bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian updating: increasing sample size during the course of a study
Authors: Moerbeek Mirjam 
Published: July 2021

AbstractBackgroundA priori sample size calculation requires an a priori estimate of the size of the effect. An incorrect estimate may result in a sample size that is too low to detect effects or that is unnecessarily high. An alternative to a priori sample size calculation is Bayesian updating, a procedure that allows increasing sample size during the course of a study until sufficient support for a hypothesis is achieved. This procedure does not require and a priori estimate of the effect size. This paper introduces Bayesian updating to researchers in the biomedical field and presents a simulation study that gives insight in sample sizes that may be expected for two-group comparisons.MethodsBayesian updating uses the Bayes factor, which quantifies the degree of support for a hypothesis versus another one given the data. It can be re-calculated each time new subjects are added, without the need to correct for multiple interim analyses. A simulation study was conducted to study what sample size may be expected and how large the error rate is, that is, how often the Bayes factor shows most support for the hypothesis that was not used to generate the data.ResultsThe results of the simulation study are presented in a Shiny app and summarized in this paper. Lower sample size is expected when the effect size is larger and the required degree of support is lower. However, larger error rates may be observed when a low degree of support is required and/or when the sample size at the start of the study is small. Furthermore, it may occur sufficient support for neither hypothesis is achieved when the sample size is bounded by a maximum.ConclusionsBayesian updating is a useful alternative to a priori sample size calculation, especially so in studies where additional subjects can be recruited easily and data become available in a limited amount of time. The results of the simulation study show how large a sample size can be expected and how large the error rate is.
Severe restless legs syndrome in a family with Alport syndrome
Authors: Sparasci Davide , Rossinelli Andrea , Ferri Raffaele , Cippà Pietro , Rinaldi Andrea , Manconi Mauro 
Published: July 2021

Abstract
Background
Restless legs syndrome (RLS) is a common sleep-related movement disorder characterized by an urge to move the legs during inactivity, especially at evening-night. RLS is highly prevalent in patients with kidney failure and have an impact on quality of life, mood, sleep quality and overall on compliance to the dialysis. Alport syndrome (AS) is a rare inherited disease, predominantly X-linked, secondary to mutations in genes encoding α3, α4 or α5 chains of type IV collagen, and characterized by hematuria, chronic kidney disease, neurosensory deafness, and lenticonus.

Case presentation
Here we describe a family with a combination of X-linked AS and severe RLS accompanied by periodic limb movements during sleep (PLMS). In the first patient we identified, RLS was complicated by a paradoxical response to dopamine agonists named “augmentation”, leading to sleep disruption, hallucinations and five peritoneal perforations during the peritoneal dialysis due to the difficulty to rest still. Therapeutic adjustments and renal transplantation improved RLS and PLMS. In two brothers, severe RLS prevented a compliance with hemodialysis. Female family members carrying the mutation were also affected by RLS, while those without the mutations were RLS-free.

Conclusions
RLS has not been reported earlier in association with AS, but the peculiar combinations observed in this family will stimulate further clinical studies and motivate nephrologists to seek for RLS symptoms and sleep disturbances in AS patients.
A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation
Authors: Nishii Yo-suke , Noto Yu-ichi , Yasuda Rei , Kitaoji Takamasa , Ashida Shinji , Tanaka Eijirou , Minami Narihiro , Nishino Ichizo , Mizuno Toshiki 
Published: July 2021

Abstract
Background
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene.

Case presentation
A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD.

Conclusion
We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.
Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer
Authors: Brock Kristian , Homer Victoria , Soul Gurjinder , Potter Claire , Chiuzan Cody , Lee Shing 
Published: July 2021

Abstract
Background
The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies.

Methods
We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions.

Results
We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption.

Conclusions
Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.
Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study)
Authors: Azim Lumbini , Hindmarch Paul , Browne Georgiana , Chadwick Thomas , Clare Emily , Courtney Paul , Dixon Lyndsey , Duffelen Nichola , Fouweather Tony , Geddes John R. , Goudie Nicola , Harvey Sandy , Helter Timea , Holstein Eva-Maria , Martin Garry , Mawson Phil , McCaffery Jenny , Morriss Richard , Simon Judit , Smith Daniel , Stokes Paul R. A. , Walker Jenn , Weetman Chris , Wolstenhulme Faye , Young Allan H. , Watson Stuart , McAllister-Williams R. Hamish 
Published: July 2021

Abstract
Background
Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson’s Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed.

Methods
The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology – Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures.

Trial registration
ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939
Protocol Version: 04-FEB-2021, Version 9.0.
Prevalence and factors associated with covert contraceptive use in Kenya: a cross-sectional study
Authors: Akoth Catherine , Oguta James Odhiambo , Gatimu Samwel Maina 
Published: July 2021

Abstract
Background
Family planning (FP) is a key intervention for preventing unplanned pregnancies, unsafe abortions, and maternal death. Involvement of both women and their partners promotes contraceptive acceptance, uptake and continuation, couple communication and gender-equitable attitude. Partner involvement is a key strategy for addressing about 17.5% of the unmet needs in FP in Kenya. This study assessed the prevalence and factors associated with covert contraceptive use (CCU) in Kenya.

Methods
We used data from the sixth and seventh rounds of the performance monitoring for accountability surveys. We defined CCU as “the use of contraceptives without a partner’s knowledge”. We used frequencies and percentages to describe the sample characteristics and the prevalence of CCU and assessed the associated factors using bivariate and multivariable logistic regressions.

Results
The prevalence of CCU was 12.2% (95% CI: 10.4–14.2%); highest among uneducated (22.3%) poorest (18.2%) and 35–49 years-old (12.8%) women. Injectables (53.3%) and implants (34.6%) were the commonest methods among women who practice CCU. In the bivariate analysis, Siaya county, rural residence, education, wealth, and age at sexual debut were associated with CCU. On adjusting for covariates, the odds of CCU were increased among uneducated women (aOR 3.79, 95% CI 1.73–8.31), women with primary education (aOR 1.86, 95% CI 1.06–3.29) and those from the poorest (aOR 2.67, 95% CI 1.61–4.45), poorer (aOR 1.79, 95% CI 1.05–3.04), and middle (aOR 2.40, 95% CI 1.52–3.78) household wealth quintiles and were reduced among those with 2–3 (aOR 0.49, 95% CI 0.33–0.72) and ≥ 4 children (aOR 0.62, 95% CI 0.40–0.96). Age at sexual debut (aOR 0.94, 95% CI 0.89–0.99) reduced the odds of CCU.

Conclusion
About one in 10 married women in Kenya use contraceptives covertly, with injectables and implants being the preferred methods. Our study highlights a gap in partner involvement in FP and calls for efforts to strengthen their involvement to increase contraceptive use in Kenya while acknowledging women’s right to make independent choices.
Reach, engagement and effectiveness of in-person and online lifestyle change programs to prevent diabetes
Authors: Golovaty Ilya , Wadhwa Sandeep , Fisher Lois , Lobach Iryna , Crowe Byron , Levi Ronli , Seligman Hilary 
Published: July 2021

Abstract
Background
COVID-19 has accelerated interest in and need for online delivery of healthcare. We examined the reach, engagement and effectiveness of online delivery of lifestyle change programs (LCP) modelled after the Diabetes Prevention Program (DPP) in a multistate, real-world setting.

Methods
Longitudinal, non-randomized study comparing online and in-person LCP in a large multistate sample delivered over 1 year. Sample included at-risk adults (n = 26,743) referred to online (n = 9) and in-person (n = 11) CDC-recognized LCP from a multi-state registry (California, Florida and Colorado) between 2015 and 2018. The main outcome was effectiveness (proportion achieving > 5% weight loss) at one-year. Our secondary outcomes included reach (proportion enrolled among referred) and engagement (proportion ≥ 9 sessions by week 26). We used logistic regression modelling to assess the association between participant- and setting -level characteristics with meaningful weight loss.

Results
Online LCP effectiveness was lower, with 23% of online participants achieving > 5% weight loss, compared with 35% of in-person participants (p < 0.001). More adults referred to online programs enrolled (56% vs 51%, p < 0.001), but fewer engaged at 6-months (attendance at ≥9 sessions 46% vs 66%, p < 0.001) compared to in-person participants.

Conclusions
Compared to adults referred to in-person LCP, those referred to online LCP were more likely to enroll and less likely to engage. Online participants achieved modest meaningful weight loss. Online delivery of LCP is an attractive strategy to deliver and scale DPP, particularly with social distancing measures currently in place. However, it is unclear how to optimize delivery models for maximal impact given trade-offs in reach and effectiveness.
Amino terminal recognition by a CCR6 chemokine receptor antibody blocks CCL20 signaling and IL-17 expression via β-arrestin
Authors: Gómez-Melero Sara , García-Maceira Fé Isabel , García-Maceira Tania , Luna-Guerrero Verónica , Montero-Peñalvo Gracia , Túnez-Fiñana Isaac , Paz-Rojas Elier 
Published: July 2021

Abstract
Background
CCR6 chemokine receptor is an important target in inflammatory diseases. Th17 cells express CCR6 and a number of inflammatory cytokines, including IL-17 and IL-22, which are involved in the propagation of inflammatory immune responses. CCR6 antagonist would be a potential treatment for inflammatory diseases such as psoriasis or rheumatoid arthritis. The aim of this study is to develop an antagonistic monoclonal antibody (mAb) against human CCR6 receptor (hCCR6).

Results
We generate monoclonal antibodies against hCCR6 immunizing Balb/c mice with hCCR6 overexpressing cells. The antibodies were tested by flow cytometry for specific binding to hCCR6, cloned by limiting dilution and resulted in the isolation and purification monoclonal antibody 1C6. By ELISA and flow cytometry, was determined that the antibody obtained binds to hCCR6 N-terminal domain. The ability of 1C6 to neutralize hCCR6 signaling was tested and we determined that 1C6 antibody were able to block response in β-arrestin recruitment assay with IC50 10.23 nM, but did not inhibit calcium mobilization. In addition, we found in a chemotaxis assay that 1C6 reduces the migration of hCCR6 cells to their ligand CCL20. Finally, we determined by RT-qPCR that the expression of IL-17A in Th17 cells treated with 1C6 was inhibited.

Conclusions
In the present study, we applied whole cell immunization for successfully obtain an antibody that is capable to neutralize hCCR6 signaling and to reduce hCCR6 cells migration and IL-17 expression. These results provide an efficient approach to obtain therapeutic potential antibodies in the treatment of CCR6-mediated inflammatory diseases.
Premenstrual dysphoric disorder is associated with the longer length from clitoris to urethra
Authors: Li Zheng , Xu Meng-jiao , Jin Ying , Zhu Bing-gen 
Published: July 2021

Abstract
Background
Premenstrual dysphoric disorder (PMDD) is a common, recently recognized, psychiatric condition among reproductive women, reflecting abnormal responsivity to ovarian steroids. Moreover, the potential organizational effect of prenatal sex hormones during PMDD has got attentions, but there have been considerably less of researches on this topic. The aim of this research was to investigate the possible role of prenatal androgen in the PMDD.

Methods
Anogenital distance (AGD), the distance between a woman’s clitoris and her urethral meatus (CUMD), left and right 2D:4D ratios were measured in 77 subjects (25 patients with PMDD), as these anthropometric indicators are considered to indirectly reflect prenatal androgen exposures in utero.

Results
Patients with PMDD had a longer CUMD than controls (25.03 ± 4.73 vs. 22.07 ± 4.30, P = 0.008), while there were no significant difference between PMDD group and control group in the AGD and right and left 2D:4D ratios.

Conclusion
Atypical high prenatal androgen exposure might predispose individuals to be susceptible to PMDD.
Patient experiences of waiting times in standardised cancer patient pathways in Norway – a qualitative interview study
Authors: Solbjør Marit , Sand Kari , Ervik Bente , Melby Line 
Published: July 2021

Abstract
Objective
Standardised cancer patient pathways (CPP) are implemented within cancer care with an aim to ensure standardised waiting times for diagnosis and treatment. This article investigates how patients in Norway experience waiting times within a CPP.

Methods
Qualitative semi-structured interviews with 19 patients who had been through CPP for breast cancer, prostate cancer or malignant melanoma in Norway.

Results
Few patients knew about the term CPP but trusted that waiting times were standardised to decrease mortality. Their experiences of waiting depended on their expectations as much as the period they waited. Patients generally felt safe about the timing of treatment, but not all expectations of a rapid response from health services were met. Short waiting times were interpreted as a sign of urgency, and a change of pace between urgent action and prolonged periods of waiting were disturbing.

Conclusions
Patients are comforted by knowing they are within a structured CPP that ensures rapid diagnosis and start of treatment. CPPs still need to be improved to avoid delays, allow for adaptions to patient needs, and include more information to avoid stress.
Health system gaps in cardiovascular disease prevention and management in Nepal
Authors: Shrestha Archana , Maharjan Rashmi , Karmacharya Biraj Man , Bajracharya Swornim , Jha Niharika , Shrestha Soniya , Aryal Anu , Baral Phanindra Prasad , Bhatt Rajendra Dev , Bhattarai Sanju , Bista Durga , Citrin David , Dhimal Meghnath , Fitzpatrick Annette L. , Jha Anjani Kumar , Karmacharya Robin Man , Mali Sushmita , Neupane Tamanna , Oli Natalia , Pandit Rajan , Parajuli Surya Bahadur , Pradhan Pranil Man Singh , Prajapati Dipanker , Pyakurel Manita , Pyakurel Prajjwal , Rai Binuka Kulung , Sapkota Bhim Prasad , Sapkota Sujata , Shrestha Abha , Shrestha Anmol Purna , Shrestha Rajeev , Sharma Guna Nidhi , Sharma Sumitra , Spiegelman Donna , Suwal Punya Shori , Thapa Bobby , Vaidya Abhinav , Xu Dong , Yan Lijing L. , Koju Rajendra 
Published: July 2021

Abstract
Background
Cardiovascular diseases (CVDs) are the leading cause of deaths and disability in Nepal. Health systems can improve CVD health outcomes even in resource-limited settings by directing efforts to meet critical system gaps. This study aimed to identify Nepal’s health systems gaps to prevent and manage CVDs.

Methods
We formed a task force composed of the government and non-government representatives and assessed health system performance across six building blocks: governance, service delivery, human resources, medical products, information system, and financing in terms of equity, access, coverage, efficiency, quality, safety and sustainability. We reviewed 125 national health policies, plans, strategies, guidelines, reports and websites and conducted 52 key informant interviews. We grouped notes from desk review and transcripts’ codes into equity, access, coverage, efficiency, quality, safety and sustainability of the health system.

Results
National health insurance covers less than 10% of the population; and more than 50% of the health spending is out of pocket. The efficiency of CVDs prevention and management programs in Nepal is affected by the shortage of human resources, weak monitoring and supervision, and inadequate engagement of stakeholders. There are policies and strategies in place to ensure quality of care, however their implementation and supervision is weak. The total budget on health has been increasing over the past five years. However, the funding on CVDs is negligible.

Conclusion
Governments at the federal, provincial and local levels should prioritize CVDs care and partner with non-government organizations to improve preventive and curative CVDs services.
The impacts of family physician plan and health transformation plan on hospitalization rates in Iran: an interrupted time series
Authors: Rouhani Samad , Esmaeili Reza , Yazdani Charati Jamshid , Khandehroo Masoud 
Published: July 2021

Abstract
Background
Low and middle income countries has recently implemented various reforms toward Universal Health Coverage (UHC). This study aims to assess the impact of Family Physician Plan (FPP) and Health Transformation Plan (HTP) on hospitalization rate in Iran.

Methods
We conducted an Interrupted Time Series (ITS) design. The data was monthly hospitalization of Mazandaran province over a period of 7 years. Segmented regression analysis was applied in R version 3.6.1.

Results
A decreasing trend by − 0.056 for every month was found after implementation of Family Physician Plan, but this was not significant. Significant level change was appeared at the beginning of Health Transformation Plan and average of hospitalization rate increased by 1.04 (P < 0.001). Also hospitalization trend increased significantly nearly 0.09 every month in period after Health Transformation Plan (P < 0.001).

Conclusions
Family physician created a decreasing trend for hospitalization in urban area of Mazandaran province in Iran. HTP with lower user fee in governmental public hospitals and clinics as well as fee-for-service mechanisms, stimulated both level and trend changes in hospital admissions. Some integrated health policy is required to optimize the implementation of diverse simultaneous reforms in low and middle-income countries.