bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating Diuretics in Normal Care (EVIDENCE): a feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension
Authors: Flynn Angela , Rogers Amy , McConnachie Lewis , Barr Rebecca , Flynn Robert W. V. , Mackenzie Isla S. , MacDonald Thomas M. , Doney Alexander S. F. 
Published: March 2022

Abstract
Background
Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK.

Methods
Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies.

Results
This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch.

Conclusion
The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas.

Trial registration
ISRCTN Registry, ISRCTN46635087. Registered on 11 August 2017
eHealth supported multi-months dispensing of antiretroviral therapy: a mixed-methods preference assessment in rural Lesotho
Authors: Scherrer Ramona , Tschumi Nadine , Lejone Thabo Ishmael , Kopo Mathebe , Motaboli Lipontso , Mothobi Buoang , Amstutz Alain , Deml Michael J. , Lerotholi Malebanye , Labhardt Niklaus Daniel 
Published: March 2022

Abstract
Background
Multi-month dispensing (MMD) of antiretroviral therapy (ART) represents one approach of differentiated service delivery (DSD) aiming to improve quality and cost-effectiveness for HIV services in resource-limited settings. However, reduction in clinic visits for people living with HIV (PLWH) should go along with out-of-clinic care tailored to PLWH`s preferences and comorbidities to maintain quality of care. eHealth supported MMD offers a potential solution.

Methods
Between October 2019 and January 2020 we assessed preferences on an eHealth supported MMD package among adult PLWH attending routine ART care at a rural clinic in Lesotho using a mixed-methods approach. Participants reported their preferences among different refill and eHealth options. They were invited to test automated text messages (SMS) informing about their viral load results, an automated tuberculosis symptoms screening call and telemedical support by an expert nurse. Telemedical service comprised a call-back option if participants required any additional support and adherence counselling for closer follow-up of participants with unsuppressed viral loads. After 6 weeks, participants were followed-up to assess perception of the chosen eHealth support using a qualitative approach.

Results
Among 112 participants (median age = 43 years; 74% female), 83/112 (75%) preferred MMD for 6–12 months (median = 9 months, IQR = [5, 12]). Neither sex, age, employment, costs and time for travel to clinic, nor the duration of taking ART correlated with the MMD preference. All 17 participants attending routine viral load measurement wished to receive the result via SMS. Fifteen (19.2%) participants requested a telemedical nurse call-back during the study period. All participants with recent unsuppressed viral load (N = 13) requested telemedical adherence counselling for closer follow-up. Among 78 participants followed-up, 76 (97%) would appreciate having the call-back option in future. Seventy-five participants (67%) received and evaluated the automated symptomatic tuberculosis screening call, overall 71 (95%) appreciated it.

Conclusions
The great majority of PLWH in this study preferred 6–12 months MMD and appreciated the additional eHealth support, including viral load results via SMS, telemedical nurse consultations and automated tuberculosis symptom screening calls. eHealth supported MMD packages appear to be a promising approach for DSD models and should be assessed for clinical endpoints and cost-effectiveness in larger studies.
Cardiotoxicity risk factors with immune checkpoint inhibitors
Authors: Brumberger Zachary L. , Branch Mary E. , Klein Max W , Seals Austin , Shapiro Michael D. , Vasu Sujethra 
Published: March 2022

Abstract
Background
Checkpoint-inhibitor immunotherapies have had a profound effect in the treatment of cancer by inhibiting down-regulation of T-cell response to malignancy. The cardiotoxic potential of these agents was first described in murine models and, more recently, in numerous clinical case reports of pericarditis, myocarditis, pericardial effusion, cardiomyopathy, and new arrhythmias. The objective of our study was to determine the frequency of and associated risk factors for cardiotoxic events in patients treated with immune checkpoint inhibitors.

Methods
Medical records of patients who underwent immunotherapy with durvalumab, ipilimumab, nivolumab, and pembrolizumab at Wake Forest Baptist Health were reviewed. We collected retrospective data regarding sex, cancer type, age, and cardiovascular disease risk factors and medications. We aimed to identify new diagnoses of heart failure, atrial fibrillation, ventricular fibrillation/tachycardia, myocarditis, and pericarditis after therapy onset. To assess the relationship between CVD risk factors and the number of cardiac events, a multivariate model was applied using generalized linear regression. Incidence rate ratios were calculated for every covariate along with the adjusted P-value. We applied a multivariate model using logistic regression to assess the relationship between CVD risk factors and mortality. Odds ratios were calculated for every covariate along with the adjusted P-value. Adjusted P-values were calculated using multivariable regression adjusting for other covariates.

Results
Review of 538 medical records revealed the following events: 3 ventricular fibrillation/tachycardia, 12 pericarditis, 11 atrial fibrillation with rapid ventricular rate, 0 myocarditis, 8 heart failure. Significant risk factors included female gender, African American race, and tobacco use with IRR 3.34 (95% CI 1.421, 7.849; P = 0.006), IRR 3.39 (95% CI 1.141, 10.055; P = 0.028), and IRR 4.21 (95% CI 1.289, 13.763; P = 0.017) respectively.

Conclusions
Our study revealed 34 significant events, most frequent being pericarditis (2.2%) and atrial fibrillation (2.0%) with strongest risk factors being female gender, African American race, and tobacco use. Patients who meet this demographic, particularly those with planned pembrolizumab treatment, may benefit from early referral to a cardio-oncologist. Further investigation is warranted on the relationship between CTLA-4 and PD-L1 expression and cardiac adverse events with ICIs, particularly for these subpopulations.
Is there any difference between the obstetric and perinatal complications of pregnancy in patients with and without repeated implantation failure in fresh and frozen-thawed embryo transfer cycles?
Authors: Dashti Saeideh , Mirzaei Maryam , Eftekhar Maryam , Mangoli Esmat 
Published: March 2022

AbstractBackgroundRepeated implantation failure (RIF) is the main challenge in assisted reproduction; the present study aimed to compare the obstetric and perinatal outcomes between RIF and control patients who experienced a successful pregnancy after fresh embryo transfer (ET) or frozen-thawed embryo transfer (FET) cycles. Data were obtained from 1150 women experiencing embryo transfer(s), consisting of 720 fresh ET and 430 FET cycles, at the Research and Clinical Center for Infertility, Yazd, Iran. The 370 women, in total, reached chemical pregnancies and finally 321 cases in fresh ET (n=216) and FET (n=105) cycles with singleton deliveries divided into two groups of control and RIF according to the number of last implantation failures. Then, the rate of obstetric and prenatal complications was compared between two groups in fresh ET and FET cycles.ResultsThe results showed a higher abortion rate in the RIF group compared to the control group in fresh and FET cycles. In the assessment of the data from the cases with singleton pregnancies in fresh and FET cycles, the results showed almost similar obstetric and perinatal complications in the patients of RIF and control groups. Although the rates of some complications like vaginal bleeding, PROM, preterm delivery, and NICU administration were higher in the RIF patients, these were not significant (P> 0.05).ConclusionThere was some variation in the normal rates of obstetric and perinatal outcomes between RIF patients compared to control. But, it seems necessary to run studies on more patients to endorse this conclusion.
Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma
Authors: Grimm Marc-Oliver , Schmitz-Dräger Bernd Jürgen , Zimmermann Uwe , Grün Christine Barbara , Baretton Gustavo Bruno , Schmitz Marc , Foller Susan , Leucht Katharina , Schostak Martin , Zengerling Friedemann , Schumacher Ulrike , Loidl Wolfgang , Meran Johannes 
Published: March 2022

PURPOSE Several anti–programmed cell death (ligand)-1 (PD-[L]1) immune checkpoint inhibitors are approved in advanced/metastatic urothelial carcinoma (mUC). Recently, improved activity of an anti–PD-1/anticytotoxic T-cell lymphocyte-4 (CTLA-4) combination versus anti–PD-1 monotherapy has been reported. We report a response-based approach starting treatment with nivolumab monotherapy with nivolumab/ipilimumab as immunotherapeutic boost. METHODS After four doses of nivolumab induction, responders continued with nivolumab maintenance therapy. Patients with stable/progressive disease received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks for 2 doses followed by nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 2 doses, if not responding to the initial boost. Responders to boosts continued with nivolumab maintenance. Between July 2017 and April 2019, 86 patients were enrolled. The median follow-up is 7.7 months. The primary end point is objective response rate (ORR) per RECIST1.1. Secondary end points include efficacy of nivolumab induction, remission rate with nivolumab/ipilimumab boosts, overall survival, and safety. RESULTS Of all patients, 42, 39, and five were first- (1L), second- (2L), and third-line (3L), respectively. The median age was 68 years. The ORR with nivolumab monotherapy (assessed at week 8) was 29% in 1L and 23% in 2/3L, respectively. Forty-one patients received early (week 8) and 11 received later nivolumab/ipilimumab boosts. ORRs with nivolumab with or without nivolumab/ipilimumab (best overall response) were 45% and 27% in 1L and 2/3L, respectively. In 1L, 7 of 17 patients receiving boosts at week 8 improved, compared with 2 of 24 in 2/3L. CONCLUSION The tailored approach of TITAN-TCC shows meaningful clinical activity supporting dual checkpoint inhibition in 1L mUC. However, starting therapy with nivolumab exclusively appears inadequate given the aggressive nature of mUC. In 2/3L, nivolumab/ipilimumab boosts with escalating ipilimumab dose did not improve efficacy outcomes versus nivolumab monotherapy. An independent 2L cohort of TITAN-TCC receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 4 doses is ongoing.
Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders
Authors: Oheim Ralf , Tsourdi Elena , Seefried Lothar , Beller Gisela , Schubach Max , Vettorazzi Eik , Stürznickel Julian , Rolvien Tim , Ehmke Nadja , Delsmann Alena , Genest Franca , Krüger Ulrike , Zemojtel Tomasz , Barvencik Florian , Schinke Thorsten , Jakob Franz , Hofbauer Lorenz C , Mundlos Stefan , Kornak Uwe 
Published: March 2022

Abstract

Context
Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs).

Objective
We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs and at defining clinical criteria for predicting monogenic forms.

Methods
Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score &lt; -2.0 and/or pathological fractures. After exclusion of secondary causes or unequivocal clinical/biochemical hallmarks of monogenic LBMDs, all participants were genotyped by targeted next-generation sequencing.

Results
In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (&gt; 2), and a high normal body mass index (BMI). In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD (eg, in LRP5) were overrepresented.

Conclusion
The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.
“The Transgender Craze Seducing Our [Sons]”; or, All the Trans Guys Are Just Dating Each Other
Authors: Adair Cassius , Aizura Aren 
Published: March 2022

Abstract
Recent antitrans discourses have critiqued trans masculinity in particular as a site of social panic and contagion for proto-trans adolescents. In extreme cases, this is framed as a seduction. Turning “seduction” from a social danger to a benefit, this essay theorizes masc4masc t4t erotics as a type of contagious gendering. The authors discuss the coming into identity that takes place via desire for trans people, including a sexual urge toward or attraction to people who look like the person one wants to be. They examine the cultural representations of ftm4ftm erotics, and what it means to think about these relationships now, in the face of their new emergence as cultural threat. The authors make a close reading of 2000s-era erotica and pornography to argue that Daddy/boy and group sex dynamics can be read as gender labor, affective and intersubjective work that produces gender and that in t4t erotics works within a framework of differentiated reciprocity. The article concludes by gesturing toward future possibilities for trans masc 4 trans masc politics and pleasures.
Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells
Authors: Siow Wei Xiong , Kabiri Yaschar , Tang Rachel , Chao Yu-Kai , Plesch Eva , Eberhagen Carola , Flenkenthaler Florian , Fröhlich Thomas , Bracher Franz , Grimm Christian , Biel Martin , Zischka Hans , Vollmar Angelika M. , Bartel Karin 
Published: March 2022

ABSTRACTLiver cancers, including hepatocellular carcinoma (HCC), are the second leading cause of cancer death worldwide, and novel therapeutic strategies are still highly needed. Recently, the endolysosomal cation channel TRPML1 (also known as MCOLN1) has gained focus in cancer research because it represents an interesting novel target. We utilized the recently developed isoform-selective TRPML1 activator ML1-SA1 and the CRISPR/Cas9 system to generate tools for overactivation and loss-of-function studies on TRPML1 in HCC. After verification of our tools, we investigated the role of TRPML1 in HCC by studying proliferation, apoptosis and proteomic alterations. Furthermore, we analyzed mitochondrial function in detail by performing confocal and transmission electron microscopy combined with SeahorseTM and Oroboros® functional analysis. We report that TRPML1 overactivation mediated by a novel, isoform-selective small-molecule activator induces apoptosis by impairing mitochondrial function in a Ca2+-dependent manner. Additionally, TRPML1 loss-of-function deregulates mitochondrial renewal, which leads to proliferation impairment. Thus, our study reveals a novel role for TRPML1 as regulator of mitochondrial function and its modulators as promising molecules for novel therapeutic options in HCC therapy.
Sulfonated and Fluorinated Aromatic Terpolymers as Proton Conductive Membranes: Synthesis, Structure, and Properties
Authors: Kumao Ren , Miyatake Kenji 
Published: March 2022

Abstract
We designed and synthesized a series of sulfonated terpolymers, SPP-PQP and SPP-BQP, containing sulfophenylene, quinquephenylene (QP) and perfluoroalkylene (PAF) or hexafluoroisopropylidene (BAF) groups whose compositions were optimized to achieve high-performance proton conductive membranes. In both series, the terpolymers were obtained as high-molecular-weight (Mn = 19.0–32.9 kDa, Mw = 99.9–198 kDa) providing bendable and transparent membranes with supposed ion exchange capacity (IEC) values (2.41–2.68 meq. g−1) by solution casting. SPP-PQP membranes exhibited higher water uptake, higher proton conductivity, and larger strain at break with increasing the PAF composition. In contrast, the membrane properties were less sensitive to the composition in the SPP-BQP membranes. Among the terpolymer membranes investigated, SPP-PQP50 showed the best-balanced properties in terms of low water uptake, high proton conductivity, and high mechanical properties probably because highly hydrophobic aliphatic PAF and more rigid QP groups both contributed to those relevant properties. Overall, the combination of different hydrophobic components in the terpolymers was effective in improving the properties of proton conductive membranes, that could not be achieved with the corresponding copolymer membranes.
The feasibility of an objective measure of the parent-child relationship in health visiting practice: assessment of the Maternal Postnatal Attachment Scale
Authors: Dunn Abigail , Bird Philippa K , Endacott Charlotte , Bywater Tracey , Howes Joanna , Dickerson Josie 
Published: March 2022

Background: Positive parent infant relationships are key to achieving long term child outcomes. Identifying parents who may need support is difficult because of a lack of robust assessment tools. Working in partnership with health services we piloted the Maternal Postnatal Attachment Scale (MPAS) in a deprived, multi-ethnic urban community in Bradford, UK. The pilot aimed to assess the clinical utility of MPAS to identify need for support: Was it administered to a representative group of women? Is MPAS valid for this population? Methods: Data were linked to a cohort study in the pilot area (Born in Bradford’s Better Start - BiBBS). Chi Square tests assessed sample representativeness (age, ethnicity, parity, English language, education, deprivation). Exploratory factor analysis explored MPAS’ validity. Results: 563 women in BiBBS were eligible, 210 (37%) completed MPAS. No differences were found between completers and non-completers, suggestive of a representative sample. In total, 336 women completed MPAS in the pilot. MPAS had ceiling effects and a satisfactory factor structure could not be identified, indicating poor psychometric properties Conclusions: Health visitors were successful in administering MPAS to a representative sample, but poor psychometric robustness indicates that MPAS is unsuitable for routine use in this setting. A gap for such a measure remains.
Non-diabetic hyperglycaemia: helping to prevent progression to type 2 diabetes
Authors: Stewart Martha 
Published: March 2022

Non-diabetic hyperglycaemia is considered to be a stage in the development of type 2 diabetes. Martha Stewart discusses how nurses working in general practice can help to prevent progression to type 2 diabetes Non-diabetic hyperglycaemia (NDH) is the current preferred term for describing glucose dysregulation that is neither diabetes nor normal. NDH is considered to be a stage in the development of type 2 diabetes and so is typically characterised by hyperglycaemia and insulin resistance and also the potential burden of long-term cardiovascular complications including eye problems, kidney disease and foot disease. The aims when managing NDH are the prevention of cardiovascular morbidity and mortality, delay/prevention of type 2 diabetes, monitoring for the development of type 2 diabetes in order to ensure prompt diagnosis and implementation of appropriate therapy for type 2 diabetes. The risk of progression from NDH to type 2 diabetes can be reduced by lifestyle interventions.