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Introduction | prediabetes’, impaired fasting glucose, Prediabetes, HIV and prediabetes, prediabetes, type 2 diabetes, type 2 diabetes mellitus, diabetes | PREDIABETES, IMPAIRED GLUCOSE TOLERANCE, PREDIABETES, TYPE 2 DIABETES, TYPE 2 DIABETES MELLITUS, DIABETES | The rapidly rising prevalence of type 2 diabetes mellitus is a global public health threat. In sub-Saharan Africa (SSA), an estimated 5% of adults are living with type 2 diabetes [Evidence on the efficacy of type 2 diabetes prevention strategies from SSA is scarce. People with blood glucose levels that fall just below the diagnostic level for diabetes are considered to have ‘prediabetes’. Prediabetes comprises heterogeneous states of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or, in high-income settings, elevated HbAIn randomised trials, delays in progression to type 2 diabetes have been demonstrated with pharmacological agents, including acarbose [The prevalence of prediabetes among people with HIV has been reported as being between 18% and 26% in SSA, although these estimates are from small studies [Dolutegravir is a HIV-integrase inhibitor that, since 2019, has been part of the first-line therapy for HIV in Tanzania [No trials have been conducted in SSA to evaluate the efficacy of metformin for the prevention of type 2 diabetes. A recent open-label trial conducted among people with HIV and prediabetes in Thailand suggested that metformin may improve glycaemic control compared with no therapy, but this study was small, with just 37 participants in each trial arm [ | PMC10474205 |
Methods | PMC10474205 | |||
Trial design and interventions | prediabetes and HIV | ADVERSE EVENTS, ADVERSE EVENT, EVENTS, ACQUIRED IMMUNODEFICIENCY SYNDROME | The Metformin Treatment for Africa (META) trial was a Phase II randomised placebo-controlled trial conducted among people with prediabetes and HIV who were taking ART. Neither the participants or the healthcare staff or the researchers were aware of participant allocation (i.e. the study was double-blinded). The trial was designed to evaluate the effects of metformin on blood glucose and to evaluate drug safety over a 12 month duration. The primary outcome measure was blood glucose levels measured 2 h following a 75 g glucose load as this was felt to provide a more consistently reproducible measure than fasting glucose. Secondary outcome measures included drug safety. Adverse events were graded using the Division of Acquired Immunodeficiency Syndrome (DAIDS) criteria and events Grade 3 or greater were reported as serious adverse events (SAEs) [ | PMC10474205 |
Interventions | ADVERSE EFFECTS | Participants were asked to take 2000 mg extended-release metformin hydrochloride, dispensed in 500 mg tablets. Placebos were identical in shape, size and appearance. All trial drugs were provided by Merck Healthcare, Darmstadt, Germany. Participants were asked to take four tablets in the evening after food. They were provided information about possible adverse effects. Participants in both arms also received brief structured advice on diet and lifestyle and on medicine adherence at every visit. Adherence was measured using a visual adherence score and by pill counts. | PMC10474205 | |
Randomisation and follow up | Eligible participants were randomised to the intervention arm or control arm using permuted block randomisation with varying block sizes of 4, 6 and 8 people chosen at random using the SAS software (SAS version 9.4, SAS Institute, Cary, NC, USA.). Each participant had a unique randomisation code. The randomisation list was held in the Electronic Data Capture database (The randomisation code was written and tested by a senior statistician (DW) and the final list was generated by an independent trial statistician (T. Chen, Liverpool School of Tropical Medicine [LSTM], Liverpool, UK), who maintained the randomisation codes. A copy of the participant allocation list was held by the META trial team’s Chief Pharmacist and his assistant, I. Tarimo (both Muhimbili National Hospital, Dar es Salaam, Tanzania). All research and clinical staff remained blinded to the allocation code.Participants were given drug supplies to last them until their next visit plus 6 days’ extra supply in case they were late returning to the clinic. The scheduled visits occurred at 2 weeks and at 1, 3, 6, 9 and 12 months after baseline. Laboratory blood tests of renal and liver function were conducted at 3-monthly intervals. In addition, participants with abnormal baseline laboratory results had unscheduled visits for clinical review and additional tests were immediately conducted to assess potential relatedness with investigational drugs. | PMC10474205 | ||
Sample size | We had no prior data from SSA. We assumed that the mean (SD) glucose level 2 h following a 75 g oral glucose load would be 10.0 (1.5) mmol/l at 12 months in the placebo arm. We calculated that a study with 160 people per arm would have 85% power to detect a difference in blood glucose levels at 2 h post a 75 g glucose load from 10 mmol/l down to 9.5 mmol/l in the metformin arm (i.e. an absolute difference of 0.5 mmol/l between the two arms) and enroled 182 people per arm to allow for losses to follow-up. | PMC10474205 | ||
Trial setting and population | acute metabolic disorders, liver or heart disease, prediabetes | PREDIABETES | The trial was conducted in the HIV clinics of four hospitals in Dar es Salaam, of which three were public hospitals (Amana, Mwananyamala and Temeke Hospitals) and one was a not-for-profit hospital (Shree Hindu Mandal Hospital). These hospitals serve largely urban populations.There is no consensus on how to define prediabetes [Individuals were invited for screening if they were aged 18 years or older, on ART, regularly attending their HIV clinic for at least 6 months, were not pregnant, did not have a history or clinical evidence of acute metabolic disorders, or kidney, liver or heart disease, and had no contraindication to metformin. Two methods were used to screen individuals to assess their eligibility: (1) purposeful sampling, whereby individuals known or suspected to have prediabetes or individuals with a high BMI (>30 kg/mIndividuals were considered eligible if they had: (1) BMI >30 kg/m | PMC10474205 |
Blood/urine sampling and data collection | HbAVenous blood samples, diabetes | ADVERSE EVENT, EVENTS, TYPE 2 DIABETES, DIABETES | On arrival at the clinic, a morning blood sample was collected via venepuncture by a research nurse, and fasting blood glucose was measured. Participants were given a 75 g anhydrous glucose solution dissolved in 300 ml non-carbonated water (Rapilose OGTT solution; Galen, Craigavon, UK) and a 2 h post glucose-load capillary blood glucose measurement was taken via finger prick. To determine glucose, a point-of-care test was performed (HemoCue Glucose 201 RT; Hemocue, Ängelholm, Sweden) immediately following venepuncture and finger prick. Further screening investigations included HbAVenous blood samples were collected every 3 months from enroled participants on arrival to the clinic. Full blood count (FBC), and analysis of total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglyceride levels were conducted at baseline and at the 12 month visit only. For the FBC, blood samples were in EDTA tubes and for biochemical analyses, blood samples were in plain tubes; these samples were transported to a centralised laboratory for processing within 2–3 h of procurement (the mean time between collection and processing was 11 h). The Architect C4100 analyser (Abbott, IL, USA) was used for biochemical analysis, whilst the CELL-DYN 3700 and CELL-DYN Ruby analysers (both Abbott) were used for haematological (FBC) analysis.Participants with suspected clinical conditions and/or abnormal laboratory markers identified through screening or enrolment procedures were referred to the appropriate clinics within the health facility. Any participants with raised BP, above 180/120 mmHg, were referred to the emergency department for immediate care. Participants in the trial who developed type 2 diabetes were referred to the diabetes service within the health facility. Adverse events were graded using the DAIDS criteria, and events that were Grade 3 or greater were reported as SAEs [Anthropometric measurements included height, weight, and waist and hip circumference, all of which were measured following removal of shoes and outer clothing. Height was measured to the nearest 1 cm using calibrated stadiometers (Seca, Hamburg, Germany) and weight to the nearest 1 kg. using calibrated Seca scales. Flexible tape measures were used to measure waist and hip circumference. The WHO definitions of threshold values were used for classifying BMI, waist circumference and waist:hip ratio [ | PMC10474205 |
Timeline and disruption due to the coronavirus disease 2019 pandemic | coronavirus disease 2019 | RECRUITMENT, CORONAVIRUS DISEASE 2019, RECRUITMENT | Recruitment began on 4 November 2019 and the last participant was enroled on 21 July 2020. Follow up of participants ended 12 months later, as planned. The first confirmed cases of coronavirus disease 2019 (COVID-19) in Tanzania occurred in mid-March 2020 and caused severe disruption [We maintained the schedule of appointments following initial meetings with participants. On 17 April 2020, Amana Hospital, our busiest recruitment site, was closed to non-COVID-19 patients, with a 24 h notice period. Trial participants were transferred to Mwananyamala Hospital, which had not previously been a trial site. On 28 August 2020, Amana Hospital was re-opened to all patients and trial participants were transferred back as this was their local health facility. | PMC10474205 |
Ethics | The protocol was approved by the LSTM Research ethics committee (reference: 17-078), by the National Institute for Medical Research (NIMR)/Ministry of Health Ethics Committee (reference: NIMR/HQ/R.8a/Vol.IX/2916), by the Tanzania National Research Ethics Committee and by the Tanzania Medicine and Devices Authority. All participants provided written informed consent to participate in the study. This trial is registered with the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( | PMC10474205 | ||
Statistical methods | fasting blood glucose, diabetes | REGRESSION, EVENTS, SECONDARY, DIABETES | Primary analyses were by intention-to-treat and included participants who were randomised and had at least one valid measurement of primary or secondary outcomes. A linear mixed model was employed for the primary endpoint analysis. The linear mixed model included treatment (metformin vs placebo), visit (midpoint and study end [i.e. approximately 6 and 12 months, respectively]), and the interaction between treatment and visit as fixed effects, controlling for baseline blood glucose values at 2 h post 75 g glucose load, and including a participant level random intercept. Restricted maximum likelihood estimation was used to fit the linear mixed model, assuming an unstructured covariance matrix. The Satterthwaite approximation for the degrees of freedom was used. This model was used to determine the difference in means of glucose levels 2 h post 75 g glucose load (and two-sided 95% CI) between the two treatment arms at midpoint and endpoint. A two-sided Continuous secondary outcomes were analysed in a similar way as the primary endpoint. For the analysis of binary secondary outcomes, a generalised linear mixed model was employed with treatment, visit, and interaction between treatment and visit as fixed effects, controlling for baseline values of each respective outcome, and including a participant level random intercept. For blood lipids, which were only measured at baseline and 12 month follow-up, estimates were derived using linear regression models controlling for baseline values. The odds ratio between the two treatment arms at each visit, together with 95% CI, was derived from the generalised mixed model. The generalised linear model was used to analyse secondary outcomes with a single follow-up measurement, controlling for baseline values. The occurrence of diabetes was summarised using the number of events and incidence rate by treatment group and analysed using a generalised linear model with Poisson distribution and log link function and with treatment as a fixed effect, to generate incidence rate ratios (IRRs) and 95% CIs. Thresholds for diabetes were defined using the respective thresholds for fasting blood glucose (≥7.0 mmol/l), 2 h postprandial blood glucose level (≥11.1 mmol/l) and HbAAnalyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA). A | PMC10474205 |
Discussion | weight gain, HIV and prediabetes, gestational diabetes, diabetes | GESTATIONAL DIABETES, ADVERSE EVENTS, COMPLICATION, LACTIC ACIDOSIS, TYPE 2 DIABETES, DIABETES | In this Phase II double-blind placebo-controlled trial among people with HIV and prediabetes, there was no significant difference in glucose levels between the metformin and placebo arms at the study end when measured by glucose levels 2 h after a 75 g glucose load or by fasting glucose. However, glucose levels 2 h post glucose load fell in both arms, and fasting blood glucose was lower at study end than at enrolment in the metformin arm but not in the placebo arm, although these declines were not significant when we controlled for baseline values.Whilst assessment of safety was not the primary endpoint of the trial, none of the abnormal laboratory/biochemical results or clinical adverse events that we observed at Grade 3 or higher could be linked to metformin. We observed no cases of lactic acidosis, an extremely rare and serious complication that has been linked to being on ART and metformin [Why did the trial show no differential effect of metformin on blood glucose compared with placebo at the 12 month follow-up? It is possible that, in this population, metformin is either ineffective or that the effect was too small for the study to detect (i.e. the study was underpowered). Our study population was comprised of mostly women who were not pregnant and this distribution was a weakness. Metformin did not confer protection against progression to type 2 diabetes among women who did not have a history of gestational diabetes in a large study in the USA that had a 10 year follow-up [Why glucose levels 2 h post glucose load fell in both arms is not clear. Metformin reduces energy intake, attenuates weight gain and, thus has a beneficial effect on body weight and visceral fat [We had severe disruption from COVID-19 whilst conducting the study. The COVID-19 pandemic started shortly after the trial began and government bodies and media started giving regular advice on the importance of a healthy diet and exercise to protect health from COVID-19, particularly for those living with type 2 diabetes. We also provided participants with basic diet and lifestyle advice at each contact, as planned. However, our contact with participants increased because of the disruption caused to health services by COVID-19 and so the frequency of advice that participants received also increased. We know from studies conducted in high-income settings that intensive structured promotion of diet and exercise is more powerful than metformin in reducing type 2 diabetes risk and that metformin has little added effect if there is substantial behaviour change related to diet and exercise [It is evident from the changes in weight (and also lipid markers [data not shown]), which improved in both arms, that diet and lifestyle behaviour changed. Metformin’s ability to improve lipid makers among individuals without diabetes but with HIV has been shown by others [Pharmacological interventions can be implemented with relative ease in our population, giving them alongside ART. Diet and exercise interventions, as tested in high-income settings, are time intensive and would be costly to implement in SSA. A recent randomised trial from South Africa comprising about 500 participants who were followed for 7–9 months, demonstrated that a behavioural intervention based on video group sessions was feasible and lowered HbAOf note, despite the severe disruption caused by the COVID-19 pandemic, over 70% of participants attended as scheduled throughout the year. This was largely because of the time taken by study researchers to build trust and partnership with participants. We did not titrate the dose of metformin, as is commonly done in the management of type 2 diabetes, primarily for ease of administration and because we felt that the extended-release formulation would be well tolerated. Despite this and the comparatively higher frequency of Grade 1 and Grade 2 side effects in the metformin arm compared with the placebo arm, reported adherence to medication was very high in both arms, and was over 98% among those who attended clinic appointments as scheduled.Our study demonstrates the high frequency of IFG and/or IGT that is present, and which remains largely undetected, in people living with HIV in SSA. It also demonstrates that it is feasible to integrate diabetes services within HIV programmes. These findings support other recent research studies conducted in this setting [In SSA, type 2 diabetes affects people at a younger age than in high-income countries [ | PMC10474205 |
Appendix | PMC10474205 | |||
Acknowledgements | We thank staff at Merck, in particular K. Brand (Merck, Darmstadt, Germany), for the supply of products, the Ministry of Health in Tanzania, and T. Chen (LSTM, Liverpool, UK; present affiliation: University of York, York, UK) for support with generation of the participant randomisation list. | PMC10474205 | ||
Data availability | The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request and with the permission of the RESPOND-Africa partnership. | PMC10474205 | ||
Funding | DER | This research was funded by the National Institute for Health Research (NIHR; project reference 16/137/87) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. KB was partially supported by an FWF (Fonds zur Förderung der wissenschaftlichen Forschung) Austrian Science Fund Lise Meitner Award (M-3069-B). The trial funder, suppliers and drug manufacturer had no role in the study design, data collection, analysis, interpretation or manuscript preparation. The corresponding author had full access to all of the data used in the study and had final responsibility for the decision to submit for publication. | PMC10474205 | |
Authors’ relationships and activities | The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. | PMC10474205 | ||
Contribution statement | RS, HL | RECRUITMENT | MJN and KR conceived the idea, and MJN and SJ led the design of the study with input from AG, SK and SM. AG and SK co-ordinated the study, and AG wrote the first draft of the paper with input from SK. KB, DW and HL conducted the statistical analysis. SJ, MJN, KR, UA, AG, SM and KB interpreted the findings. KR was the senior trial diabetologist and clinician, supported by UA. EM, RS and GC were the lead researchers at each site and were involved in recruitment, management and follow up of participants. SM oversaw all activity in Tanzania. EvW managed the data with input from AG, KB and SK. SJ co-ordinated the final write-up of the article with input and revisions from AG, KR, UA, MJN, SM, KB, DW, EM, RS, GC, HL and EvW on different parts of the article. All authors saw and approved the final version of the manuscript. AG is responsible for the integrity of this work as a whole. | PMC10474205 |
References | PMC10474205 | |||
1. Introduction | depression, sleep disorders, mood disorders | Emerging science shows that probiotic intake may impact stress and mental health. We investigated the effect of a 6-week intervention with Psychosocial stress is a significant and increasing burden nowadays in our society, is a risk factor for mood disorders including depression and sleep disorders [Dietary interventions, such as the intake of pre- and probiotics, can modulate the microbiota–gut–brain axis. Probiotics, live microorganisms that provide health benefits when consumed in adequate amounts [Based on the effects we observed with | PMC10383821 | |
2. Materials and Methods | PMC10383821 | |||
2.1. Study Design and Population | This randomized, placebo-controlled, 2-arm, parallel, double-blind exploratory clinical trial was conducted in Switzerland between December 2020 and August 2021. Being an exploratory trial, no a priori sample size calculation was performed. Out of a total of 49 eligible volunteers, 47 completed the study (see | PMC10383821 | ||
2.2. Intervention | Products were supplied in the form of dry powder contained in aluminum sachets. In alignment with previous preclinical and clinical trials [ | PMC10383821 | ||
2.3. Procedure | COLD | The experimental procedure comprised two separate testing visits (visit 2: baseline; visit 3: post-intervention) performed at baseline and after 6 weeks starting at 1:00 p.m. following a 24 h abstention from alcohol, coffee (caffeinated or decaffeinated), other caffeinated products, or any other stimulant. Prior to the test visits, participants collected a fecal sample at home and awakening saliva samples as previously described [Subsequently, participants performed the Maastricht Acute Stress Test (MAST) according to procedure described in Smeets et al. (2012). In brief, the MAST consisted in a first 5 min period of instruction (stress anticipation), followed by a 10 min period of physical (hand immersion in cold water), with cognitive (mental arithmetic trials) and social (videotaping) stressors alternately administered by a trained experimenter [ | PMC10383821 | |
2.4. Salivary Cortisol | Salivary cortisol awakening response was quantified at baseline and after 6-week supplementation as an index of the hypothalamic–pituitary–adrenal (HPA) axis activity in relation to chronic stress [ | PMC10383821 | ||
2.5. Autonomic Parameters | SKIN, COLD | Autonomic parameters were collected by means of a portable-computer-based data acquisition system with AcqKnowledge software (BIOPAC Systems Inc., Camino Goleta, CA, USA), using a finger photoplethysmograph and electrodermal activity (EDA) transducers. They were placed on the nondominant hand of the participants. The photoplethysmograph provided data for heart rate and heart rate variability (HRV) that were analyzed with Kubios HRV software (Kubios software, Premium 3.3.1, Finland). HRV parameters of interest were the root mean square of successive differences between normal heartbeats in millisecond (RMSSD), the mean of heart rate (Mean HR), the peak in the low-frequency band (LF) (0.04–0.15 Hz), the peak in the high-frequency band (HF) (0.15–0.4 Hz), and the ratio of low-frequency to high-frequency peaks (LF:HF). The electrodermal sensor provided the Skin Conductance Level (SCL) in microsiemens. SCL was processed with AcqKnowledge software using a smoothing baseline removal with a window width of 2 s, a low-pass filter with a cutoff frequency of 1 Hz, and a linear interpolation method. The waveform was resampled to 7.813 Hz, and phasic EDA was subtracted from the signal. Both cardiac and electrodermal data were computed for periods of different lengths. They correspond to 5 min baseline before instructions were given (Before), 5 min stress anticipation (during the instructions; During 1), the average of cold hand immersions (During 2), the average of mental arithmetic trials (During 3), and 8 periods of rest after the stressor (After 1; After 2; After 3; After 4; After 5; After 6; After 7; After 8), as shown in | PMC10383821 | |
2.6. Fecal BL NCC3001 Abundance Analysis | Fecal | PMC10383821 | ||
2.7. Statistical Analysis | depression, anxiety | Statistical analyses were conducted on 45 subjects that were randomized to one of the two arms (Psychological endpoints related to acute stress (PANAS, STAI-6, and VAS) and general assessments (PSS-14, HADS, GSRS, and PSQI) were used to assess the effect of the intervention by estimating the treatment difference (probiotic vs. placebo) at the post-intervention visit by an analysis of covariance (ANCOVA) model including treatment as independent variable as well as the three covariates: gender, DASS-42, and the pre-treatment value considered as baseline.Since saliva cortisol measurements feature multiple timepoints, data were summarized using four parameters that were then analyzed using the same ANCOVA model: area under the curve (AUCg), area under the curve incremental to the first timepoint considered as baseline (AUCi), maximum concentration (Cmax), and incremental maximum concentration (ICmax). For the autonomic parameters, the variables of interest were the changes from the pre-stressor value that was considered as baseline. These differences vs. baseline were analyzed using a linear mixed model with treatment, visit, treatment*visit, gender, DASS-42, and baseline (pre-stressor timepoint) as fixed and subject as random effects.For endpoints not meeting the model assumptions of normality, a Box-Cox transformation was applied. In such cases, a back-transformation with bias adjustment was applied to obtain an estimate of the effect on the original scale. When models did not converge or model assumptions were severely violated, a Wilcoxon rank-sum test was used together with the Hodges–Lehmann estimator and an associated nonparametric 95% confidence interval.In order to summarize the main findings of the whole study in a single descriptive figure, a principal component analysis (PCA) was performed on the difference between baseline and post-intervention of heart rate and PSS-14 as active variables and PSQI total score, PSQI subjective sleep quality score, HADS depression score, HADS anxiety score, cortisol acute response to experimental stress, cortisol awakening response, RMSSD at baseline (first period), RMSSD After 8 period, and DASS-42 baseline as passive variables. This PCA was performed on z-score-transformed variables.The statistical significance level was fixed at 5%, without adjustments for multiplicity, due the exploratory nature of the study. All analyses were performed using SAS BASE 9.4/SAS STAT 15.1 on the SAS Life Science Analytics Framework (SAS LSAF, SAS Institute Inc., Cary, NC, USA) version 5.2.3. | PMC10383821 | |
3. Results | Demographic and clinical characteristics at enrollment were well-balanced across the 45 participants (probiotic | PMC10383821 | ||
3.1. Increased Abundance of BL NCC3001 in Stool Shows That the Probiotic Was Successfully Delivered | Supplementation with | PMC10383821 | ||
3.2. Probiotic Intervention Reduced Perceived Stress Score | After 6-week intervention with | PMC10383821 | ||
3.3. Impact of the Probiotic Intervention on Subjective Reports Independent of Acute Stress | depression, gastrointestinal symptoms, anxiety | At baseline, both the probiotic and placebo groups showed an average score under 8 on both the anxiety (HADS-A) and depression (HADS-D) subscales, with no significant difference between the groups (see Our population showed median, first, and third quartiles scores between 0 and 1 on the PSQI subscales (see To investigate the impact of the probiotic on the potential pathways of the gut–brain communication, the cortisol concentration upon waking was assessed as a marker of the HPA axis activity. Notably, we did not find any effect of the probiotic on the salivary cortisol awakening response compared to placebo (CAR AUCg: We also investigated the gastrointestinal symptoms in this population experiencing mild-to-moderate stress using the Gastrointestinal Symptom Rating Scale (GSRS). No signs of gut discomfort were detected. The two experimental groups displayed comparable values (see | PMC10383821 | |
3.4. Impact of the Probiotic Intervention on Stress and Autonomic Nervous System Parameters Linked to Acute Stress Response | The salivary cortisol concentration progressively increased up to 20 min following acute stress and then progressively decreased up to the last salivary sample at 40 min post-stressor. The cortisol stress response (AUCg and Cmax) was lower in the probiotic group compared to the placebo group at baseline, and the opposite pattern was observed post-intervention (Relative to baseline, stress responses on autonomic parameters were characterized by an increase in HR, the LF peak, and SCL during the stressor (see We observed a statistically significant difference between the two groups post-intervention for the positive PANAS change score from the pre-stressor stage ( | PMC10383821 | ||
3.5. Multivariate Analysis Revealed Positive Correlation between Stress Reduction and Reductions in Anxiety and Depression | anxiety | Multivariate analysis revealed a positive correlation between the reduction in perceived stress with the reductions in anxiety (r = 0.32, | PMC10383821 | |
4. Discussion | sleep disturbance, anxiety, pain, depression, stress reduction | This exploratory trial evaluated the effect of Our main findings are in line with a recent meta-analysis assessing the effects of probiotics on stress in healthy subjects, showing that probiotics can reduce the subjective stress level in healthy volunteers without having a significant effect on the cortisol concentration [The baseline data obtained from subjective reports clearly showed a healthy population without suspicion of sleep disturbance. Although this initial status left limited space for improvement, we observed improved subjective sleep quality. This finding is in line with a recent study that showed an overall improvement in sleep quality and the duration of sleep using another The MAST procedure induced the anticipated increase in salivary cortisol [The finding that participants in the placebo group increased their positive mood scores on the PANAS after the MAST stressor was unexpected but may be due to the participants in this group feeling relieved that the study procedures were over with, since these participants reported a higher pain experience.In contrast to the One possible explanation for the lack of significant results on any other stressor-dependent subjective measures is that the sample size may not have been large enough to detect any differences.To investigate whether the probiotic intervention led to an overall change across all assessed parameters, we conducted a multivariate analysis that revealed a positive correlation between stress reduction and reductions in anxiety and depression. This positive association is in line with findings that perceived stress may increase negative emotions such as anxiety and depression [There are several mechanisms that could link the probiotic effect to the gut microbiome and host, leading to the reduction in perceived stress and the correlating benefits for anxiety and depression. For example, Overall, our results support the potential of specific probiotics being used to reduce perceived stress and will guide future clinical trial design to confirm the observed changes. Nevertheless, it is important to note that this exploratory clinical trial has several limitations. A larger, powered trial is warranted to confirm the findings of this exploratory trial, though the current findings can guide the design of any future confirmatory clinical studies in terms of effect size and expected variability. Moreover, the dosage and duration of probiotic supplementation play a key role in their effectiveness for reducing stress and improving mood. Some studies showed that higher doses of probiotics [Our results show, for the first time, that long-term oral supplementation with | PMC10383821 | |
Supplementary Materials | The following supporting information can be downloaded at Click here for additional data file. | PMC10383821 | ||
Author Contributions | Conceptualization, J.H., S.C.M., P.S., G.B. and M.V.; methodology, J.H., C.L., M.V., B.D., K.V. and L.V.O.; formal analysis, L.L., A.R. and N.R.-D.; investigation, C.L., M.S., S.K. and M.V.; data curation, L.L., J.H., N.R.-D., M.B., M.V., B.B., B.D., K.V. and L.V.O.; writing—original draft preparation, M.B., N.R.-D. and J.H.; writing—review and editing, all authors; visualization, N.R.-D., M.B., L.L., A.R. and J.H.; project administration, P.S., S.C.M., J.H. and M.B. All authors have read and agreed to the published version of the manuscript. | PMC10383821 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Canton de Vaud (project ID 2020-00959; approved 26.10.2020) (registered under NCT05226520). | PMC10383821 | ||
Informed Consent Statement | Written informed consent was obtained from all subjects involved in the study and was obtained from all subjects involved in the study to publish this paper. | PMC10383821 | ||
Conflicts of Interest | C.L. | M.B., N.R.-D., C.L., L.L., S.K., M.S., A.R., B.B., P.S., M.V., G.B., S.C.M. and J.H. are employees of Société des Produits Nestlé S.A., Switzerland. B.D., K.V. and L.V.O. declare that they have no conflict of interest. | PMC10383821 | |
References | Depression, Anxiety | CONSORT flowchart depicting the progression of participants through the study. DASS-42, Depression, Anxiety and Stress Scale; SAF, Safety Analysis Set; FAS, Full Analysis Set.Effects of 6 weeks of intervention with Differential cortisol response at waking and to acute stress: (Impact of the probiotic intervention on subject mood assessments linked to acute stress response. (Demographic and clinical characteristics at enrollment (FAS). FAS, Full Analysis Set; BMI, Body Mass Index; DASS, Depression Anxiety and Stress Scale.Psychological scores—independent of MAST. HADS-A, HADS Anxiety Score; HADS-D, HADS Depression Score. Inferential statistics: Effect of Physiological responses to MAST. Effect of Psychological responses to MAST. Effect of | PMC10383821 | |
1. Introduction | infection, pulmonary arterial hypertension, coronavirus disease 2019 | CORONAVIRUS DISEASE 2019, MUSCLE RELAXATION, INFECTION, PULMONARY ARTERIAL HYPERTENSION, SECONDARY, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME | Pulmonary arterial hypertension (PAH) is common in severe coronavirus disease 2019 (COVID-19) and worsens the prognosis. Sildenafil, a phosphodiesterase-5 inhibitor, is approved for PAH treatment but little is known about its efficacy in cases of severe COVID-19 with PAH. This study aimed to investigate the clinical efficacy of sildenafil in patients with severe COVID-19 and PAH. Intensive care unit (ICU) patients were randomly assigned to receive sildenafil or a placebo, with 75 participants in each group. Sildenafil was administered orally at 0.25 mg/kg t.i.d. for one week in a placebo-controlled, double-blind manner as an add-on therapy alongside the patient’s routine treatment. The primary endpoint was one-week mortality, and the secondary endpoints were the one-week intubation rate and duration of ICU stay. The mortality rate was 4% vs. 13.3% (Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection promotes the development of pulmonary arterial hypertension (PAH) [Sildenafil is a potent and selective inhibitor of phosphodiesterase-5 (PDE-5), the enzyme that enhances smooth muscle relaxation via the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway [This study aimed to investigate the effect of sildenafil on the course and outcome of severe COVID-19 with PAH. | PMC10223625 |
2. Materials and Methods | PMC10223625 | |||
2.1. Study Setting | SECONDARY, PULMONARY HYPERTENSION | A randomized, double-blind, placebo-controlled, prospective clinical trial was carried out between 9 June 2020 and 12 February 2022 in the intensive care departments of three hospitals in Kyiv, Ukraine: City Clinical Hospital NO. 4, and two multi-profile commercial hospitals, “Manufaktura” and “Raiering”. The study was conducted on random Kyiv City inhabitants (caucasian). Patients with severe COVID-19 and pulmonary hypertension were randomly assigned to receive either sildenafil or a placebo. The primary endpoint was the mortality rate; secondary endpoints were the intubation rate and the duration of ICU stay. | PMC10223625 | |
2.2. Study Population | pulmonary embolism, hypertension, insufficiency, interstitial pneumonia | PULMONARY EMBOLISM, PCT, SARS-COV-2 INFECTION, INTERSTITIAL PNEUMONIA, HYPERTENSION | Adult patients with severe COVID-19 and PAH who met the following inclusion and exclusion criteria were recruited to the study.Inclusion criteria:SARS-CoV-2 infection (confirmed with a positive reverse transcription polymerase chain reaction (RT PCR test));Bilateral interstitial pneumonia confirmed with a computed tomography (CT) scan;Arterial partial pressure of oxygen (PaOPulmonary hypertension (PH) ≥ 40 mmHg based on Doppler ultrasonography;Informed consent of the patient or their legal representative to participate in the study.Exclusion criteria:Circulatory instability with 80 mmHg < systolic blood pressure < 180 mmHg;High risk of pulmonary embolism (PE) as defined by ESC Guidelines [Clinically significant active bleeding;Kidney insufficiency with creatinine clearance (Cockcroft-Gault formula) < 30 mL/min;Severe liver failure;Retinitis pigmentosa;Hypersensitivity to sildenafil or enoxaparin sodium;Pregnancy or breastfeeding;Participation in other clinical trials.All patients participating in the study received the standard treatment for severe COVID-19 according to the local protocol:methylprednisolone 0.5 mg/kg daily orally;enoxaparin 60 anti-Xa IU/kg once daily if D-dimer < 5 µg/mL, or 100 anti-Xa IU/kg once daily if D-dimer levels ≥ 5 µg/mL;antibiotics in the presence of pathogenic bacterial flora in sputum, urine, or blood;an infusion volume calculated to ensure zero or slightly negative daily fluid balance;oxygen therapy with or without non-invasive ventilation to maintain respiratory index PaOintubation and pressure-controlled mechanical ventilation if PaOstandard treatment of comorbidities.Patients were randomly assigned to one of two groups:Group 1 (treatment group, S)—sildenafil (Superviga, Zdorovye, Ukraine) was administered orally at a dose of 0.25 mg/kg three times a day for seven days after enrolment;Group 2 (control group, C)—placebo was administered in a double-blind manner.The following parameters were measured in all patients one day before the start of the treatment and seven days after the start of the treatment: complete blood count, arterial blood gases, C-reactive protein (CRP), procalcitonin (PCT), fibrinogen, D-dimer, Il-6, and ferritin. Doppler measurement of pulmonary artery pressure (PAP) was also performed. | PMC10223625 |
2.3. Statistical Analysis | MedCalc | PMC10223625 | ||
4. Discussion | pulmonary artery hypertension, death | PULMONARY ARTERY HYPERTENSION, VASODILATATION | Our research demonstrated that in patients with severe COVID-19 and pulmonary artery hypertension, treatment with sildenafil resulted in a five times lower risk of death, four times lower risk of intubation with invasive mechanical ventilation, and a shorter ICU hospitalization period by 4 days compared to treatment with the placebo. This is only if adjusted for PAH, and, without this adjustment, the differences in mortality and intubation rates did not demonstrate statistical significance.The main mechanism of sildenafil’s action is vasodilatation due to PDE-5 inhibition. In our study, after a 7-day treatment period, an 11 mm Hg (from 63 to 52 mm Hg, 17.5%, In addition to its vasodilative effect, sildenafil was proven to have several other properties [Data about sildenafil administration in severe COVID-19 patients are surprisingly rare and the groups studied are very small. Santamarina et al. [The primary endpoint in our study was mortality. The mortality rate was 4% and 13.3% (Almost identical results we obtained for intubation. Again, the difference in the intubation rate was statistically insignificant between the groups (8% vs. 18.7%; The length of ICU hospitalization was the third parameter investigated in our study. Sildenafil treatment resulted in a statistically significant shortening in mean ICU stays from 19 days in the placebo group to 15 days in the treatment group (Overall, our results agreed with the infrequent data from other researchers: sildenafil treatment yields beneficial results, but not in every case, and sometimes statistical significance was achieved. We demonstrated that the clinical effectiveness of this treatment is positive and significant but only if adjusted for PAH. This allows us to speculate that among COVID-19 patients, the higher the PAH, the more effective sildenafil treatment may be. Consequently, these patients should be considered a target group for treatment with sildenafil.Our study has some limitations. Firstly, although three centers were involved, they covered a population limited by territory, with only 75 participants in each arm. Secondly, the treatment only lasted one week, with no follow-up period. A statistically significant clinical effect could probably be achieved if the duration of treatment and follow-up were longer. Thus, it seems reasonable to verify the results obtained in a multicenter study with more participants and longer treatment and follow-up periods, and perhaps with a more selective group of patients. | PMC10223625 |
Author Contributions | Conceptualization, O.V.O., W.B. and M.R.; methodology, O.V.O.; software, V.G.G.; formal analysis, O.V.O., W.B., M.R., V.G.G., Y.V.O., O.V.S., S.O.D., O.S.K. and A.Ś.; investigation, O.V.O., Y.V.O., O.V.S., S.O.D., A.Ś. and O.S.K.; data curation, O.V.O. and V.G.G.; writing—original draft preparation, O.V.O. and W.B.; writing—review and editing, O.V.O., W.B. and M.R.; visualization, V.G.G.; supervision, W.B. and M.R.; project administration, O.V.O.; funding acquisition, O.V.O. and M.R. All authors have read and agreed to the published version of the manuscript. | PMC10223625 | ||
Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Bioethics Committee of the Kyiv City Clinical Hospital No. 4. (Decision No. 1, dated 2 January 2020). | PMC10223625 | ||
Informed Consent Statement | Written informed consent was obtained from all subjects involved in the study. | PMC10223625 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available due to ethical aspects. | PMC10223625 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10223625 | ||
References | death | REGRESSION | Systolic pulmonary artery pressure before (sPAP1) and after (sPAP2) treatment with sildenafil (S) or the placebo (C), respectively. Solid circles—treatment with sildenafil; empty circles—treatment with placebo. Median, minimum, and maximum values and interquartile ranges are presented.ROC curve predicting risk of death in the two-factor logistic regression model.ROC curve predicting risk of intubation in the two-factor logistic regression model.Duration of ICU hospitalization for surviving patients treated with sildenafil (S) or placebo (C), respectively. Median, minimum, and maximum values and interquartile ranges are presented.Basic clinical and laboratory data in the study groups, median (QI–QIII) for continuous variables, and numerical values (%) for categorical variables.sPAP—systolic pulmonary artery pressure; C—control group; S—sildenafil group. Laboratory test reference ranges: interleukin-6 < 4.0 pg/mL, procalcitonin < 0.02 ng/mL, fibrinogen 2.0–4.0 g/L, CRP < 5.0 mg/L, D-dimer < 500 µg/L, leukocytes 4.0–9.0 × 10Analysis of risk of death in a single-factor logistic regression model.sPAP—systolic pulmonary artery pressure; C—control group; S—sildenafil group. Laboratory test reference ranges: interleukin-6 < 4.0 pg/mL, procalcitonin < 0.02 ng/mL, fibrinogen 2.0–4.0 g/L, CRP < 5.0 mg/L, D-dimer < 500 µg/L, leukocytes 4.0–9.0 × 10Multivariate logistic regression model for predicting the risk of mortality.sPAP—systolic pulmonary artery pressure; C—control group; S—sildenafil group.Single-factor logistic regression model for predicting risk of intubation.sPAP—systolic pulmonary artery pressure; C—control group; S—sildenafil group. Laboratory test reference ranges: interleukin-6 < 4.0 pg/mL, procalcitonin < 0.02 ng/mL, fibrinogen 2.0–4.0 g/L, CRP < 5.0 mg/L, D-dimer < 500 µg/L, leukocytes 4.0–9.0 × 10Multivariate logistic regression model for predicting the risk of intubation.sPAP—systolic pulmonary artery pressure; C—control group; S—sildenafil group. | PMC10223625 |
Background | PEx, exhaled breath | LUNG DISEASES | Surfactant phospholipid (PL) composition plays an important role in lung diseases. We compared the PL composition of non-invasively collected exhaled breath particles (PEx) with bronchoalveolar lavage (BAL) and induced sputum (ISP) at baseline and following endotoxin (LPS) challenges. | PMC10623716 |
Methods | PEx | PEx and BAL were collected from ten healthy nonsmoking participants before and after segmental LPS challenge. Four weeks later, PEx and ISP were sampled in the week before and after a whole lung LPS inhalation challenge. PL composition was analysed using mass spectrometry. | PMC10623716 | |
Results | PEx | The overall PL composition of BAL, ISP and PEx was similar, with PC(32:0) and PC(34:1) representing the largest fractions in all three sample types (baseline PC(32:0) geometric mean mol%: 52.1, 56.9, and 51.7, PC(34:1) mol%: 11.7, 11.9 and 11.4, respectively). Despite this similarity, PEx PL composition was more closely related to BAL than to ISP. For most lipids comparable inter-individual differences in BAL, ISP, and PEx were found. PL composition of PEx was repeatable. The most pronounced increase following segmental LPS challenge was detected for SM(d34:1) in BAL (0.24 to 0.52 mol%) and following inhalation LPS challenge in ISP (0.45 to 0.68 mol%). An increase of SM(d34:1) following segmental LPS challenge was also detectable in PEx (0.099 to 0.103 mol%). The inhalation challenge did not change PL composition of PEx. | PMC10623716 | |
Conclusion | PEx | Our data supports the peripheral origin of PEx. The lack of PL changes in PEx after inhalation challenge might to be due to the overall weaker response of inhaled LPS which primarily affects the larger airways. Compared with BAL, which always contains lining fluid from both peripheral lung and central airways, PEx analysis might add value as a selective and non-invasive method to investigate peripheral airway PL composition. | PMC10623716 | |
Trial registration | NCT03044327, first posted 07/02/2017. | PMC10623716 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12890-023-02718-8. | PMC10623716 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10623716 | ||
Background | PEx, exhaled breath | CHRONIC LUNG DISEASE, INFLAMMATORY RESPONSE | Alterations of surfactant phospholipid (PL) composition play an important role in acute and chronic lung diseases [There is currently a broad consent that exhaled breath particles (PEx) are formed when collapsed distal airways (~14So far, nothing is known about the PL composition of PEx at baseline and under inflammatory conditions. Therefore, we collected PEx in an experimental endotoxin challenge and compared its PL composition with BAL and ISP samples. In this two-period study, healthy volunteers underwent a segmental LPS challenge with bronchoscopies and BAL in the first part and a whole lung inhalation LPS challenge with sputum induction in the second part resulting in a clear inflammatory response in BAL and ISP [ | PMC10623716 |
Methods | PMC10623716 | |||
Study design | We included ten healthy non-smoking participants (7 male and 3 females, smoking history < 1 pack-year, mean (SD) age 38 ± 10y), with normal lung function (FEV | PMC10623716 | ||
Sample collection | FHLC, PEx | IMPACTION | PEx were collected by impaction on polytetrafluoroethylene (PTFE) membranes (FHLC 02500, Merck, Germany) using the PExA® instrument (PExA AB, Sweden). Subjects were asked to perform deep breathing maneuvers to increase the PEx emission [ | PMC10623716 |
Lipid analysis | PEx | PEx samples were extracted from the PTFE membrane using [methanol:dichloromethane:40 mM ammonium acetate(aq)] in the ratios [6:3:2], which was also used as diluent for lipids extracted from BAL and ISP. The latter were extracted using Bligh and Dyer two-phased extraction. The organic phase with lipids was recovered, evaporated under nitrogen, then solubilized in 100 µl of methanol and finally diluted to the optimal assay concentration before analysis by reverse-phase liquid chromatography – mass spectrometry (LC–MS). For further details please refer to the online supplement. | PMC10623716 | |
Statistics | Relative quantification was made by expressing the molar amount of each individual lipid as a percentage of the sum of lipids analyzed in the sample. All samples were analyzed in duplicate injections and the average was used. Relative standard deviation for duplicates had an average of 2.4% (range 0–14%) and QC samples were distributed throughout the run to assess method stability during the run. Data was log transformed and was provided as geometric mean and standard deviation. Repeated measures ANOVA was used for the comparison between visits. Multivariate analysis was made using the SIMCA software (SIMCA, Sartorius AG, Germany). Difference between sampling method were evaluated by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA). The OPLS-DA model cross validation was based on a grouping by subject id, so that all data from one subject was removed from the model and then predicted by the model. The coefficients of variation (CV) for repeated PEx measurements were calculated separately for each lipid. For this, the standard deviation of all subjects was divided by the mean value for all subjects. As the CVs were not normally distributed, we provided their medians and IQR for all lipids in the results. A value below 10 can be considered as good. No correction for multiple testing was done due to the exploratory nature of our study. | PMC10623716 | ||
Discussion | PEx | DISEASE, INFLAMMATORY RESPONSE, LEAKAGE | Our data demonstrates that, despite an overall similarity, the PL composition of PEx is more closely related to BAL than to ISP, which is in line with the proposed peripheral origin of PEx. PEx analysis was capable to show the inter-individual differences in the level of some lipids that were observed in BAL and ISP. Repetitive PEx sampling demonstrated that PL analysis in PEx yielded very reproducible data. LPS affected most targeted lipids in the challenged lobe but only the increase of SM(d34:1) could be detected in PEx, which are sampled from all lobes. The inhalation challenge showed a similar, but an overall weaker response. In addition, it most likely acted predominantly in the central airways and was therefore not detectable in PEx. The lipid composition of PEx provide further circumstantial support for the suggested mechanism for particle formation during re-opening of small peripheral airways. The peripheral lung origin of PEx could be an advantage for the study of PL composition compared to BAL, which naturally also contains portions of larger airways.We standardized our LC/MS analysis of lipids, by always using the same amount of BAL, ISP and PEx collection filters extraction fluid. Internal standard was added to these samples prior to the processing, however, this cannot account for variable PL recovery and dilution during collection of BAL and ISP or potential dilution effects due to LPS-induced leakage of fluid into the airways. Therefore, normalization of lipid data was performed. There are two major approaches. First, reference to a major or abundant lipid, e.g. PC(32:0) can be made with computation of the ratio of each lipid relative to this reference. This bears the risk, that the selected reference lipid itself is affected by the LPS challenge (or disease). Therefore, we normalized each lipid to the sum of all analysed lipids. The resulting mol% have the additional benefit, that the relative levels between BAL, ISP and PEx can be better compared. Due to the lack of normalization not all changes shown in Table S1 are comparable to those shown in Table The OPLS-DA analysis was performed to identify differences in the lipid profile between sampling methods. For this analysis we selected the BAL baseline visit, and the ISP and PEx baseline visits which were performed on the same day. There is no visit, for which baseline visits from all three methods are available and we are aware that this approach favors a closer similarity between PEx and ISP Nevertheless, our analysis showed that there was a greater similarity between BAL samples and PEx samples. With induced sputum being derived from the more central airways [PC(32:0) or dipalmitoyl-phosphatidylcholine (DPPC) is an essential PL for maintaining low surface tension of airway lining fluid. It displayed the lowest inter-individual variability, indicating that its function requires a well-defined concentration. It is known that inter-individual differences between lipid levels exist [Both segmental and inhalation LPS challenge resulted in a clearly detectable neutrophilic influx [Overall, the changes in PL composition in PEx were small. It could be argued, that PEx analysis is therefore not sensitive enough to detect LPS induced inflammatory changes. However, it needs to be kept in mind, that the segmental LPS challenge is limited to one lobe of the lung, while PEx are sampled from the small airways of all five lobes.The inhalation LPS challenge elicited only minimal PL changes in PEx and a smaller, but basically similar inflammatory response in ISP as compared to BAL from the challenged segment. It could be argued again, that PEx analysis was not sensitive enough to detect these small LPS induced changes. But it needs to be considered, that based on the inhalation maneuver and particle size of the inhaled LPS, the majority of LPS-induced changes in PL composition are probably limited to the larger airways. The small increments in PEx SM(d34:1) would then indicate that inflammation-related changes to proximal lung PL composition have to be substantial before they can be detected in samples from the distal lung. Based on our data it is tempting to conclude that the PExA analysis could even be a better tool than BAL to investigate PL composition in the peripheral lung. Not only because it is non-invasive, which will enable new study designs with more frequent sampling, but also because it samples ELF undiluted and with potentially less contaminations from larger airways as compared to BAL. | PMC10623716 |
Limitations | asthma, COPD | COPD, DISEASE, ASTHMA | Due to the complex design and long duration of the study we were only aiming to include 10 participants. Naturally we used BAL to analyse the effects of segmental LPS challenge. Due to ethical reasons, we restricted the analysis of the inhalation challenge to ISP, which due to its more central origin is not directly comparable to BAL. Therefore, our data interpretation remains speculative in some aspects and generates hypothesis which would need to be proven in different study designs. The LPS induced changes were not large in the healthy subjects. This might have been different in asthma or COPD patients, however, due to the variability in disease status between patients and over time, such a study would have required a much larger group of subjects. | PMC10623716 |
Conclusion | PEx | Taken together, this study provides evidence that the PL composition of PEx is more closely related to BAL than to ISP, and that PEx analysis is robust and apparently especially suited to investigate the PL composition in the distal lung. | PMC10623716 | |
Acknowledgements | LUNG | Dr. Anthony Suffredini, NIH Clinical Center, kindly provided Clinical Center Reference Endotoxin. This study was funded by the German Center for Lung Research. We also like to thank the Team of the Fraunhofer ITEM Clinical Airway Research for conducting the study. | PMC10623716 | |
Authors’ contributions | PEx | JMH and OH designed the study. PL, GK, AP were responsible for the lipid analysis, and PL acquired the lipid data. ACO provided the PExA instrument and was a consultant for PEx sampling and analysis. PL and OH performed the data analysis and, together with JMH, outlined the manuscript. ACO, GK and AP participated in the manuscript preparation and revised the manuscript. All authors read and approved the final version of the manuscript. | PMC10623716 | |
Funding | LUNG | Open Access funding enabled and organized by Projekt DEAL. This study was funded by the German Center for Lung Research, the Swedish Research Council for Health, Working Life and Welfare (FORTE project Nr 2017–02-064), and the European Respiratory Society (ERS) Short-Term Research Fellowship 2017 (project NR STRTF201704-00160). | PMC10623716 | |
Availability of data and materials | The datasets generated and/or analysed during the current study are not publicly available due data protection regulations but are available from the corresponding author on reasonable request. | PMC10623716 | ||
Declarations | PMC10623716 | |||
Ethics approval and consent to participate | The study was conducted in accordance with local laws, regulations and GCP guidelines (CPMP/ICH/135/95), the protocol was approved by the ethics committee of the Hannover Medical School and registered at Clinicaltrials.gov (NCT03044327, 07/02/2017) and all subjects gave their written informed consent. | PMC10623716 | ||
Consent for publication | Not applicable. | PMC10623716 | ||
Competing interests | OH, GK, AP and JMH have no competing interest. PL has stocks in PExA AB. ACO is a chairholder of PExA AB. | PMC10623716 | ||
References | PMC10623716 | |||
Background | shock | CARPAL TUNNEL SYNDROME (CTS), SHOCK | Applying radial extracorporeal shock wave therapy (R-ESWT) with LCI(local corticosteroid injection) in carpal tunnel syndrome (CTS) management is gaining momentum. The objective is to actualize the topic of this study.
| PMC10314506 |
Methods | pain, CTS | In this prospective randomized controlled trial, forty patients with mild to moderate CTS are divided into two sham- R-ESWT and R-ESWT groups subject to LCI(local corticosteroid injection). The first group received four sessions of sham-ESWT weekly, which involved sound but no energy; the second group received R-ESWT at equal intervals and were assessed for pain score (VAS score) and symptoms (GSS) baseline, 1st month, 3rd month, and 6th month.
| PMC10314506 | |
Results | pain | A considerable improvement is observed in both groups for pain at ( | PMC10314506 | |
Conclusion | CTS | The R-ESWT + LCI combined therapy course is the first line of treatment in patients with mild to moderate symptoms and leads to control and reduction of symptoms and the need for surgery, thus a primary concern in CTS treatment with an orthopedist. | PMC10314506 | |
Keywords | PMC10314506 | |||
Introduction | nerve compression, Edema, tendonitis, CTS, hypothyroidism | SHOCKS, CARPAL TUNNEL SYNDROME, EDEMA, TENDONITIS, FIRES, HYPOTHYROIDISM, PERIPHERAL NEUROPATHY | Carpal tunnel syndrome (CTS), which appears by the pressure exerted on the median nerve in the carpal tunnel, is the most common peripheral neuropathy. Edema, tendonitis, and hormonal changes like hypothyroidism and menopause are involved and manual activity can play a role in increasing nerve compression [Electrohydraulic shockwaves are the high-energy acoustic waves generated by the underwater explosion with high voltage electrodes. These shockwaves are of two types: (1) Radial shockwaves, the surface shocks, which are better for bigger treatment areas of superficial indications. Radial shockwaves are emitted through a pneumatic mechanism. Compressed air fires a projectile, which in turn strikes a metal tool called a transmitter. This impact emits a wave that is transmitted radially, dissipating its intensity as it goes through the different tissue layers. (2) Focused shockwaves, the hard shocks penetrate deeper into the tissues than Radial shockwaves and target one specific area. The Focused shockwaves are beneficial to tissues close to the bone calcifications and non-unions. This shockwave is defined as a noninvasive procedure with a sequence of single-wave pulses at (100 MPa) pressure and (G10 Nsecs) velocity over a short period of (10 Kiloseconds) time generated on the body and concentrated in a specific part of the body [ | PMC10314506 |
Methods and materials | paresthesia, thenar muscle weakness, CTS, infection, dysesthesia, Rheumatoid, Tinel, trauma | SYSTEMIC DISEASE, SCAR, PARESTHESIA, MOTOR NEUROPATHY, INFECTION | This is a prospective clinical trial run from February to August 2020 on 47 patient within the 30 to 60 age range with paresthesia, dysesthesia, and thenar muscle weakness, in Akhtar Hospital (Tehran), who tested positive for Phalen and Tinel test. The tests’ outcomes are confirmed by neurophysiological tests (EMG-NCV) for mild to moderate CTS.Severity of CTS is as follows: normal (grade 0); very mild (grade 1), CTS demonstrable only with most sensitive tests; mild (grade 2), sensory nerve conduction velocity slow on finger/wrist measurement, normal terminal motor latency; moderate (grade 3), sensory potential preserved with motor slowing, distal motor latency to abductor pollicis brevis (APB) < 6.5 ms; severe (grade 4), sensory potentials absent but motor response preserved, distal motor latency to APB < 6. 5 ms; very severe (grade 5), terminal latency to APB > 6.5 ms; extremely severe (grade 6), sensory and motor potentials effectively unrecordable (surface motor potential from APB < 0.2 mV amplitude)[The exclusion criteria consist of diagnosis of sensory and/or motor neuropathy other than CTS, previous wrist trauma, surgery for CTS, treatment with ultrasound, ESWT, or local corticosteroid injection, pregnancy, infection at the treatment site, scar burn, and systemic diseases (Rheumatoid arthritis-lupus erythema-scleroderma).The study protocol is subject to the Institutional Review Board and the Ethics Committee of Shahid Beheshti University of Medical Sciences regulations, which are explained to the participants[IR.SBMU.RETECH.REC.1399.1150]. Applying night splints and other oral medications is prohibited during the course, and all patients sign an informed consent. The subjects are labeled and randomly assigned through a random assignment sequence generated by the software to group 1 (sham -ESWT) and group 2(ESWT). | PMC10314506 |
Treatment protocol | paresthesia, numbness, weakness/clumsiness, pain | PARESTHESIA | The triamcinolone acetone (1 ml) + lidocaine (1 ml) is injected into all the patients between the palmaris longus tendon (PL) and the flexor carpi ulnaris tendon (FCU) in the wrist area once [All participants underwent clinical follow-up before beginning the treatment, at the end of the 1st, 3rd, and 6th months for VAS scores, and filled out the GSS questionnaire. This questionnaire covers the pain, numbness, paresthesia, weakness/clumsiness, and nocturnal waking [ | PMC10314506 |
Statistical analysis | pain | The statistical analyses are run in SPSS software (SPSS, Inc., Chicago, IL, USA, Version 16) with a significance level of 5% and a 95% confidence interval. Descriptive data are reported as the mean ± SD. A chi-square test is run for qualitative variables, and a student’s t test is run to compare pain and Global symptom scores between the subject groups. Repeated measurements of ANOVA are applied to compare the Visual Analog Scale score and Global Symptom score trends within and between the groups. | PMC10314506 | |
Discussion | CTS, osteoarthritis, inflammation | OSTEOARTHRITIS, DISEASES, INFLAMMATION | ESWT is a new noninvasive procedure applied extensively in recent years in treating soft tissue diseases like osteoarthritis [In many studies, nitric oxide produced by ESWT contributes to an increase in the angiogenesis growth factors’ level and inhibits inflammation through the suppressive production of pro-inflammatory cytokines [It can be deduced that this study is the first where corticosteroids are consumed as a supplementary with ESWT in patients with mild to moderate CTS; consequently, this study is subject to many limitations, like a small statistical population and short-term follow-up period. Another important restricting component here is the gender with a high count of females; if the same were males, the results might have varied. Accordingly, evaluation of the components that would indicate the possible mechanisms of ESWT and corticosteroids’ simultaneous action in future studies are of primary concern. | PMC10314506 |
Author contributions | MG and RM offer main title, and SB and MG prepared figures. MG and RM wrote the main manuscript text. All authors reviewed the manuscript. | PMC10314506 | ||
Funding | No funding. | PMC10314506 | ||
Availability of data and materials | Not applicable. | PMC10314506 | ||
Declarations | PMC10314506 | |||
Ethical approval and consent to participate | The Ethics Committee of Shahid Beheshti University of Medical Sciences regulations, which are explained to the participants [IR.SBMU.RETECH.REC.1399.1150]. | PMC10314506 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10314506 | ||
References | PMC10314506 | |||
1. Background | obesity, cardiometabolic and cognitive health outcomes [, cardiovascular disease, diabetes [A | OBESITY, CARDIOVASCULAR DISEASE, CVD, METABOLIC DISEASES, METABOLIC SYNDROME, DYSLIPIDEMIA | These authors contributed equally to this work.The impact of a Mediterranean diet on the intestinal microbiome has been linked to its health benefits. We aim to evaluate the effects of a Mediterranean diet supplemented with dairy foods on the gut microbiome in Australians at risk of cardiovascular disease. In a randomised controlled cross-over study, 34 adults with a systolic blood pressure ≥120 mmHg and with risk factors for cardiovascular disease were randomly allocated to a Mediterranean diet with 3–4 daily serves of dairy foods (Australian recommended daily intake (RDI) of 1000–1300 mg per day (MedDairy)) or a low-fat (LFD) control diet. Between each 8-week diet, participants underwent an 8-week washout period. Microbiota characteristics of stool samples collected at the start and end of each diet period were determined by 16S rRNA amplicon sequencing. MedDairy-associated effects on bacterial relative abundance were correlated with clinical, anthropometric, and cognitive outcomes. No change in the overall faecal microbial structure or composition was observed with either diet (Diet is a fundamental determinant of metabolic health and immune regulation. There is clear evidence linking the impact of dietary patterns on the development of metabolic diseases, including obesity [Long-term dietary patterns also play an important role in shaping the intestinal commensal microbiota [The Mediterranean diet (MedDiet) is characterised by high consumption of vegetables, fruits, nuts, legumes, cereals, and extra virgin olive oil (EVOO); moderate consumption of fish, eggs, poultry, dairy foods, and red wine; and low consumption of red meat (animal proteins) and discretionary foods, including cakes, sweets, and fast foods [Epidemiology-based studies have reported that higher adherence to the MedDiet is associated with lower prevalence of central obesity, dyslipidemia, metabolic syndrome, and a reduced risk of diabetes [A traditional MedDiet provides approximately 700–820 mg of calcium per day, which is below the Australian recommended daily intake (RDI) of 1000–1300 mg per day [The recommended calcium intake varies between populations, in accordance with health-related behaviours and the relative risk of calcium-related health outcomes [We undertook a MedDairy dietary intervention trial in an Australian adult population at risk of CVD to evaluate whether a MedDiet enriched with dairy products promotes beneficial cardiometabolic and cognitive health outcomes [ | PMC10459086 |
2. Materials and Methods | PMC10459086 | |||
2.1. Study Overview | CVD | CVD, CARDIOVASCULAR DISEASE | A randomised controlled trial with a 2 × 2 cross-over design was used to compare a Mediterranean diet supplemented with adequate dairy foods (MedDairy or MD) against a low-fat (LFD) control diet in individuals at risk of cardiovascular disease (CVD) (study protocol has been described previously [ | PMC10459086 |
2.2. Participants | elevated systolic blood pressure, hypertensive, CVD | CVD, CARDIOVASCULAR DISEASE | The MedDairy study recruited adults with a risk of cardiovascular disease (CVD). Inclusion criteria were age between 45 and 75 years, an elevated systolic blood pressure (SBP) of ≥120 mmHg, not on hypertensive medication, and a diagnosis of at least two of the following: overweight/obesity (body mass index, BMI ≥ 25 kg/m | PMC10459086 |
2.3. Study Intervention | Participants followed a MedDairy or LFD diet intervention for 8 weeks, separated by an 8-week washout phase where participants returned to their habitual diet. Participants were stratified by gender and age and randomly assigned to their first dietary phase (MedDairy or LFD) by a blinded independent staff member. Instructions on how to adopt each diet were provided by a dietitian at the start of each dietary phase. Detailed descriptions of the MedDairy and LFD dietary phases and instructions are as previously reported [The low-fat diet was modelled after the PREDIMED trial [ | PMC10459086 |
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