bluuebunny/crossref_metadata_2025 huggingface dataset:
Immediate implantation of ultrafine fiber slow-release system based on cell electrospinning to induce osteogenesis of mesenchymal stem cells
Authors: Lu Tao , Yang Long , Li Zhuoyang , Liu Yin , Xu Shun'en , Ye Chuan
Published: December 2023

This study presents the development and evaluation of a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB) ultrafine fiber slow-release system for in vivo osteogenic induction of human umbilical cord mesenchymal stem cells (HUCMSCs). Utilizing dual-nozzle and cell electrospinning techniques, the system encapsulates L-ascorbic acid-2-phosphate magnesium (ASP), β-glycerophosphate sodium and dexamethasone (DEX) within the fibers, ensuring sustained osteogenic differentiation. The scaffold’s morphology, characterization, hydrophilicity, mechanical properties and cellular behavior were examined. Immediate subcutaneous implantation in rabbits was conducted to observe its ectopic osteogenic induction effect. Successfully fabricated P34HB ultrafine fiber slow-release system. Characterization confirmed the uniform distribution of HUCMSCs and inducing components within the scaffold, with no chemical reactions affecting the active components. In vitro tests showcased a prolonged release of DEX and ASP, while biocompatibility assays highlighted the scaffold’s suitability for cellular growth. Alizarin Red, type I collagen, and osteopontin (OPN) staining verified the scaffold’s potent osteogenic induction effect on HUCMSCs. Notably, immediate implantation into New Zealand White rabbits led to significant new bone formation within 8 weeks. These findings underscore the system’s potential for immediate in vivo implantation without prior in vitro induction, marking a promising advancement in bone tissue engineering.
State of the science and recommendations for using wearable technology in sleep and circadian research
Authors: de Zambotti Massimiliano , Goldstein Cathy , Cook Jesse , Menghini Luca , Altini Marco , Cheng Philip , Robillard Rebecca
Published: December 2023

Wearable sleep-tracking technology is of growing use in the sleep and circadian fields, including for applications across other disciplines, inclusive of a variety of disease states. Patients increasingly present sleep data derived from their wearable devices to their providers and the ever-increasing availability of commercial devices and new-generation research/clinical tools has led to the wide adoption of wearables in research, which has become even more relevant given the discontinuation of the Philips Respironics Actiwatch. Standards for evaluating the performance of wearable sleep-tracking devices have been introduced and the available evidence suggests that consumer-grade devices exceed the performance of traditional actigraphy in assessing sleep as defined by polysomnogram. However, clear limitations exist, for example, the misclassification of wakefulness during the sleep period, problems with sleep tracking outside of the main sleep bout or nighttime period, artifacts, and unclear translation of performance to individuals with certain characteristics or comorbidities. This is of particular relevance when person-specific factors (like skin color or obesity) negatively impact sensor performance with the potential downstream impact of augmenting already existing healthcare disparities. However, wearable sleep-tracking technology holds great promise for our field, given features distinct from traditional actigraphy such as measurement of autonomic parameters, estimation of circadian features, and the potential to integrate other self-reported, objective, and passively recorded health indicators. Scientists face numerous decision points and barriers when incorporating traditional actigraphy, consumer-grade multi-sensor devices, or contemporary research/clinical-grade sleep trackers into their research. Considerations include wearable device capabilities and performance, target population and goals of the study, wearable device outputs and availability of raw and aggregate data, and data extraction, processing, and analysis. Given the difficulties in the implementation and utilization of wearable sleep-tracking technology in real-world research and clinical settings, the following State of the Science review requested by the Sleep Research Society aims to address the following questions. What data can wearable sleep-tracking devices provide? How accurate are these data? What should be taken into account when incorporating wearable sleep-tracking devices into research? These outstanding questions and surrounding considerations motivated this work, outlining practical recommendations for using wearable technology in sleep and circadian research.
Genetic Manipulation Approaches to Enhance the Clinical Application of NK Cell-Based Immunotherapy
Authors: Maia Andreia , Tarannum Mubin , Romee Rizwan
Published: December 2023

Natural killer (NK) cells are a subset of cytotoxic lymphocytes within the innate immune system. While they are naturally cytotoxic, genetic modifications can enhance their tumor-targeting capability, cytotoxicity, persistence, tumor infiltration, and prevent exhaustion. These improvements hold the potential to make NK-cell-based immunotherapies more effective in clinical applications. Currently, several viral and non-viral technologies are used to genetically modify NK cells. For nucleic acid delivery, non-viral methods such as electroporation, lipid nanoparticles, lipofection, and DNA transposons have gained popularity in recent years. On the other hand, viral methods including lentivirus, gamma retrovirus, and adeno-associated virus, remain widely used for gene delivery. Furthermore, gene editing techniques such as clustered regularly interspaced short-palindromic repeats-based, zinc finger nucleases, and transcription activator-like effector nucleases are the pivotal methodologies in this field. This review aims to provide a comprehensive overview of chimeric antigen receptor (CAR) arming strategies and discuss key gene editing techniques. These approaches collectively aim to enhance NK cell/NK cell CAR-based immunotherapies for clinical translation.
Evaluation of a microencapsulated form of zinc oxide on weanling pig growth performance, fecal zinc excretion, and small intestinal morphology
Authors: Dahmer Payton L , Jones Cassandra K , Ferreyra Franco M
Published: December 2023

A total of 300 pigs (DNA 200 × 400; initially 6.0 ± 0.08 kg body weight [BW]) were used in a 42-d study to evaluate a microencapsulated form of zinc oxide. At weaning, pigs were randomly allocated to pens, and pens were randomly assigned to dietary treatments with 5 pigs per pen and 12 pens per treatment. Dietary treatments were 1) negative control (CON; standard nursery diet containing 110 ppm Zn in the form of zinc sulfate from trace mineral premix); 2) control diet with 400 ppm added Zn from ZnO included in phases 1 and 2 (Low-ZnO); 3) control diet with 3,000 ppm added Zn from ZnO included in phase 1 and 2,000 ppm added Zn from ZnO included in phase 2 (High-ZnO); 4) control diet with 400 ppm added Zn from microencapsulated ZnO included in phases 1 and 2 (Low-MZnO; Vetagro S.p.A., Reggio Emilia, Italy); 5) control diet with 3,000 ppm added Zn from microencapsulated ZnO in phase 1 and 2,000 ppm added Zn from microencapsulated ZnO in phase 2 (high-MZnO; Vetagro S.p.A., Reggio Emilia, Italy). On days 10 and 28, fecal samples from 2 pigs per pen were collected for fecal Zn concentrations, and on day 28, 30 pigs (n = 6) were euthanized, and small intestinal tissues were collected to evaluate morphology. For the entire treatment period (days 0 to 28) there was no evidence of differences in average daily gain (ADG), average daily feed intake (ADFI), or G:F (P > 0.05). During the common phase 3 (days 28 to 42) pigs fed the negative control, High-MZnO, or Low-MZnO had improved (P < 0.0001) ADG and ADFI compared to pigs fed High- or Low-ZnO. For the entire experiment (days 0 to 42), pigs fed Low-ZnO or High-ZnO had reduced (P < 0.0001) ADG compared to those fed the negative control. A significant treatment × day interaction (P = 0.04) was observed for fecal Zn concentrations, where the level of Zn excreted in the feces was dependent on the sampling day in pigs fed a low level of ZnO or low level of microencapsulated ZnO. There was no evidence (P > 0.05) that small intestinal morphology differed significantly between treatments. In summary, feeding a microencapsulated form of ZnO did not alter piglet growth performance during the treatment period. Pigs fed a low level of ZnO or microencapsulated ZnO had reduced fecal Zn excretion by the end of the feeding period, but no significant impacts were observed on piglet small intestinal morphology.
Acute Mesenteric Ischemia: Anatomy, Imaging Techniques, and Pathophysiology
Authors: Xu Adrian QingYu , Nakanote Ken , Hegde Siddhi , Bastawrous Sarah , Chan Alex , Weaver Jennifer , Revels Jonathan , Wang Sherry S.
Published: December 2023

Acute mesenteric ischemia is frequently a rapidly life-threatening condition in which the radiologist may play a crucial role in early diagnosis and thus improve patient outcome. The small and large bowels are supplied by the celiac trunk, superior mesenteric artery, and inferior mesenteric artery with watershed zones at the splenic flexure (Griffith's point) and rectosigmoid junction (Sudeck's point). Important bowel collateral circulation is the superior-inferior pancreaticoduodenal anastomosis, marginal artery of Drummond, and arc of Riolan. The most common cause of acute mesenteric ischemia is arterial embolism or thrombosis with less common causes being veno-occlusive and other nonocclusive causes. CT angiography evaluation is the first-line modality with high sensitivity and specificity for identifying acute mesenteric ischemia. Dual-energy CT is an emerging modality, which may be helpful in subtle cases.
Urine TIMP2.IGFBP7 reflects kidney injury after moderate volume paracentesis in patients with ascites: A randomized control study
Authors: Suksamai Anuchit , Khaoprasert Sanpolpai , Chaiprasert Amnart , Chirapongsathorn Sakkarin
Published: December 2023

Background

Patients with cirrhosis undergoing therapeutic paracentesis are at risk of developing kidney injury, but this has not been well evaluated in a non-large volume paracentesis setting.

Objective

The aims of this study were to determine the risk and consequence of acute kidney injury (AKI) and its progression in patients with decompensated cirrhosis after moderate volume paracentesis by use of a urine test measuring tissue inhibitor of metalloproteinases-2 (TIMP2) and (IGFBP7).

Methods

A randomized, prospective cohort study was performed. All outpatients with decompensated cirrhosis with ascites and diuretic complications were enrolled and randomized into 3 liters and 5 liters of paracentesis groups. Serial urine samples were analyzed for [TIMP2]*[IGFBP7] concentration before and after paracentesis.

Results

A total of 90 patients with decompensated cirrhosis were consecutively enrolled during the study period. After screening, 29 patients were enrolled in the 3-liter paracentesis group, and 25 patients were enrolled in the 5-liter paracentesis group. The mean of the MELD score was 8 ± 1.2. Urine TIMP2.IGFBP7>2, rising urine TIMP2, and rising urine TIMP2/urine Cr were shown in patients within the 5-liter group for 48% (p = 0.015), 32% (p = 0.049) and 76% (p =0.010), respectively. There was no statistical difference between the two groups in the rapid decline of GFR, admission, or death.

Conclusion

Urine TIMP2.IGFBP7>2 predicted renal tubular injury in patients in the ascites release 5 L group therefore, ascites release 5 L may not be safe. Kidney injury could occur even less than 5 liters of ascites release in decompensated cirrhosis as demonstrated.

The national clinical registration number was TCTR20191116003.
Treatment preferences among people at risk of developing tuberculosis: a discrete choice experiment
Authors: Kamchedzera Wala , Quaife Matthew , Msukwa-Panje Wezi , Burke Rachael M , Macpherson Liana , Kumwenda Moses , Twabi Hussein H , Quartagno Matteo , MacPherson Peter , Esmail Hanif
Published: December 2023

Diagnosing and treating tuberculosis (TB) early, prior to bacteriological conformation (e.g. bacteriologically-negative but radiologically-apparent TB) may contribute to more effective TB care and reduce transmission. However, optimal treatment approaches for this group are unknown. It is important to understand peoples’ preferences of treatment options for effective programmatic implementation of people-centred treatment approaches.

We designed and implemented a discrete choice experiment (DCE) to solicit treatment preferences among adults (≥18 years) with TB symptoms attending a primary health clinic in Blantyre, Malawi. Quantitative choice modelling with multinomial logit models estimated through frequentist and Bayesian approaches investigated preferences for the management of bacteriologically-negative, but radiographically-apparent TB.

128 participants were recruited (57% male, 43.8% HIV-positive, 8.6% previously treated for TB). Participants preferred any treatment option compared to no treatment (odds ratio [OR]: 0.17; 95% confidence interval [CI]: 0.07, 0.42). Treatments that reduced the relative risk of developing TB disease by 80% were preferred (OR: 2.97; 95% CI: 2.09, 4.21) compared to treatments that lead to a lower reduction in risk of 50%. However, there was no evidence for treatments that are 95% effective being preferred over those that are 80% effective. Participants strongly favoured the treatments that could completely stop transmission (OR: 7.87, 95% CI: 5.71, 10.84), and prioritised avoiding side effects (OR: 0.19, 95% CI: 0.12, 0.29). There was no evidence of an interaction between perceived TB disease risk and treatment preferences.

In summary, participants were primarily concerned with the effectiveness of TB treatments and strongly preferred treatments that removed the risk of onward transmission. Person-centred approaches of preferences for treatment should be considered when designing new treatment strategies. Understanding treatment preferences will ensure that any recommended treatment for probable early TB disease is well accepted and utilized by the public.
Intracranial Plaque Characteristics of Recurrent Ischemic Stroke After Intensive Medical Therapy for a 6-month Follow-up
Authors: Shi Zhang , Zhang Boyu , Zhao Ming , Zhang Shujie , Li Jing , Liu Qi , Zeng Mengsu , Lin Jiang , Lu Jianping , Wang He
Published: December 2023

BACKGROUND

Intensive medical management has been recommended to ischemic stroke of intracranial atherosclerosis (ICAS), but 9.4-15% probability of recurrent stroke remains an inevitable reality. The characteristics of high-risk intracranial plaque that contribute to stroke recurrence after intensive therapy is unclear.

METHODS

All the patients for acute ischemic stroke due to ICAS underwent the 3D head&neck high-resolution vessel wall magnetic resonance imaging (hr-VW-MRI) at baseline and received intensive medical management within 90 days in this two-center and prospective study. The clinical risk factors and blood biomarkers were recorded. The morphological features, such as minimal lumen area (MLA), and histogram parameters including entropy were assessed based on MR images. The primary endpoint event after 6 months is recurrence of ischemic events (hyperintense signals on diffusion-weighted images or TIA in the ipsilateral vascular territory). Cox regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for recurrent events.

RESULTS

222 patients (age, 59.5±12.1; males, 153) were included in the subsequent analysis. After an average of six months of follow-up (average days, 177.4±23.1), 38 patients have reached the primary endpoint. After adjusting the age, BMI and gender, the multivariate Cox regression demonstrated that three clinical factors including smoking (HR=4.321; 95%CI, 1.838-10.161;P=0.001), taking exercise (HR=0.409; 95%CI, 0.198-0.843;P=0.015) and blood pressure management (HR=0.180; 95%CI, 0.073-0.443;P=0.001), and two MR-related parameters (MLA [HR=0.771; 95%CI, 0.625-0.951;P=0.015] and entropy [HR=0.274; 95%CI, 0.130-0.576;P=0.001]) were significant predictors of recurrent ischemic stroke. The Kaplan– Meier curve depicted that the cumulative incidences of patients with all high-risk features were significantly higher than those without(P < 0.001).

CONCLUSIONS

The plaque characteristics based on 3D head&neck hr-VW-MRI may provide complementary values over traditional clinical features in predicting ischemic recurrence for ICAS and help risk stratification of patients at risk of recurrent stroke.
Financial Cost Analysis Associated with a Locomotor Exercise Randomized Controlled Trial in Chronic Stroke
Authors: Hazen Emily M. , Bartsch Bria L. , Billinger Sandra A.
Published: December 2023

Background

Post-stroke recovery trials pose distinct recruitment and retention challenges, and understanding the financial requirements of conducting randomized controlled trials is crucial to ensure sufficient resources for successful study execution. The purpose of this analysis was to quantify the costs at a single site with a large catchment area of the Moderate-Intensity Exercise Versus High-Intensity Interval Training to Recover Walking Post-Stroke, HIT Stroke Trial.

Methods

To determine cost, study expense reports were gathered and divided into four categories: oversight, recruitment, retention, and outcome assessments. Categories were then further divided into chronological order for initial contact and prescreening, consenting, initial screening, and baseline testing. The 12-week intervention was divided into 4-week blocks: intervention block 1, post 4-week outcome testing, intervention block 2, post 8-week outcome testing, intervention block 3, and post 12-week outcome testing.

Results

Total direct cost for site execution was $539,768 with cost per participant approximated as $35,984. Oversight costs accounted for 65.8% of the budget at $355,661. To achieve goals related to inclusive participant recruitment ($21,923) and retention ($28,009), our site costs totaled $49,932. Direct study-related costs included screening assessments ($5,905), baseline assessments ($15,028), intervention ($76,952), and outcome assessments ($36,288).

Conclusion

Clinical trials on walking rehabilitation and exercise, especially those involving multiple assessment visits, require intensive oversight. This cost analysis provides important and critical insight into the expenses required to successfully execute an exercise-based walking rehabilitation trial in the United States.
Mitochondrial morphology and function in mitochondrial disease
Authors: Faitg Julie , Davey Tracey , Laws Ross , Lawless Conor , Tuppen Helen , Fitton Eric , Turnbull Doug , Vincent Amy E.
Published: December 2023

Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. The morphology of this network is maintained by the balance between mitochondrial fusion and fission, necessary for the proper functioning of the mitochondrial energetics as well as the maintenance of mitochondria DNA (mtDNA) (Chan, 2006; Friedman and Nunnari, 2014; Glancy et al., 2015). If the balance between the two processes is slightly perturbed, dramatic changes in mitochondrial morphology can occur.

However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do soin situand none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Using this technique, we examine the relationship between 3D mitochondrial morphology and mitochondrial activity in human skeletal muscle.

Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity, and a typical mosaic pattern of enzyme deficiency with both COX normal and deficient fibres present in the same biopsy.

Using COX-SBFSEM, we can distinguish three distinct mitochondrial populations within muscle fibres: COX normal (+), COX intermediate (±) and COX deficient (-) mitochondria. COX+ mitochondria were larger and more complex than the COX- mitochondria, However, in fibres that were generally COX-, there was no apparent difference between the three types of mitochondria and all mitochondria in fibres that are COX- overall are fragmented and spherical. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in fibres that are generally COX+ and that the spatial pattern is less clear in fibres that are predominantly COX± and COX- .
Long-Term Immunogenicity Study of an Aluminum Phosphate-Adjuvanted Inactivated Enterovirus A71 Vaccine in Children: An Extension to a Phase 2 Study
Authors: Chiu Nan-Chang , Lin Chien-Yu , Chen Charles , Cheng Hao-Yuan , Hsieh Erh-Fang , Liu Luke Tzu-Chi , Chiu Cheng-Hsun , Huang Li-Min
Published: December 2023

Abstract

Background

EV-A71 causes hand, foot, and mouth disease with potentially fatal complications such as encephalitis and acue flaccid myelitis in infants and children. This study examined the long-term immunity conferred by EV71vac, an inactivated EV-A71 vaccine based on the B4 subgenotype adjuvanted with aluminum phosphate, in children from the age of > 2 months to < 6 years for up to 5 years after the first immunization.

Methods

A total of 227 subjects from age of 2 months to 6 years who had previously received either EV71vac or placebo in the phase 2 clinical study were enrolled. Subjects were split into age groups: 2 years to < 6 years (Group 2b), 6 months to < 2 years (Group 2c), and 2 months to < 6 months (Group 2d). Serum samples were taken periodically for up to five years after the first dose for immunogenicity against EV-A71.

Results

At year 5, the neutralizing antibody titers against B4 subgenotype remained high at 621.38 to 978.20, 841.40 to 1159.93, and 477.71 to 745.07 for Groups 2b, 2c, and 2d, respectively. Cross-neutralizing titers at year 5 were 99.14 to 444.30 and 341.94 to 998.20 against B5 and C4a subgenotypes, respectively. Nearly all subjects remained seroprotected at year five (95.8 to 100%). No long-term safety issues were reported.

Conclusion

This study shows that using the current dosing regimen, EV71vac conferred persistent immunity against EV-A71 for at least five years after the first vaccination in children from the age of two months to six years.

EV-A71 neutralizing antibody persisted at high level throughout five years post vaccination in children of two months to six years old.
Genetics, primary care records and lifestyle factors for short-term dynamic risk prediction of colorectal cancer: prospective study of asymptomatic and symptomatic UK Biobank participants
Authors: Ip Samantha , Harrison Hannah , Usher-Smith Juliet A. , Barclay Matthew , Tyrer Jonathan , Dennis Joe , Yang Xin , Lush Michael , Renzi Cristina , Pashayan Nora , Denaxas Spiros , Lyratzopoulos Georgios , Antoniou Antonis C. , Wood Angela
Published: December 2023

Objectives

To quantify the contributions of polygenic scores, primary care records (presenting symptoms, medical history and common blood tests) and lifestyle factors, for short-term risk prediction of colorectal cancer (CRC) in both all and symptomatic individuals.

Design

Prospective cohort study.

Setting

UK Biobank with follow-up until 2018.

Participants

All participants with linked primary care records (n=160,507), and a subcohort of participants with a recent (last two years) presentation of a symptom associated with CRC (n=42,782).

Main outcome measures

Outcome was the first recorded CRC diagnosis within two years. Dynamic risk models with time-varying predictors were derived in a super-landmark framework. Contributions to model discrimination were quantified using novel inclusion-order-agnostic Shapley values of Harrel’s C-index using cross-validation.

Results

C-indices [95% CIs] were 0.73 [0.72-0.73] and 0.69 [0.68-0.70] for the models derived in all and symptomatic participants respectively. The Shapley contributions to model discrimination [95% CIs] differed between the two groups of participants for different predictors: 33% [25%-42%] (34% [9%-75%] in the symptomatic participants) for core predictors (e.g., age, sex, smoking), 16% [8%-26%] (8% [-21%-35%]) for polygenic scores, 32% [19%-43%] (41% [16%-73%]) for primary care blood tests, 11% [4%-17%] (9% [-25%-37%]) for primary care medical history, 6% [0%-11%] (–5% [-32%-13.4%]) for additional lifestyle factors and 3% [-2%-7%] (13% [-19%-41%]) for symptoms.

Conclusions

Polygenic scores contribute substantially to short-term risk prediction for CRC in both general and symptomatic populations; however, the contribution of information in primary care records (including presenting symptoms, medical history and common blood tests) is greater. There is, however, only a small contribution by the additional lifestyle risk factors which are not routinely collected in primary care.
Epidemiology of alcohol use and alcohol use disorder among female sex workers in Mbeya City, Tanzania
Authors: Augustine Andrew Kapaya , Maganga Lucas , Francis Joel Msafiri
Published: December 2023

Background

Alcohol misuse is a global concern, contributing to 5.3% of total deaths and 132.6 million disability-adjusted life years worldwide. In Sub-Saharan African countries, the prevalence of Alcohol Use Disorder (AUD) has risen, especially among female sex workers, due to increased availability and advertising. However, there are limited studies on alcohol use and AUD among female sex workers in Tanzania.

Study Objective

This study aimed to determine the prevalence, patterns, and factors associated with alcohol use and AUD among sex workers in Mbeya city, Tanzania.

Methods

In this cross-sectional study, 212 female sex workers in Mbeya city, Tanzania, seeking enrolment in the National Institute for Medical Research Mbeya Medical Research Centre’s registration cohort from July to November 2022. Structured interviews covered socio-demographics, alcohol screening (AUDIT-C and Timeline Follow Back Calendar), and sexual behaviours data. Data were analysed using Stata version 17. Descriptive analysis assessed alcohol consumption and AUD prevalence. Factors associated with alcohol use and AUD at bivariate analysis were identified using Chi-square/Fisher’s exact tests. All variables with p-value ≤ 0.20 multivariable logistic regression models were done to identify factors associated with alcohol use and AUD.

Results

Among 212 participants, 86.6% reported alcohol use in the past 12 months, 85% in the past 30 days, and 98.5% met AUD criteria. Factors linked to recent alcohol consumption included primary education or higher, income above the median, and more than 10 sexual partners. Education level, marital status, income, and having dependents were significantly associated with heavy drinking episodes.

Discussion and conclusion

The prevalence of AUD, alcohol use, and heavy episodic drinking were high among female sex workers in Mbeya city. Socio-demographic factors and risky sexual behaviours were associated with alcohol use and heavy episodic drinking highlighting the need for targeted interventions to combat alcohol abuse among female sex workers within the HIV program.
An estimation of global genetic prevalence of PLA2G6-associated neurodegeneration
Authors: Kurtovic-Kozaric Amina , Singer-Berk Moriel , Wood Jordan , Evangelista Emily , Panwala Leena , Hope Amanda , Heinrich Stefanie M. , Baxter Samantha , Kiel Mark J.
Published: December 2023

Background

PLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated.

Methods

To provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium.

Results

In the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and VUS variants are included, the overall genetic prevalence was estimated to be 1 in 220,322 pregnancies, with the highest genetic prevalence in African/African-American populations at 1 in 86,012 pregnancies. Similarly, the highest carrier frequencies observed were in African/African-American and Asian populations.

Conclusion

Our estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.
Immunogenicity and Safety of a 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14TM) administered to 6-8 weeks old healthy Indian Infants: A single blind, randomized, active-controlled, Phase-III study
Authors: Matur Ramesh V , Thuluva Subhash , Gunneri Subbareddy , Yerroju Vijay , Mogulla Rammohan reddy , Thammireddy Kamal , Paliwal Piyush , Mahantshetty Niranjana S , Ravi Mandyam Dhati , Prashanth S. , Verma Savita , Narayan Jai Prakash
Published: December 2023

Background

Introduction of pneumococcal conjugate vaccines (PCV) reduced the cases of pneumococcal disease at global level. However, there is an increase in clinical and economic burden of PD from non-PCV serotypes, particularly in pediatric and elder population. In this study, immunogenicity and safety of the BE’s 14-valent PCV (PNEUBEVAX 14TM; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) in comparison to PCV-13 was evaluated in infants.

Methods

This is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants in 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs) and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS IgG concentration and functional antibody titers by opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study.

Findings

The safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature and no severe or serious AEs were reported. Primary immunogenicity objective was met for all 14 serotypes. For the twelve common serotypes non-inferiority to those 12 serotypes in PCV-13 was met. Additional serotypes in BE-PCV-14 (22F and 33F) also met NI criteria as defined by WHO TRS-977. A significant seroconversion, about 69% for serotype 6A was observed even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes in PCV-13.

Interpretations

BE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. All serotype-specific IgG responses were comparable to those in PCV-13. These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine.

The study was prospectively registered with clinical trial registry of India-CTRI/2020/02/023129
Pitfalls in Time-to-Event Analysis of Registry Data: A Tutorial based on Simulated and Real Cases
Authors: Alligon Mickaël , Mahlaoui Nizar , Bouaziz Olivier
Published: December 2023

Survival analysis (also referred to as time-to-event analysis) is the study of the time elapsed from a starting date to some event of interest. In practice, these analyses can be challenging and, if methodological errors are to be avoided, require the application of appropriate techniques. By using simulations and real-life data based on the French national registry of patients with primary immunodeficiencies (CEREDIH), we sought to highlight the basic elements that need to be handled correctly when performing the initial steps in a survival analysis. We focused on right censoring, left truncation, competing risks, and recurrent events. Our simulations show that ignoring these aspects induces a bias in the results; we then explain how to analyze the data correctly in these situations. Rare disease registries are extremely valuable in medical research. We discuss the application of appropriate methods for the analysis of time-to-event from the CEREDIH registry. The objective of this tutorial article is to provide clinicians and healthcare professionals with better knowledge of the issues facing them when analyzing time-to-event data.

Key messages box

When comparing naïve approaches and the proper methodology, we show that:

Not considering right censoring leads to underestimation of survival

Not considering left truncation leads to overestimation of survival

Treating competing risks as right-censoring leads to overestimation of survival

Appropriate recurrent event methods allow to study all events for each patient and not only account for the first event.
Hybrid immunity improves the immune response after fourth Covid-19 vaccine dose in individuals with medical conditions predisposing to severe Covid-19
Authors: Ekström Nina , Leino Tuija M. , Juutinen Aapo , Lehtonen Toni , Haveri Anu , Liedes Oona , Vara Saimi , Salo Heini , Palmu Arto A. , Nohynek Hanna , Martelius Timi , Melin Merit
Published: December 2023

Background

Data on Covid-19 booster vaccinations and subsequent infections on immune responses in the immunocompromised is limited. We studied antibody responses after the fourth dose and subsequent breakthrough infection to define patient groups benefiting most from boosters.

Methods

In Finland, fourth vaccine (booster) doses were first recommended for severely immunocompromised individuals, whom we invited to participate in 2022. We assessed spike protein specific IgG antibody levels and neutralizing antibodies (NAb) against the ancestral and Omicron BA.1 strains one month after the fourth dose from 488 adult participants and compared to the levels of 35 healthy controls after 3 doses. We used Bayesian generalized linear modelling to assess factors explaining antibody concentrations after the fourth dose. We assessed vaccine-induced and hybrid immunity six months after the last vaccine dose.

Results

Chronic kidney disease (CKD) and immunosuppressive therapy (IT) were identified as factors explaining sub-optimal antibody responses. The proportion of participants with a normal antibody response and NAbs were significantly lower in CKD patients as compared to controls. By the 6-month sampling one third of the participants became infected, which enhanced antibody levels notably in most immunocompromised participants.

Conclusions

Impaired antibody responses, especially NAbs against the Omicron lineage, predict limited protection in individuals with CKD, and highlight the need for alternative pharmaceutical preventive strategies. Vaccination strategies should take into account development of robust hybrid immunity responses also among the immunocompromised.
The relationship between low levels of albuminuria and cardiovascular mortality among apparently healthy adults
Authors: Claudel Sophie E , Waikar Sushrut S , Schmidt Insa M. , Vasan Ramachandran S. , Verma Ashish
Published: December 2023

Background

Albuminuria is associated with cardiovascular events among adults with underlying cardiovascular disease and diabetes, even at low levels of urinary albumin excretion. We hypothesized that low levels of albuminuria in the ‘normal’ range (urinary albumin-to-creatine ratio (UACR) <30 mg/g) are associated with cardiovascular death among apparently healthy adults.

Methods

We studied adults who participated in the 1999-2014 National Health and Nutrition Examination Survey. We excluded participants with baseline cardiovascular disease, hypertension, diabetes, estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, those who were currently pregnant, and those who had received dialysis in the last year. After excluding these conditions, only 5.0% of the remaining population had UACR ≥30 mg/g (N=873) and were excluded. The final sample size was 16,247. We assessed the relationship between UACR and cardiovascular and all-cause mortality using multivariable-adjusted Cox proportional hazards models. Models were adjusted for age, sex, race or ethnicity, smoking status, systolic blood pressure, hemoglobin A1c, total cholesterol, health insurance, food insecurity, serum albumin, body mass index, use of statins, and eGFR.

Results

Mean age was 38.9 years (SD 13.6) and 53.7% were women. The median length of follow-up was 12.2 years. In multivariable-adjusted models, each doubling of UACR (within the <30 mg/g range) was associated with a 36% higher risk of cardiovascular death [HR 1.36 (95% confidence interval (CI) 1.11-1.65)] and a 28% higher risk of all-cause mortality [HR 1.28 (95%CI 1.17-1.41)]. The highest tertile of UACR (7.1-29.9 mg/g) was associated with an 87% higher risk of cardiovascular death [HR 1.87 (95%CI 1.20-2.92)] and 59% higher risk of all-cause mortality [HR 1.59 (95%CI 1.28-1.96)], compared with the lowest tertile (< 4.3 mg/g).

Conclusions

In a nationally representative sample of relatively healthy community-dwelling adults, higher levels of albuminuria in the conventionally “normal” range <30 mg/g in healthy individuals are associated with greater mortality. Overall, our findings contribute to the growing body of evidence on the existence of a risk gradient across all levels of albuminuria, even in the so-called normal range.
Detecting QT prolongation From a Single-lead ECG With Deep Learning
Authors: Alam Ridwan , Aguirre Aaron D. , Stultz Collin M.
Published: December 2023

Background and Aims

For a number of antiarrhythmics, drug loading requires a 3-day hospitalization with monitoring for QT-prolongation. Automated QT monitoring with wearable ECG monitors would facilitate out-of-hospital care. We aim to develop a deep learning model that infers QT intervals from ECG lead-I – the lead most often acquired from ambulatory ECG monitors – and we use this model to detect clinically meaningful QT-prolongation episodes during Dofetilide drug loading.

Methods

Using 4.22 million 12-lead ECG recordings from 903.6 thousand patients at the Massachusetts General Hospital, we develop a deep learning model, QTNet, that infers QT intervals from lead-I. Over 3 million ECGs from 653 thousand patients are used to train the model and an internal-test set containing 633 thousand ECGs from 135 thousand patients was used for testing. QTNet is further evaluated on an external-validation set containing 3.1 million ECGs from 667 thousand patients at another institution. QTNet was used to detect Dofetilide-induced QT prolongation in a publicly available database (ECGRDVQ-dataset) containing ECGs from subjects enrolled in a clinical trial evaluating the effects of antiarrhythmic drugs.

Results

QTNet achieves mean absolute errors of 12.63ms (internal-test) and 12.30ms (external-validation) for estimating absolute QT intervals. The associated Pearson correlation coefficients are 0.91 (internal-test) and 0.92 (external-validation). For the ECGRDVQ-dataset, QTNet detects Dofetilide-induced QTc prolongation with 87% sensitivity and 77% specificity. The negative predictive value of the model is greater than 95% when the pre-test probability of drug-induced QTc prolongation is below 25%.

Conclusions

Drug-induced QT prolongation risk can be tracked from ECG lead-I using deep learning. This research leads the path toward out-of-hospital care using wearable ECG devices for antiarrhythmic therapies.

What’s New?

Using only Lead-I ECG, a novel deep neural network, QTNet, can estimate the QT intervals that are similar to those generated from the 12-lead ECG by the clinical ECG machines, with a mean absolute error of 12ms and a Pearson correlation coefficient of 0.91.

The same QTNet, when applied without any fine-tuning on an external population undergoing Dofetilide loading, can identify whether and when clinically critical QT prolongation occurs after the drug loading. In comparison to manual annotations of QT intervals by clinical experts, QTNet achieves 87% sensitivity and 77% specificity.

QTNet is a novel regression model that can be used on Lead-I ECG streams, potentially from wearable devices at out-of-hospital settings, for health critical applications such as drug-induced QT prolongation tracking.
Distributed Statistical Analyses: A Scoping Review and Examples of Operational Frameworks Adapted to Healthcare
Authors: Lemyre Félix Camirand , Lévesque Simon , Domingue Marie-Pier , Herrmann Klaus , Ethier Jean-François
Published: December 2023

Data from multiple organizations are crucial for advancing learning health systems. However, ethical, legal, and social concerns may restrict the use of standard statistical methods that rely on pooling data. Although distributed algorithms offer alternatives, they may not always be suitable for healthcare research frameworks. This paper aims to support researchers and data custodians in three ways: (1) providing a concise overview of the literature on statistical inference methods for horizontally partitioned data; (2) describing the methods applicable to generalized linear models (GLM) and assessing their underlying distributional assumptions; (3) adapting existing methods to make them fully usable in healthcare research. A scoping review methodology was employed for the literature mapping, from which methods presenting a methodological framework for GLM analyses with horizontally partitioned data were identified and assessed from the perspective of applicability in healthcare research. From the review, 41 articles were selected, and six approaches were extracted for conducting standard GLM-based statistical analysis. However, these approaches assumed evenly and identically distributed data across nodes. Consequently, statistical procedures were derived to accommodate uneven node sample sizes and heterogeneous data distributions across nodes. Workflows and detailed algorithms were developed to highlight information-sharing requirements and operational complexity.
A triple bottom line approach to antimicrobial stewardship: the effects of simplifying treatment
Authors: Balm Michelle , Bupha-Intr Olivia , Sinha Tanya , Kelly Matthew , Stewart Lucy , Stephen Ruth , Blackmore Tim , Bloomfield Max
Published: December 2023

Aim

Our antimicrobial guidelines (AGs) were changed in 2021 to recommend once-daily ceftriaxone in place of three-times-daily cefuroxime as preferred cephalosporin. This analysis sought to assess the effects of this on incidence ofClostridioides difficileinfection (CDI), third-generation cephalosporin resistant Enterobacterales (3GCR-E), and resource utilisation.

Method

Before and after analysis of 30-day CDI and 3GCR-E incidence following receipt of cefuroxime/ceftriaxone pre- and post-AG change. Total nursing time and waste production relating to cefuroxime/ceftriaxone delivery were calculated pre- and post-change.

Results

CDI incidence was 0.6% pre- and 1.0% post-change (adjusted odds ratio [aOR] 1.44, p=0.07) and 3GCR-E incidence 3.5% and 3.1% (aOR 0.90, p=0.33). Mean per-quarter estimated nursing administration time decreased from 2065 to 1163 hours (902 nurse-hour reduction) and antibiotic-related waste generation from 1131kg to 748kg (383kg reduction). Overall days of therapy per-quarter of cefuroxime/ceftriaxone were unchanged between periods.

Conclusion

This simplification of our AG from a three-times-daily to a once-daily antibiotic resulted in considerable savings for our hospital (roughly 1.7 full-time equivalent nurses and over a tonne of waste yearly), with no significant increases in CDI or 3GCR-E. The impact of dosing schedules on non-antibiotic-spectrum factors, such nursing time and resource usage, is worthy of consideration when designing AGs.