7 and TLR9. HCQ can potentially hinder the processing of TLRs by raising the pH of the endosome. Thus, HCQ reduces the transcription of type-1 interferons by interfering with TLR7 and TLR9 signaling; this has immunomodulatory and anti-inflammatory effects.Demographic characteristics and baseline ocular characteristics of the study (hydroxychloroquine) and control (placebo) groups.OCT: optical coherence tomography; Sd: standard deviation.Drusen volume growth as calculated by area and height, measured using optical coherence tomography. | PMC10055796 |
Background | trichomoniasis, gonorrhea, chlamydia | STIS, SEXUALLY TRANSMITTED INFECTION, TRICHOMONIASIS, GONORRHEA | Prevalence of gonorrhea, chlamydia, and trichomoniasis is high among adolescents and young adults in rural South Africa, and higher among women and those residing in urban/periurban areas.Recent population-representative estimates of sexually transmitted infection (STI) prevalence in high HIV burden areas in southern Africa are limited. We estimated the prevalence and associated factors of 3 STIs among adolescents and young adults (AYA) in rural South Africa. | PMC10655853 |
Methods | trichomoniasis, gonorrhea, chlamydia | STIS, MAY, REGRESSION, TRICHOMONIASIS, GONORRHEA | Between March 2020 and May 2021, a population-representative sample of AYA aged 16 to 29 years were randomly selected from a Health and Demographic Surveillance Site in rural KwaZulu-Natal, South Africa, for a 2 × 2 factorial randomized controlled trial. Participants in 2 intervention arms were offered baseline testing for gonorrhea, chlamydia, and trichomoniasis using GeneXpert. Prevalence estimates were weighted for participation bias, and logistic regression models were used to assess factors associated with STIs. | PMC10655853 |
Results | gonorrhea, chlamydia | STIS, TRICHOMONIASIS, GONORRHEA | Of 2323 eligible AYA, 1743 (75%) enrolled in the trial. Among 863 eligible for STI testing, 814 (94%) provided specimens (median age of 21.8 years, 52% female, and 71% residing in rural areas). Population-weighted prevalence estimates were 5.0% (95% confidence interval [CI], 4.2%–5.8%) for gonorrhea, 17.9% (16.5%–19.3%) for chlamydia, 5.4% (4.6%–6.3%) for trichomoniasis, and 23.7% (22.2%–25.3%) for any STI. In multivariable models, female sex (adjusted odds ratio [aOR], 2.24; 95% CI, 1.48–3.09) and urban/periurban (vs. rural) residence (aOR, 1.48; 95% CI, 1.02–2.15) were associated with STIs; recent migration was associated with lower odds of STI (aOR, 0.37; 95% CI, 0.15–0.89). Among those with an STI, 53 (31.0%) were treated within 7 days; median time to treatment was 11 days (interquartile range, 6–77 days). | PMC10655853 |
Conclusions | syphilis, Curable, gonorrhea, chlamydia | SEXUALLY TRANSMITTED INFECTIONS, STIS, SYPHILIS, TRICHOMONIASIS, GONORRHEA | We identified a high prevalence of curable STIs among AYA in rural South Africa. Improved access to STI testing to enable etiologic diagnosis and rapid treatment is needed.Curable sexually transmitted infections (STIs) are common worldwide, with more than 1 million new cases of gonorrhea, chlamydia, trichomoniasis, or syphilis estimated to occur globally every day.Because of a lack of accessible and affordable diagnostic testing, STIs in low- and middle-income countriess are predominantly managed using a syndromic approach.In South Africa, which has among the highest HIV incidence and prevalence rates worldwide, | PMC10655853 |
MATERIALS AND METHODS | PMC10655853 | |||
Study Setting | deaths | This study was conducted within the HDSS in uMkhanyakude district in rural KwaZulu-Natal, South Africa. Since 2000, the Africa Health Research Institute (AHRI; formerly Africa Centre for Health and Population Studies) has been conducting annual household-based surveys to collect data on births, deaths, demographics, and migration patterns. The HDSS was expanded in 2017 to cover 845 km | PMC10655853 | |
Study Design | This study reports baseline data from a 2 × 2 factorial randomized controlled trial evaluating the acceptability, feasibility, and preliminary population-level impact of integrated sexual and reproductive health (SRH) services with or without peer support on the prevalence of transmissible HIV. | PMC10655853 | ||
Study Procedures | gonorrhea, chlamydia | TRICHOMONIASIS, GONORRHEA | After informed consent, participants randomized to either of the 2 SRH arms were offered home-based STI specimen collection. For female participants, research staff described the procedure to self-collect a vaginal swab. Menstruating females provided urine specimens. Male participants were instructed to collect a first-catch urine specimen. All participants were provided an AYFS clinic referral to receive their STI test results in 7 days. Participants were informed that if any test results return positive and they do not present to the clinic, research staff will attempt to contact them to ensure they receive treatment. Treatment of STI was provided according to South African national clinical guidelines (single-dose ceftriaxone and azithromycin for gonorrhea, single-dose azithromycin or 7-day course of doxycycline for chlamydia, single-dose metronidazole for trichomoniasis). | PMC10655853 |
Data collection | SEXUALLY TRANSMITTED INFECTION | Sexually transmitted infection specimens were transported to the AHRI central laboratory in Durban. Testing for | PMC10655853 | |
Statistical analysis | REGRESSION | We summarized participants' demographic data using medians and interquartile ranges (IQRs) for continuous variables and frequency counts and percentages for categorical variables. Frequency counts and percentages with 95% confidence intervals (CIs) were calculated for the prevalence estimate of each individual STI and prevalence of any STI. To account for participation bias, we calculated weighted prevalence estimates to account for the stratified sample design, calculated as the inverse probability of study participation in strata defined by age group and sex. We used logistic regression to estimate the odds ratios and 95% CIs for factors associated with the presence of any curable STI and factors associated with treatment in univariate and multivariable models. Age and sex were included a priori in the multivariable model; other factors with | PMC10655853 | |
Ethical considerations | The study protocol was approved by the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (BREC/00000473/2019), the University College of London Research Ethics Committee (5672/003), and the Mass General Brigham Institutional Review Board (2021P002574). Written informed consent was obtained from all participants 18 years or older; verbal assent with written informed consent from a parent or guardian was obtained for all participants aged 16 to 17 years. | PMC10655853 | ||
Patient and public involvement | The peer support and sexual health intervention was co-created with young people in uMkhanyakude district and delivered by peers. Young people and the AHRI community advisory board were involved from research inception through to analysis. Study findings were shared with the research participants and their communities, as well as health officials and program implementers. | PMC10655853 | ||
DISCUSSION | infection, chlamydia, HIV among adolescent girls, trichomoniasis, gonorrhea, decrease loss | STIS, INFECTION, TRICHOMONIASIS, SEQUELAE, GONORRHEA | We found a very high prevalence of curable STIs among adolescents and young adults in a predominantly rural area of KwaZulu-Natal, South Africa. This study confirms the acceptability of home-based STI specimen collection among adolescents and young adults, as more than 90% of study participants who were offered STI testing provided specimens. The prevalence of STI was significantly higher among female than male participants overall, even when adjusted for age and other demographic factors. The sex difference in prevalence was most pronounced for trichomoniasis and chlamydia; prevalence of gonorrhea was similar between male and female participants. Participants residing in urban/periurban areas were more likely to have an STI than those residing in rural areas. Despite multiple contact attempts by study staff, only 1 of 3 participants who tested positive for an STI was treated within 7 days. Difficulties in follow-up contact compounded by a low (6.8%) treatment refusal indicates a need for a robust tracking system and strategies to maximize treatment reach, and underscores the need for point-of-care STI tests to enable same-day treatment and decrease loss to follow-up.In this cohort, women had a higher STI prevalence than men overall, particularly trichomoniasis and chlamydia. These results mirror both national-level estimates of STI prevalence in South Africa and previous studies among adolescents and young adults in rural KwaZulu-Natal; in both cases, chlamydia prevalence was over twice as high among women than men.We found a substantially higher prevalence of chlamydia and gonorrhea in this cohort than in a previous study conducted in the same geographic area in 2016 to 2017.We additionally found that young men and women residing in urban or periurban areas were more likely to have an STI than those residing in rural areas, even after adjustment for other demographic factors, including age, employment status, and migration history. A recent study evaluating transmissible HIV among adolescent girls and young women exposed to the PEPFAR-supported DREAMS intervention, conducted at the same study site, similarly found that urban/periurban residence was associated with transmissible HIV.Despite the robust infrastructure of the randomized trial and the long-standing experience of AHRI conducting research that is strongly linked with public sector health clinics in this area, less than half of the participants with STIs were able to be treated within 7 days, and less than two-thirds within 4 weeks. Those living in urban areas were less likely to be treated within 7 days, possibly because of a higher rate of employment or difficulty tracking participants. Those in the highest socioeconomic tertile were more likely to be treated within 7 days, which may reflect either greater access to technology such as mobile phones for contact by study staff, or easier access to clinic for treatment. Diagnostic testing for STIs remains inaccessible in most resource-limited settings, because of high costs and a need for laboratory infrastructure; when STI testing is available in such settings, it is often restricted to centralized laboratories. For this study, STI specimens were transported from the rural study site to a centralized research laboratory in Durban (approximately 230 km away), resulting in an extended time from specimen collection to test result. Loss to follow-up increases with extensions in test turnaround time, and delays in treatment lead to the potential for ongoing transmission and increased risk for sequelae of untreated infection. A study assessing community-based STI testing for adolescents and young adults in Zimbabwe found that, even with an expected 90-minute time to result, only 67% of those with positive test results were treated.Our assessment of factors associated with STIs was limited by the scope of demographic data available and lack of contemporaneous data on symptoms and sexual risk behavior. The trial did not include study-specific questionnaires at the time of enrollment to measure the real-world effect of offering the combination of interventions. Demographics were thus linked from annual HDSS household surveys. These surveys include annually updated, individual- (e.g., education level, employment status) and household-level (e.g., socioeconomic status, rural vs. urban residence) data. Despite a lack of detail regarding sexual risk behavior, the HDSS data provide information on several important demographics that are standardized across prior studies and have previously been found to be associated with STIs and HIV in this area.In conclusion, we found a very high prevalence of curable STIs among adolescent and young adult men and women, which is higher than in a previous study 5 years ago, in a predominantly rural area with high HIV incidence in KwaZulu-Natal, South Africa. The prevalence of STI was higher among women than men and among those residing in urban/periurban areas than those residing in rural areas. Despite multiple attempts by study staff, fewer than two-thirds of participants with positive test results were able to be treated within 4 weeks. These results highlight the need for implementation of STI testing and treatment programs in settings with both STIs and HIV, as well as the need for point-of-care STI tests to allow immediate treatment for those who test positive and decrease loss to follow-up. | PMC10655853 |
Supplementary Material | PMC10655853 | |||
SUPPLEMENTARY MATERIAL | N.M. | ALLERGY, INFECTIOUS DISEASE | Acknowledgments: The authors thank all the participants who contributed data to this study, as well as the entire Africa Health Research Institute (AHRI) research team.Conflict of Interest and Sources of Funding: J.J. has received in-kind research support from Binx Health. All other authors declare no conflicts of interest.This work was supported by the National Institutes of Health through the National Institute of Mental Health (R01MH114560) and the National Institute of Allergy and Infectious Disease (T32AI007433, K24AI141036), the Wellcome Trust (201433/Z/16/Z), 3ie International Initiative for Impact Evaluation, the Bill and Melinda Gates Foundation (INV-033650), and the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery. M.S. is an National Institute for Health Research (NIHR) Professor (NIHR 301634). (N.M.) is an NIHR Research Professor (2017-08-ST2-008). G.H. is supported by a Sir Henry Dale fellowship from the Wellcome Trust and Royal Society (grant number 210479/Z/18/Z). N.C. is supported by a training fellowship from the NIHR (using the UK's Official Development Assistance Funding) and Wellcome (grant reference number 224309/Z/21/Z) under the NIHR-Wellcome Partnership for Global Health Research. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other funders.This research was funded in part by the Wellcome Trust (grant numbers 201433/Z/16/Z and 210479/Z/18/Z). For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.Trial registration: Data availability statement: Data are available upon request. Data can be can accessed and downloaded through the AHRI data repository: Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site ( | PMC10655853 |
REFERENCES | PMC10655853 | |||
Objective: | anaemia | ANAEMIA, SECONDARY | To assess the effect of daily egg consumption for six months on linear growth (primary outcome), weight-for-age, weight-for-length, mid-upper arm circumference-for-age, head circumference-for-age Z-scores, gross motor milestones development, anaemia and iron status (secondary outcomes) in a low socioeconomic community. | PMC10830362 |
Participants: | Infants aged 6 to 9 months living in the peri-urban Jouberton area, in the Matlosana Municipality, South Africa. | PMC10830362 | ||
Design: | A randomised controlled trial with a parallel design was implemented. Eligible infants were randomly allocated to the intervention ( | PMC10830362 | ||
Results: | anaemia, overweight | ANAEMIA, WASTING | Baseline prevalence of stunting, underweight, wasting, overweight and anaemia was 23·8 %, 9·8 %, 1·2 %, 13·8 % and 29·2 %, respectively, and did not differ between groups. Overall, 230 and 216 participants in the intervention and control groups completed the study, respectively. There was no intervention effect on length-for-age, weight-for-age, weight-for-length Z-scores, gross motor milestone development, anaemia and iron status. | PMC10830362 |
Conclusions: | wasting, motor milestones, anaemia | ANAEMIA | Daily egg intake did not affect linear growth, underweight, wasting, motor milestones development, anaemia and iron status. Other interventions are necessary to understand the effect of animal-source food intake on children’s growth and development. This trial was registered at | PMC10830362 |
Keywords | head circumference (HC)-for-age, animal-source foodsAgainst, stunting, anaemia | ANAEMIA, SECONDARY | Although the global prevalence of childhood stunting is decreasing gradually, it continues to remain high in Asia and sub-Saharan AfricaChicken eggs (hereafter ‘egg’) have been identified as easily accessible and relatively more affordable in comparison to other animal-source foodsAgainst this background, the primary aim of the present study was to investigate the efficacy of daily egg consumption on length-for-age Z-score (LAZ) and the prevalence of stunting of infants from a low socioeconomic community in South Africa. The secondary aim was to assess the effect of egg consumption on weight-for-age (WAZ), weight-for-length (WLZ), mid-upper arm circumference-for-age (MUACZ) and head circumference (HC)-for-age (HCZ) Z-scores, gross motor milestones development, anaemia and iron status of infants from a low socioeconomic community in South Africa. | PMC10830362 |
Methods | PMC10830362 | |||
Trial design and participants | WEST, RECRUITMENT | This study was a 6-month follow-up randomised controlled trial with parallel design conducted in the peri-urban Jouberton area, Klerksdorp, in the Matlosana Municipality in North West province, South Africa. Recruitment and enrolment occurred from 16th February 2021–7th July 2021, while exiting from the study occurred six months from the day of enrolment. The study site has high rate of unemployment, and the typical diet of the infants is maize meal porridge, rice, legumes, sweets and savoury snacks | PMC10830362 | |
Interventions | The randomised controlled trial consisted of two groups, the intervention group (Trained fieldworkers visited participants weekly to distribute the eggs and to remind the mothers to give one egg per day. Information on adherence to egg intake, morbidity symptoms using a diary, gross motor milestones development using the pictorial chart and a seven-day unquantified food frequency questionnaire, for all the infants, was collected during the weekly visits. All questionnaires had previously been used in a similar study | PMC10830362 | ||
Sample size calculation | stunting reduction | The sample size calculation was done by considering two primary outcomes representing stunting reduction in relation to the intervention. Based on previous studies | PMC10830362 | |
Outcomes | Outcome assessment of the trial occurred at three time points, baseline, midpoint (three months from baseline) and endpoint (six months from baseline). In general, all assessments took place at the central study site, except for weekly morbidity, adherence, food frequency questionnaire and follow-up gross motor milestones development assessments. Infants’ date of birth, birth weight and length, and gestational age were recorded from the clinic booklet; in the absence of gestational age in the booklet, maternal recall of gestational age was recorded. Information on household characteristics, including household food insecurity experience | PMC10830362 | ||
Anthropometric outcome procedures | Anthropometric data on the infants were collected at all three time points. Infants were undressed and weighed to the nearest 0·01 kg using two standardised digital infant scales (Seca 334 and 727). Recumbent length was measured to the nearest 0·1 cm using an infantometer (Seca 416). Mid-upper arm circumference and head circumference measurements were taken to the nearest 0·1 cm using Seca 201 and 212 measuring tapes, respectively. All measurements were taken in duplicate. If the values of the duplicate measurements differed by more than 0·01 kg for weight, 0·5 cm for length, or 0·2 cm for mid-upper arm circumference and head circumference, a third and/or a fourth measurement was taken, and the two closest values were recorded. In the case where a baby could not lie or sit still, the indirect method was used, where mothers were weighed with and without the infant. The mothers’ height and weight were taken at baseline to assess their BMI. The anthropometric measurements of the infants were converted to LAZ, WAZ, WLZ, MUACZ and HCZ using WHO child growth standard specific for age and sex | PMC10830362 | ||
Gross motor milestone development outcome procedures | Information on developmental milestones was collected at baseline and during the weekly home visits, using a 14-item (pull to sit, creep 1, sit 1, sit 2, all fours, creep 2, crawl, stand 1, walk 1, stand 2, walk 2, run, jump and stand on one foot) pictorial chart based on the WHO’s standards | PMC10830362 | ||
Anaemia and iron status outcome procedures | A trained professional nurse collected capillary blood samples by means of finger and/or heel prick at baseline and endpoint. Hb was measured on the day of blood collection using a portable Hb HemoCue Hb 201+ system (Angelholm, Sweden). In addition to these, blood samples were collected into lithium heparin Microvette® CB 300 (Sarstedt), centrifuged for 10 min at 2000 g and separated for plasma, aliquoted into 0·2 ml Eppendorf tubes, cooled to ∼6°C and transported on the same day on ice packs in a cooler for storage at –80°C at the Centre of Excellence for Nutrition’s laboratory until analysis. Plasma ferritin (PF) to assess body iron stores and plasma soluble transferrin receptor (sTfR) and inflammatory markers, C-reactive protein and | PMC10830362 | ||
Randomisation | There was a random assignment of eligible infants in a 1:1 ratio. A randomisation sequence of pseudo-random numbers, generated by the RANNOR function of the SAS software package version 9·4, generated the allocation codes. There was a dataset with a list of 500 tags (250 tags for each group) generated. This list of tags merged into a sequence of random numbers generated from an underlying normal distributed variable. The sorting of the generated random numbers was so that there was a random list of codes and tags obtained; this was used to randomly assign an equal number of 250 participants per group. | PMC10830362 | ||
Blinding | BLIND | Due to the nature of the study, the intervention was not blind to field staff, the nurse and mothers; however, there was blinding of all questionnaire and anthropometric assessments to the assessors and the statistician during the effect and sensitivity analysis of both the intervention and control group. | PMC10830362 | |
Statistical methods | Baseline characteristics were described using median and interquartile range or counts and percentages for continuous and categorical variables, respectively. A linear mixed model analysis with random intercept unstructured covariance of the repeated measures was applied. The same model based on the binomial distribution with logit link was applied for dichotomous outcomes. Hb values were corrected for altitude | PMC10830362 | ||
Sensitivity analysis | SENSITIVITY | Sensitivity analyses were done by excluding infants with low birthweight (birthweight < 2·5 kg), those with Hb, PF and sTfR out of the range of ± 3 | PMC10830362 | |
Results | Figure
Flow chart of study participants | PMC10830362 | ||
Baseline analysis | inflammation, disability | INFLAMMATION, IRON DEFICIENCY, IRON DEFICIENCY ANAEMIA | Table
Baseline characteristics of participants by intervention groupLAZ: length-for-age Z-score, WAZ: weight-for-age Z-score, WLZ: weight-for-length Z-score, MUACZ: Mid-upper arm circumference-for-age Z-score, HCZ: head circumference-for-age Z-score, IDA: iron deficiency anaemia, IDE: iron deficiency erythropoiesis.Corrected for altitude using a factor of –0.2(27).Corrected for inflammation using the BRINDA method (31, 32).Values presented as median and interquartile range and all such values, unless specified.Includes child, old age pension and disability grant.Both inside and outside the house. | PMC10830362 |
Ancillary analyses | SECONDARY | No statistically significant difference was observed for primary and secondary outcomes of interests when sensitivity analyses were done by excluding infants with low birthweight (Supplementary Table | PMC10830362 | |
Adverse events | death, allergy | ADVERSE EVENTS, ALLERGY | There was no difference between the incidence of adverse events among the intervention and control groups. Only eight (1·6 %) infants experienced severe adverse events, defined based on hospitalisation, six (2·4 %) infants in the intervention group and two (0·8 %) in the control group. There were no egg-related serious adverse events reported. Although three (0·6 %) infants died while in the study, the cause of death was not related to the study, and they all occurred in the control group. Nutrient adequacy, morbidity and allergy symptoms will be examined in detail in future analyses. | PMC10830362 |
Discussion | anaemia, wasting, stunting, allergies | ANAEMIA, SECONDARY, WASTING, ALLERGIES | This randomised controlled trial investigated the effects of daily consumption of an egg for a period of six months on growth, gross motor milestone development, anaemia and iron status of 6- to 9-month-old infants from a low socioeconomic community in South Africa. We found no significant intervention effect on linear growth (LAZ) and stunting prevalence – the primary outcomes of interest. Similarly, there was no effect found on our secondary outcomes of interest, namely WAZ, WLZ, MUACZ, HCZ, gross motor milestones development (standing and walking without support), anaemia or iron status. The findings of this study agree with a similar Malawian study, where it was found that the provision of an egg per day for a period of six months to infants had no overall intervention effect on linear growth and stunting prevalenceOverall, our estimated prevalence of stunting, underweight and wasting at study completion was similar to that reported in the 2016 South African Demographic and Health SurveyAn egg intervention study by lannotti There was no intervention effect on the infants’ ability to stand and walk without support. Our finding is similar to that of Prado Although there was no intervention effect on anaemia or iron status (PF and sTfR), there was an increase in the overall prevalence of anaemia, ID, IDA and IDE at the end of the six months of follow-up period, and the prevalence rates signify a moderate to high public health problemSecondly, the whole egg consists of the yolk and egg white or albumenSmuts This study has some limitations. Firstly, there was no direct observation of egg intake by infants in the intervention group but reported by the mother in an adherence diary. Thus, we cannot exclude the fact that there may have been sharing of the weekly ration of eggs with other household members, which could have attenuated our outcomes. Secondly, although the field workers received training to collect information on gross motor milestones development, the self-reported nature of the date on which a developmental milestone was achieved by the mothers may have impacted on the accuracy of the developmental outcome. Again, it could be speculated that assessing gross motor milestones development may require more than six-month intervention period, thus assessing other developmental outcomes, such as fine motor, language, social development could have provided different results. Lastly, it could be that the provision of one egg per day in addition to the normal dietary intake of the infants does not make a big enough difference to impact linear growth and development.This notwithstanding, this study has many strengths. The study was well-powered to detect small effects due to the large sample size and low rate of dropout. There were weekly household visits to stock up the intervention eggs, check for allergies and morbidity symptoms and to ensure adherence to taking the study eggs. To avoid intra-household sharing of the weekly ration of seven eggs for the infants in the intervention group, there was an additional five eggs provided to each household every week. In addition, this study provided the household of the control group with 5 kg maize meal every month during the six months of follow-up intervention period and 4 dozen eggs at the endpoint, which may have been an incentive for those in the control group to remain in the study. Lastly, although not completely blinded due to the study’s nature, there was full blinding of the field assessors and statistician to the treatment assignment and effect size analysis.In conclusion, daily egg intake for six months in 6- to 9-month-old infants did not have any overall intervention effect on linear growth (LAZ), stunting prevalence, gross motor milestones development, anaemia, or iron status. Our study showed that relying solely on the intervention of daily egg consumption may not be sufficient to address the growth, development and nutritional status of infants and young children in low socioeconomic communities. This suggests that additional approaches and interventions should be considered to complement or enhance the effects of egg consumption, such as incorporating other dietary sources, improving dietary diversity or implementing strategies to enhance nutrient absorption and bioavailability. | PMC10830362 |
Supporting information | PMC10830362 | |||
Ricci et al. supplementary material 1 | Ricci et al. supplementary material | PMC10830362 | ||
Ricci et al. supplementary material 2 | Ricci et al. supplementary material | PMC10830362 | ||
Ricci et al. supplementary material 3 | Ricci et al. supplementary material | PMC10830362 | ||
Acknowledgements | WEST, BENSON | The authors thank the Eggcel-growth study team and the mothers/caregivers who consented for their children to participate in the study. We thank the fieldworkers for their hard work during the data collection. We also thank the Walk a Mile in My Shoe, the North West Department of Health, the local clinics and the Matlosana Municipality for their immense support during the data collection. Lastly, we are grateful to Sr. Alida Anthony for organising all our logistics and supplies; Ronel Benson and Henriëtte Claasen for helping with the administrative work and finances; Mrs Cecile Cooke for the laboratory analysis; Mr. Thabang Phinda, Mrs. Mary Mary Sennelo, Mamokete Pule and Mrs. Elizabeth Wesi for assisting with the data collection | PMC10830362 | |
Financial support | This study was funded by the Douglas George Murray Trust. The funders had no influence on the study design, data collection, analysis, interpretation of the data, writing of the manuscript or the decision to submit the manuscript for publication. | PMC10830362 | ||
Conflict of interest | The authors declare that they have no known competing financial and non-financial interests with the potential to bias the work reported in this paper. | PMC10830362 | ||
Authorship | C.M.S., M.F., H.S.K., L.M., C.R. and H.R. designed the study. H.R. was the study coordinator and contributed by supervising field data collection, quality control and the conceptualisation and design of the manuscript. H.R. wrote the first draft of the manuscript, coordinated the statistical analysis, interpretation of the result and remarks from all co-authors. C.R. performed the power calculation and statistical analyses and assisted with the interpretation of the result. R.N., M.V., L.M., H.S.K., C.R., M.F., C.M.S. edited the manuscript. M.F. and C.M.S. supervised the study. All authors actively participated in the field data collection, writing of the manuscript and gave final approval for publication. | PMC10830362 | ||
Ethics of human subject participation | This manuscript forms part of a PhD thesis. The study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving research study participants were approved by the North-West University Health Research Ethics Committee (NWU-00452–19-A1) and was registered on the clinicaltrials.gov (NCT05168085). Permission was sought from the South African National and Provincial Department of Health, the local clinics in the study area and the community leaders to do the study. Written informed consent was obtained from all parents/legal guardians. | PMC10830362 | ||
Supplementary material | For supplementary material accompanying this paper visit | PMC10830362 | ||
References | PMC10830362 | |||
Objective: | To examine the influence of the LOGICA RCT (randomized controlled trial) upon the practice and outcomes of laparoscopic gastrectomy within the Netherlands. | PMC10829898 | ||
Background: | Following RCTs the dissemination of complex interventions has been poorly studied. The LOGICA RCT included 10 Dutch centers and compared laparoscopic to open gastrectomy. | PMC10829898 | ||
Methods: | Gastrointestinal Cancer | REGRESSION, GASTROINTESTINAL CANCER | Data were obtained from the Dutch Upper Gastrointestinal Cancer Audit (DUCA) on all gastrectomies performed in the Netherlands (2012–2021), and the LOGICA RCT from 2015 to 2018. Multilevel multivariable logistic regression analyses were performed to assess the effect of laparoscopic versus open gastrectomy upon clinical outcomes before, during, and after the LOGICA RCT. | PMC10829898 |
Results: | COMPLICATIONS, CARDIAC COMPLICATIONS | Two hundred eleven patients from the LOGICA RCT (105 open vs 106 laparoscopic) and 4131 patients from the DUCA data set (1884 open vs 2247 laparoscopic) were included. In 2012, laparoscopic gastrectomy was performed in 6% of patients, increasing to 82% in 2021. No significant effect of laparoscopic gastrectomy on postoperative clinical outcomes was observed within the LOGICA RCT. Nationally within DUCA, a shift toward a beneficial effect of laparoscopic gastrectomy upon complications was observed, reaching a significant reduction in overall [adjusted odds ratio (aOR):0.62; 95% CI: 0.46–0.82], severe (aOR: 0.64; 95% CI: 0.46–0.90) and cardiac complications (aOR: 0.51; 95% CI: 0.30–0.89) after the LOGICA trial. | PMC10829898 | |
Conclusions: | The wider benefits of the LOGICA trial included the safe dissemination of laparoscopic gastrectomy across the Netherlands. The robust surgical quality assurance program in the design of the LOGICA RCT was crucial to facilitate the national dissemination of the technique following the trial and reducing potential patient harm during surgeons learning curve. | PMC10829898 | ||
Keywords: | tumor | GASTRIC CANCER, TUMOR, COMPLICATION | Randomized controlled trials (RCTs) of surgical interventions represent the highest level of clinical evidence and often can lead to the widespread adoption of new surgical techniques. However, surgical RCTs are often undertaken in highly controlled clinical environments, in selected patients, and with procedures performed by a selected experienced group of surgeons, often in high-volume centers. Therefore, the generalizability of findings from surgical RCTs to the comparatively uncontrolled environment of national practice is questionable.The Laparoscopic versus Open Gastrectomy for Gastric Cancer trial published in 2021, recruited and randomized patients from 2015 to 2018 between laparoscopic and open gastrectomy.For the patient, gastrectomy may be considered a technically less demanding operation with a lower complication rate when compared with esophagectomy.The aim of this present study was to examine the influence of the LOGICA trial upon the practice and clinical outcomes from laparoscopic gastrectomy nationally within the Netherlands. To achieve this aim, specific objectives of this study were to (1) evaluate patient and tumor factors driving allocation to laparoscopic gastrectomy at a national level; (2) compare clinical outcomes from laparoscopic with open gastrectomy in both the RCT (LOGICA) | PMC10829898 |
METHODS | PMC10829898 | |||
Data Sets | POSTOPERATIVE COMPLICATIONS | Data were obtained from the DUCA, which provided comprehensive data on all gastrectomies performed in the Netherlands between 2012 and 2021, and the LOGICA RCT, which ran from February 2015 to August 2018. The LOGICA data set included 46 variables, registering postoperative complications in accordance with the requirements of the DUCA registry at that time, and 516 variables were included within DUCA data set. All variables from the DUCA data set with >50% of data missing and those not relevant to the study objectives were excluded. | PMC10829898 | |
Patients | GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA, COMPLICATIONS | All patients who underwent gastrectomy within the LOGICA RCT were included. From the DUCA data set, all patients who underwent a gastrectomy for gastric or gastroesophageal junction adenocarcinoma were included. We excluded all patients with missing data regarding overall complications (n=4), 30-day or in-hospital mortality (n=3), and surgical approach (n=1). The flowchart with inclusion and exclusion criteria is shown in Supplementary Fig. 1, Supplemental Digital Content 1, | PMC10829898 | |
Statistical Analysis | tumor, pneumonia, anastomotic leakage, Comorbidity | TUMOR, INTRAOPERATIVE COMPLICATIONS, PNEUMONIA, EVENT, PULMONARY COMPLICATIONS, CARDIAC COMPLICATIONS, REGRESSION, COMPLICATIONS | Patient, tumor, and treatment characteristics of patients who underwent laparoscopic versus open gastrectomy were compared within the LOGICA and DUCA data sets using univariate analyses. These characteristics included sex, age, body mass index, American Society of Anesthesiologists score, Charlson Comorbidity Index, tumor location, cT, cN, cM, neoadjuvant treatment, surgical procedure, and year of surgery. Mann-Whitney Multilevel multivariable logistic regression analyses were performed to assess the effect of laparoscopic versus open gastrectomy upon clinical outcomes, including length of hospital stay, readmission, reoperation and endoscopic/radiologic reintervention, oncological outcomes, including resection radicality (R0) and number of resected lymph nodes; and complications including; intraoperative complications, overall complications, severe complications ≥Clavien-Dindo grade IIIa), anastomotic leakage, cardiac complications, pulmonary complications, pneumonia, and 30-day/in-hospital mortality), while adjusting for patient, tumor and treatment variables, as described above. To adjust for potential changes over time, year of surgery was added as a random effect factor within the multivariate model in the event the log-likelihood ratio test showed a better fit compared with the original model. In case of insufficient degrees of freedom to correct for the entire correction model, only confounders leading to a >10% change in odds ratio of the outcome were included in the multivariate model. These analyses were repeated to assess the effect of laparoscopic gastrectomy upon outcomes before (January 2012 to January 2015), during (February 2015 to August 2018), and after (September 2018 to December 2021) the LOGICA trial in the DUCA data set. Subgroup analyses were performed to match the DUCA data set to the inclusion and exclusion criteria of the LOGICA trial (curative resection, D2-lymphadenectomy, and M0), to classify conversions in the open cohort (per-protocol), and by excluding the first 20 laparoscopic gastrectomy cases of each center in the DUCA data set. Overall, | PMC10829898 |
RESULTS | PMC10829898 | |||
Baseline Characteristics | tumor, Tumor, Comorbidity | TUMOR, TUMOR, COMPLICATION | In total, 211 patients from the LOGICA RCT (105 open vs 106 laparoscopic) and 4131 patients from the DUCA data set (1884 open vs 2247 laparoscopic) were included. In the LOGICA RCT, patients who underwent laparoscopic gastrectomy had a significantly higher body mass index and more often did not receive neoadjuvant therapy when compared with open gastrectomy. At a national level, the DUCA database showed laparoscopic gastrectomy was used more often in female patients, higher American Society of Anesthesiologist-score patients, and M0 patients when compared with open surgery. Further significant differences were seen in age, Charlson Comorbidity Index, tumor location, cT, cN, neoadjuvant therapy, and year of surgery (Table Patient, Tumor, and Treatment Characteristics of Patients That Underwent Laparoscopic Versus Open Gastrectomy in the LOGICA and DUCA Data SetsBold values are statistically significant.n (%); Median (IQR).Pearson χOverall complication and 30-day/in-hospital mortality rates after minimally invasive (MI) versus open gastrectomy, as well as the percentage of minimally invasive resections of all gastrectomies. The time frame of the LOGICA trial is represented by the gray background fill. | PMC10829898 |
Effects of Laparoscopic Gastrectomy on Clinical Outcomes Compared With Open Gastrectomy | tumor, cardiac complications, Comorbidity | TUMOR, CARDIAC COMPLICATIONS | Besides a significantly reduced risk of an in-hospital stay above the median of 7 days [adjusted odds ratio (aOR): 0.56; 95% CI: 0.31–0.99], no significant effect of laparoscopic gastrectomy on postoperative clinical outcomes was observed within the LOGICA RCT (Table Multivariate Comparison of Clinical and Pathologic Outcomes of Laparoscopic Versus Open Gastrectomy in the LOGICA and DUCA Data SetsBold values are statistically significant.n (%); median (IQR).Adjusted odds ratio. Corrected for: sex, age, BMI, Charlson Comorbidity Index, ASA-score, tumor location, cT stage, cN stage, cM stage, neoadjuvant therapy, type of gastrectomy, and year of surgery as random effect factor. In case of insufficient degrees of freedom for correction for the entire correction model, only confounders leading to a 10% change in odds ratio were included in the multivariable model. Year of surgery was added as random effect factor to the model in case the log-likelihood ratio test showed a better fit compared with the original multivariable model.Neoadjuvant therapy.Surgical procedure.BMI.Wilcoxon rank sum test.BMI indicates body mass index.Subgroup analyses of matching the DUCA data set to the inclusion and exclusion criteria of the LOGICA RCT showed consistent results with clinical benefits observed with laparoscopic gastrectomy, including significantly less overall and cardiac complications and a lower risk of an in-hospital stay above the median of 8 days (Supplementary Table 1, Supplemental Digital Content 1, | PMC10829898 |
Effects of Laparoscopic Gastrectomy on Outcomes Before, During, and After the LOGICA Trial |
Figure Forest plots showing the effect of laparoscopic versus open gastrectomy on postoperative clinical outcomes during: the LOGICA RCT (A); the DUCA data set before the start of the LOGICA RCT (B); the DUCA data set during the LOGICA RCT (C); the DUCA data set after the end of the LOGICA RCT (D). | PMC10829898 | ||
DISCUSSION | learning or proficiency gain, cancer, tumor, upper gastrointestinal Dutch | TUMOR, POSTOPERATIVE COMPLICATIONS, CANCER, PULMONARY COMPLICATIONS, GASTRIC CANCER | The results of the LOGICA randomized controlled trial across 10 experienced upper gastrointestinal Dutch centers showed that laparoscopic gastrectomy was associated with no significant improvements in length of hospital stay or postoperative complications when compared with open gastrectomy.When considering the external validity of a RCT concerning surgical interventions in surgical oncology, it is essential to remain acutely aware of the complexity of the intervention under investigation and the mechanism for its implementation within and following the RCT. Our research group previously examined the external validity of the TIME trial, which showed a substantial reduction in pulmonary complications associated with totally minimally invasive compared with open esophagectomy.There are important differences between this present study concerning the LOGICA trial and the previously conducted study concerning the TIME trial.The learning or proficiency gain curve is well described in the surgical literature and describes adverse patient outcomes as surgeon gain proficiency in performing a surgical technique.Given the importance of the findings of this present study it is crucial to consider the strengths and limitations in terms of study design. First, this study is novel in that it has shown the importance of a well-conducted RCT with a robust SQA program in facilitating the dissemination of a challenging surgical procedure nationally. Second, the data analyzed were collated from 2 well-validated sources, a well-designed RCT and a large well-validated national data set concerning surgery for gastric cancer. Third, given the underlying differences in patient and tumor characteristics between the study groups, the analysis conducted was appropriate with adjustment for known and measured confounding factors. The main limitations of the study include the potential effect of unmeasured confounding factors that evolved during the study period, including the introduction of enhanced recovery protocols and the ongoing centralization of cancer surgical services to high-volume centers within the Netherlands. Specific improvements in perioperative care and intraoperative and postoperative technology may also have contributed to improvements in clinical outcomes over the study period observed in the laparoscopic gastrectomy group. However, given the lack of improvement in postoperative morbidity seen from open gastrectomy over the study period (Fig. In conclusion, the result of this study suggests the wider benefits of the LOGICA trial include safe dissemination of laparoscopic gastrectomy across the Netherlands, and further ongoing progression through the surgical learning curve may lead to the true benefit of a technique being observed only after the evaluating trial. The importance of a robust SQA program in the design of the RCT is crucial to facilitate the national dissemination of the technique following the trial and reducing potential patient harm during the surgeons learning curve. | PMC10829898 |
Supplementary Material | PMC10829898 | |||
ACKNOWLEDGEMENTS | The authors thank to all surgeons, physician assistants and registrars for registration of data in the DUCA database, as well as the DUCA scientific committee for the approval and scientific input on this study.S.R.M. and M.R.V. are to be credited as joint first authors.The authors report no conflicts of interest.Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, | PMC10829898 | ||
REFERENCES | PMC10829898 | |||
Background | pancreatic tumors | PANCREATIC TUMORS | Academic Editor: Hu Wang Nimotuzumab exerts its antitumor effect (mainly antiproliferative, proapoptotic, and antiangiogenic) by blocking the epidermal growth factor receptor overexpressing between 30 and 95% in pancreatic tumors cells. | PMC10162878 |
Methods | pancreatic tumors | PANCREATIC TUMORS, ADVERSE EVENT, ADVERSE EVENT | A prospective, nonrandomized, uncontrolled, open-label, and multicenter clinical trial was conducted to evaluate the safety and effectiveness of nimotuzumab combined with gemcitabine as first-line treatment in unresectable locally advanced or metastatic pancreatic tumors in a real-world condition. Adverse events, their intensity, severity, and causality were determined using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Median overall survival, median progression-free survival, and 1- and 2-year survival rates were determined by using the Kaplan-Meier. | PMC10162878 |
Results | nausea, anemia, abdominal pain | ADVERSE EVENTS, DISEASE, METASTATIC DISEASE, ANEMIA | 69 patients were included. The proportion of related serious adverse events was 1.2%. The most frequent adverse events were nausea (10%), anemia (8%), and abdominal pain (8%). Objective response was achieved in 18.5% of the patients and disease control in 43.1%. Patients with locally advanced disease achieved a median overall survival of 16.36 months (95% CI; 14.35-18.38); 1- and 2-year survival rates of 72.2 and 29.2 months, respectively; a median progression-free survival of 9.6 months (95% CI; 4.91-14.20); and a 1-year progression-free survival rate of 39%. Patients with metastatic disease achieved a median survival of 6.23 months (95% CI; 4.32-8.13); 1- and 2-year survival rates of 18.1 and 3.0 months, respectively; a median progression-free survival of 7.6 months (95% CI; 6.08-9.90); and 1- and 2-year PFS rates of 20.5 and 5.1 months, respectively. | PMC10162878 |
Conclusions | pancreatic adenocarcinoma | PANCREATIC ADENOCARCINOMA | Nimotuzumab combined with gemcitabine represents a safe and effective first-line treatment option for patients with advanced pancreatic adenocarcinoma in real-world conditions. Survival benefits were increased in those patients who received 8 or more doses of nimotuzumab. This trial is registered with | PMC10162878 |
1. Introduction | tumor, cancer of the pancreas [, cancer, pancreatic tumors, pancreatic cancer, tumors, arrest, pancreatic adenocarcinoma | TUMOR, LYSIS, PANCREATIC DUCTAL ADENOCARCINOMA, TISSUE INVASION, PROLIFERATION, CANCER, GROWTH SUPPRESSION, TUMOR GROWTH, CYTOTOXICITY, DISEASES, PANCREATIC TUMOR, PANCREATIC CANCER, METASTASIS, PANCREATIC TUMORS, DISEASE, CANCER OF THE PANCREAS, TUMORS, ARREST, PANCREATIC ADENOCARCINOMA | In 2020, pancreatic cancer (of 36 most common types of cancer) was ranked the 14The most used cytotoxic drug for the treatment of pancreatic adenocarcinoma has been gemcitabine, as monotherapy or combined with other treatments. The combination of gemcitabine plus nab-paclitaxel results more effective for locally advanced diseases than the rest of the combinations. The selection of the most appropriate regimen for each patient continues to depend on clinicopathologic stratification, and the development of appropriate biomarkers remains as a challenge [The molecular characterization, the epigenomic, and the genomic profile of pancreatic adenocarcinoma have allowed a better understanding of the disease and have opened the doors to the study of other therapeutic approaches. The deeply immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma, the dense stroma, the presence of inhibitory cytokines, few inhibitory T cells, and the low mutational tumor burden have played an important role in the failure of immunotherapy for the treatment of cancer of the pancreas [The epidermal growth factor receptor (EGFR) is overexpressed in pancreatic tumor cells where it is believed to promote cell survival, proliferation, tissue invasion, and metastasis formation while inhibiting apoptosis [Nimotuzumab is a humanized monoclonal antibody that mainly exerts its mechanism of action by competitively inhibiting the binding of the EGF ligand to the extracellular domain of the EGFR. The binding to EGFR leads to a further inhibition of the homodimerization or heterodimerization of this receptor and subsequent autophosphorylation of its tyrosine residues. The consequent inhibition of different canonical and noncanonical ligand-induced signal-transduction pathways results in suppression of tumor growth, inhibition of the mitogenic stimulation of malignant cells, and, therefore, their persistent proliferation and invasiveness. The processes of angiogenesis and metastasis are also inhibited, and apoptosis is activated. Nimotuzumab also elicits other immune responses such as the activation of natural killer (NK) cells and tumor cell lysis through antibody-dependent cellular cytotoxicity (ADCC). Furthermore, nimotuzumab activates adaptive immunity through tumor antigen- (TA-) specific CD8+ T cells and increases the expression of the human leukocyte antigen (HLA) class I-dependent antigen presentation molecule (known as signal 1) that allows induced T cells to recognize and kill EGFR+ tumor cells, reversing one EGFR-mediated mechanism of immune escape that can benefit tumors [Nimotuzumab has been evaluated in clinical trials for the treatment of different types of cancer, obtaining evidence of benefits in terms of therapeutic effect and a broad safety profile [Gao et al. found that nimotuzumab combined with gemcitabine-based chemoradiation promotes the enhancement of the cell cycle arrest, growth suppression, and apoptosis of EGFR-overexpressed pancreatic cancer cell lines PANC-1 [The present study was carried out to evaluate the safety and effect of nimotuzumab combined with gemcitabine in unresectable locally advanced or metastatic pancreatic tumors in a Cuban real-world conditions. | PMC10162878 |
2. Materials and Methods | PMC10162878 | |||
2.1. Study Design | toxicity, death, pancreatic tumor | PANCREATIC TUMOR | A prospective, uncontrolled, nonrandomized, open, and multicenter study was conducted, to evaluate the safety and effectiveness of nimotuzumab, in combination with gemcitabine, in first-line treatment or recurrent patients with locally advanced and unresectable or metastatic pancreatic tumor in the real-world conditions. All included patients received a nimotuzumab fixed dose of 400 mg intravenously as a 30-minute infusion, once a week. The appearance of unacceptable toxicity were considered cause of definitive interruption, as well as the patient's refusal or death, and also, the discontinuation of nimotuzumab treatment for more than three weeks. Patients also received gemcitabine 1000 mg/m | PMC10162878 |
2.2. Ethical Considerations | ICH | The study was conducted in agreement with the general principles adopted by the international community regarding biomedical research in human subjects, with current state regulations according to the requirements of the Cuban national regulatory agency, as well as in the Guide to Good Clinical Practices of the International Harmonization Conference (ICH E6). Besides, it was approved by the Cuban Minister of Public Health, the Institutional Ethics Committees of each hospital, and CECMED. The informed written consent was obtained from the patients before their inclusion in the investigation. | PMC10162878 | |
2.3. Eligible Patients | malignancy, ascites | ASCITES, PANCREATIC CANCER | The main inclusion criteria are as follows: patients aged ≥ 18years who meet the diagnostic criteria and expressed written willingness to participate in the study by signing the informed consent, life expectancy equal to or greater than 3 months, clinical status according to ECOG criteria ≤ 2, and patients fit for chemotherapy and with normal renal and hepatic function according to laboratory parameters.The main exclusion criteria are as follows: prior anticancer chemotherapy including adjuvant gemcitabine for pancreatic cancer, any investigational agent received concurrently or within the last 30 days, major surgery within the previous 3 weeks, previous or concurrent malignancy other than pancreatic cancer, uncontrolled ascites, or other clinically significant comorbidities. | PMC10162878 |
2.4. Methods | Tumors | ADVERSE EVENT, ADVERSE EVENTS, EVENT, TUMORS, ADVERSE EVENT | The safety and effectiveness analyses were performed with all included patients who received at least one dose of nimotuzumab. The main variable was the proportion of patients with serious adverse events related to the administration of nimotuzumab (very probable, probable, and possible), and the corresponding 95% confidence interval was calculated. The frequency of patients with each adverse event was calculated, and the frequency distributions of each type of reported event. Severity and causality were determined by using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0).The effectiveness analysis was performed independently for each stratum: locally advanced, metastatic, or recurrent patients, and overall survival (OS) and progression-free survival (PFS) were determined. The clinical response was evaluated as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. | PMC10162878 |
2.5. Statistical Analysis | Descriptive methods were used for patient's demographic and clinic characteristics, treatment exposure, and safety analysis. For the analysis of overall survival, median values and 95% confidence interval (CI) were estimated. OS and PFS were determined by the Kaplan-Meier methodology, and 1- and 2-year survival rates were estimated. For the clinical response, a point estimate and a 95% CI were performed for the proportion of patients with complete response (CR) and objective response (CR+PR). Statistical analysis was performed with SPSS program (version 21.0). | PMC10162878 | ||
3. Results | MAY, METASTATIC DISEASE | Between June 2017 and May 2020, 177 patients were evaluated. Of these, 69 were included in the study (The largest number included were patients with metastatic disease. The data on the baseline characteristics of all the patients analyzed are summarized in | PMC10162878 |
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