bluuebunny/crossref_metadata_2025 huggingface dataset:
Reviewing the impact of obesity on inflammatory bowel disease and considerations for optimizing management
Authors: Ghusn Wissam , Loftus Edward V. , Johnson Amanda M.
Published: April 2024

Purpose of review

This review examines the complex relationship between obesity and inflammatory bowel disease (IBD), encompassing their potentially shared pathogenesis, the impact of obesity on the natural history and treatment outcomes of IBD, and the management of obesity in the patient with IBD.

Recent findings

Obesity represents a state of chronic inflammation that may not only contribute to IBD pathogenesis, but also influence disease progression, complications, and response to treatment. Increased visceral adiposity may carry negative prognostic implications for disease and treatment-specific outcomes. Antiobesity medications, endoscopic bariatric therapies, and even bariatric surgery may be effective and well tolerated in selected patients with IBD.

The intersection of obesity and IBD presents a significant clinical challenge, with obesity influencing the natural history of IBD and potentially affecting treatment efficacy. As obesity prevalence among IBD patients rises, a tailored approach to management is crucial, taking into account the individualized risks and benefits of various treatment strategies, including lifestyle interventions, pharmacotherapy, endoscopic procedures, and bariatric surgery.
Update on applications of endoscopic cryotherapy in the gastrointestinal tract
Authors: Enslin Sarah , Kaul Vivek
Published: April 2024

Purpose of review

Endoscopic cryotherapy has emerged as a minimally invasive procedure for targeted tissue ablation within the gastrointestinal tract. This review aims to provide a comprehensive overview of current clinical applications of EC with a review of the pertinent literature.

Recent findings

Endoscopic cryotherapy has demonstrated safety and efficacy for various gastrointestinal conditions. Recent studies have highlighted the efficacy of endoscopic cryotherapy, including both liquid nitrogen-based spray cryotherapy and the novel cryoballoon focal ablation system, in achieving complete eradication of dysplasia and neoplasia in Barrett's esophagus. Endoscopic cryotherapy has also shown promise as a second-line treatment option for patients with dysplastic Barrett's esophagus refractory to radiofrequency ablation and as an alternative to surgical resection for duodenal adenomas, when endoscopic resection is not feasible. Innovative applications for the treatment of gastrointestinal bleeding and management of benign refractory esophageal strictures have also been reported.

Endoscopic cryotherapy represents a safe, effective, and well tolerated therapeutic option for various clinical scenarios in gastrointestinal endoscopy, including challenging disease states such as refractory Barrett's esophagus and advanced esophageal cancer. Advancements in cryotherapy technology and ongoing research continue to explore additional clinical indications and expand the role of endoscopic cryotherapy in patient care with an aim toward improved patient outcomes.
Access to Urogynecologic Care in Federally Qualified Health Centers: A Mystery Caller Study
Authors: Pascual Micah G. , Novin Atieh , Corbisiero Michaele Francesco , Unciano Sydney , Hachicha Yasmine , Shelden Natalie , Bresnitz Wyanet , Ferzandi Tanaz , Muffly Tyler M.
Published: April 2024

Importance

Federally Qualified Health Centers (FQHCs) play an important role in providing care to underserved populations. However, little is known about the availability of urogynecology services at FQHCs.

Objectives

This study aimed to assess the availability of appointments for urogynecology care and to determine the prevalence of FQHCs offering urogynecologic services.

Study Design

A total of 362 FQHCs across the United States were randomly selected from the Health Resources and Services Administration website, based on specific inclusion criteria. Researchers called the FQHCs and requested the earliest available appointment for pelvic organ prolapse. The availability of urogynecologic services such as pessary fittings, pelvic floor physical therapy, and urodynamic studies was also inquired.

Results

A total of 362 FQHCs located in 46 states and the District of Columbia were called. On average, the 362 FQHCs had been established for 19.9 (SD ±15) years, were located in urban areas, and served a median county population of 24,573. Of the 220 FQHCs successfully contacted, 81% (180/220) reported that they could provide care for a patient with pelvic organ prolapse at an appointment 29.1 business days (SD ±30 days) from the date of the call, on average. However, only a small percentage of these FQHCs offered in-office pessary fittings (11%), complex multichannel urodynamics testing (8.6%), or pelvic floor physical therapy (5%).

Conclusion

The availability of treatments for pelvic floor disorders at FQHCs is limited. These findings highlight a potential disparity in access to urogynecology services for individuals with public insurance.
Laser and Pelvic Floor Muscle Training for Urinary Incontinence: A Randomized Clinical Trial
Authors: Rocha-Rangel Samantha Conde , Pereira Gláucia Miranda Varella , Juliato Cassia Raquel Teatin , Brito Luiz Gustavo Oliveira
Published: April 2024

Importance

Pelvic floor muscle training (PFMT) is considered the first option as a conservative treatment for female stress urinary incontinence (SUI). However, there is still debate whether energy-based devices are effective for treating SUI.

Objective

The objective of this study was to assess whether PFMT and fractional CO2 laser therapy may improve symptoms in women with SUI.

Study Design

A parallel, randomized, nonblinded, noninferiority trial included 94 of 144 women 18 years or older with SUI randomized into 2 groups. The CO2 laser group (n = 47) received 3 vaginal applications at monthly intervals. The PFMT group (n = 47) underwent 2 weekly sessions. Primary outcome was the mean difference of International Consultation on Incontinence Questionnaire—Urinary Incontinence Short-Form (ICIQ-UI-SF) total scores between groups after 3 and 6 months. Main secondary outcomes were questionnaires for assessment of pelvic floor symptoms (Pelvic Floor Impact Questionnaire—Short Form 7 [PFIQ-7]), sexual function (Female Sexual Function Index [FSFI]), and improvement after treatment (Patient Global Impression of Improvement [PGI-I]).

Results

A reduction in the ICIQ-UI-SF total score, PFIQ total score, and the Urinary Impact Questionnaire score was perceived between baseline and 3–6 months in both groups. CO2 laser did not reach the noninferiority margin when compared with PFMT in both follow-up periods and analyses. Pelvic floor muscle training has improved the FSFI desire domain between baseline and 3–6 months, whereas CO2 laser improved the FSFI orgasm, pain, and total score after 3 months and FSFI orgasm and total score after 6 months. PGI-I assessment has shown an improvement in both groups.

Conclusion

Fractional CO2 laser therapy was noninferior to PFMT after 3–6 months of treatment. Both groups presented a reduction in the ICIQ-UI-SF scores, and both methods could be considered for women with SUI.
Global Outcomes Benchmarks in Laparoscopic Liver Surgery for Segments 7 and 8: International Multicenter Analysis
Authors: Lopez-Lopez Victor , Morise Zeniche , Gomez Gavara Concepción , Gero Daniel , Abu Hilal Mohammed , Goh Brian KP , Herman Paulo , Clavien Pierre-Alain , Robles-Campos Ricardo , Wakabayashi Go ,   the Laparoscopic Liver Surgery Multicenter Study Group
Published: April 2024

BACKGROUND:

In recent years, there has been growing interest in laparoscopic liver resection (LLR) and the audit of the results of surgical procedures. The aim of this study was to define reference values for LLR in segments 7 and 8.

STUDY DESIGN:

Data on LLR in segments 7 and 8 between January 2000 and December 2020 were collected from 19 expert centers. Reference cases were defined as no previous hepatectomy, American Society of Anesthesiologists score less than 3, BMI less than 35 kg/m2, no chronic kidney disease, no cirrhosis and portal hypertension, no COPD (forced expiratory volume 1 <80%), and no cardiac disease. Reference values were obtained from the 75th percentile of the medians of all reference centers.

RESULTS:

Of 585 patients, 461 (78.8%) met the reference criteria. The overall complication rate was 27.5% (6% were Clavien-Dindo 3a or more) with a mean Comprehensive Complication Index of 7.5 ± 16.5. At 90-day follow-up, the reference values for overall complication were 31%, Clavien-Dindo 3a or more was 7.4%, conversion was 4.4%, hospital stay was less than 6 days, and readmission rate was <8.33%. Patients from Eastern centers categorized as low risk had a lower rate of overall complication (20.9% vs 31.2%, p = 0.01) with similar Clavien-Dindo 3a or more (5.5% and 4.8%, p = 0.83) compared with patients from Western centers, respectively.

CONCLUSIONS:

This study shows the need to establish standards for the postoperative outcomes in LLR based on the complexity of the resection and the location of the lesions.
Prospective Outpatient Follow-Up of Early Cognitive Impairment in Patients with Mild Traumatic Brain Injury and Intracranial Hemorrhage
Authors: Jebbia Mallory , Stopenski Stephen , Grigorian Areg , Kuza Catherine , Bloom Samuel , Rao Pranthi , Alvarez Claudia , Dolich Matthew , Nguyen Ninh , Nahmias Jeffry
Published: April 2024

BACKGROUNG:

Mild traumatic brain injury (mTBI) encompasses a spectrum of disability including early cognitive impairment (ECI). The Brain Injury Guidelines suggest that patients with mTBI can be safely discharged from the emergency department. Although half of patients with mTBI with intracranial hemorrhage (ICH) have evidence of ECI, it is unclear what percentage of these patients’ ECI persists after discharge. We hypothesize a significant proportion of trauma patients with mTBI and ECI at presentation have persistent ECI at 30-day follow-up.

STUDY DESIGN:

A single-center prospective cohort study including adult trauma patients with ICH or skull fracture and a Glasgow Coma Scale of 13 to 15 on arrival was performed. Participants were screened for ECI using the Rancho Los Amigos Scale (RLA), and ECI was defined as an RLA less than 8. We compared ECI and non-ECI groups for demographics, injury profile, CT imaging (eg Rotterdam CT score) and outcomes with bivariate analysis. Thirty-day follow-up telephone calls were performed to re-evaluate RLA for persistent ECI and concussion symptoms.

RESULTS:

From 62 patients with ICH or skull fracture and mTBI, 21 (33.9%) had ECI. Patients with ECI had a higher incidence of subarachnoid hemorrhage (85.7% vs 46.3%, p = 0.003) and higher Rotterdam CT score (p = 0.004) compared with those without ECI. On 30-day follow-up, 6 of 21 (26.6%) patients had persistent ECI. In addition, 7 (33.3%) patients had continued concussion symptoms.

CONCLUSIONS:

More than one-third of mTBI patients with ICH had ECI. At 30-day postdischarge follow-up, more than one-fourth of these patients had persistent ECI and 33% had concussion symptoms. This highlights the importance of identifying ECI before discharge as a significant portion may have ongoing difficulties reintegrating into work and society.
Trend of Vancomycin resistance among Enterococcal meningitis patients in North India – an observational analysis
Authors: Jamwal Ashima , Varghese Gerlin , Sarawat Deepika , Tejan Nidhi , Patel Sangram Singh , Sahu Chinmoy
Published: April 2024

Introduction: Among bacterial meningitis, enterococcal meningitis is extremely uncommon and typically nosocomial in origin.
Aim: This study was done to estimate the prevalence of Vancomycin-resistant Enterococcal meningitis and to assess the risk factors amongst these patients. Also, resistance pattern of these Vancomycin resistant Enterococcal isolates towards other antibiotics were also assessed.
Materials and methods: This observational analysis was done in the Microbiology department of a tertiary care referral center from January 2021 to July 2023. Cerebrospinal fluid (CSF) samples of all cases of suspected meningitis were included in the study and sent to Microbiology lab for culture and sensitivity. Culture was done on chocolate agar, 5% blood agar and MacConkey agar and incubated aerobically for 72 hours. After incubation, the isolate was identified by MALDI-ToF MS. Sensitivity was done using Kirby Bauer disk diffusion method and interpreted using CLSI 2023 M-100 clinical breakpoints. The patients’ demographic details, associated risk factors, type of surgery done and the clinical outcome of the patients were analyzed.
Statistical analysis: Clinical data and values were entered in Excel sheet. Univariate analysis of the risk factors was done and p-values <0.05 were considered significant.
Results: A total of 2352 CSF samples were cultured, of which, 292 (12.4%) samples showed growth on culture. Enterococcus species were isolated in 30 (10.3%) samples. The predominant species was Enterococcus faecalis (n=17; 56.7%). Majority of the patients presented with fever (50%) and headache (33.3%). The risk factors in these patients were hypertension (40%) and diabetes mellitus (33.3%). All the patients had an extra-ventricular drain (EVD) present in them. Intracranial surgery was done in 15 patients. Only 1 (3.3%) patient died due to enterococcal meningitis. Of these, 6 (20%) isolates were Vancomycin resistant. Statistically significant risk factors in these patients were hypertension, prolonged hospital stay of >21 days. Majority of the isolates were resistant to Levofloxacin, high level gentamicin, doxycycline and ampicillin. Removal of the EVD helped in better prognosis of the patients
Conclusion: Early detection is crucial for a positive clinical result since vancomycin resistant enterococcal meningitis is associated with a high morbidity rate.
Global review of meta-analyses reveals key data gaps in agricultural impact studies on biodiversity in croplands
Authors: Bonfanti Jonathan , Langridge Joseph , Avadí A. , Casajus N. , Chaudhary A. , Damour G. , Estrada-Carmona N. , Jones S. K. , Makowski D. , Mitchell M. , Seppelt R. , Beillouin Damien
Published: April 2024

Aim

Agriculture depends heavily on biodiversity, yet unsustainable management practices continue to affect a wide range of organisms and ecosystems at unprecedented levels worldwide. Addressing the global challenge of biodiversity loss requires access to consolidated knowledge across management practices, spatial levels, and taxonomic groups.

Location

Global

Time period

1994 to 2022

Major taxa studied

Animals, microorganisms, plants.

Methods

We conducted a comprehensive literature review synthesising data from all meta-analyses about the impacts of agricultural management practices on biodiversity in croplands, covering field, farm, and landscape levels. From 200 retained meta-analyses, we extracted 1,885 mean effect sizes (from 69,850 comparisons between a control and treatment) assessing the impact of management practices on biodiversity, alongside characterising over 9,000 primary papers.

Results

Seven high-income countries, notably the USA, China, and Brazil dominate agricultural impact studies with fertiliser use, phytosanitary interventions and crop diversification receiving widespread attention. The focus on individual practices overshadows research at the farm and landscape level. Taxonomically, Animalia, especially arthropods, are heavily studied while taxa such as annelids and plants receive comparatively less attention. Effect sizes are predominantly calculated from averaged abundance data. Significant gaps persist in terms of studies on the effects of agricultural interventions on specific taxonomic groups (e.g. annelids, mammals) and studies analysing functional traits.

Main conclusions

Our study highlights the importance of analysing the effects of combined practices to accurately reflect real-world farming contexts. While abundance metrics are common, reflecting several biodiversity facets and adopting a more balanced research approach across taxa are crucial for understanding biodiversity responses to agricultural changes and informing conservation strategies. Given the unbalanced evidence on impacts of agricultural practices on biodiversity, caution is required when utilising meta-analytical findings for informing public policies or integrating them into global assessment models like life-cycle assessments or global flux models.
Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature
Authors: Sothers Hanna , Hu Xianzhen , Crossman David K. , Si Ying , Alexander Matthew S. , McDonald Merry-Lynn N. , King Peter H. , Lopez Michael A.
Published: April 2024

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease due to loss-of-function mutations in theDYSTROPHINgene. DMD-related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of TGFβ family of cytokines. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20-fold upregulation ofSmad8transcription. However, the role of BMP4 in severely affected DMD skeletal muscle is unknown. We hypothesized that transcriptomic signatures in severely affected human DMD skeletal muscle are driven by BMP4 signaling. Transcriptomes from skeletal muscle biopsies of late-stage DMD vs. non-DMD controls and C2C12 muscle cells with or without BMP4 stimulation were generated by RNA-Seq and analyzed for single transcript differential expression as well as by Ingenuity Pathway Analysis and weighted gene co-expression network analyses. A total of 2,328 and 5,291 transcripts in the human muscle and C2C12 muscle cells, respectively, were differentially expressed. We identified an overlapping molecular signature of 1,027 genes dysregulated in DMD muscle that were induced in BMP4-stimulated C2C12 muscle cells. Highly upregulated DMD transcripts that overlapped with BMP4-stimulated C2C12 muscle cells includedADAMTS3, HCAR2, SERPING1, SMAD8, andUNC13C.The DMD transcriptome was characterized by dysregulation of pathways involving immune function, extracellular matrix remodeling, and metabolic/mitochondrial function. In summary, we define a late-stage DMD skeletal muscle transcriptome that substantially overlaps with the BMP4-induced molecular signature in C2C12 muscle cells. This supports BMP4 as a disease-driving regulator of transcriptomic changes in late-stage DMD skeletal muscle and expands our understanding of the evolution of dystrophic signaling pathways and their associated gene networks that could be explored for therapeutic development.
Lysosome-acidifying nanoparticles rescue A30P α-synuclein induced neuronal death in cellular andDrosophilamodels of Parkinson’s disease
Authors: Lo Chih Hung , Ren Mengda , Loi Gavin Wen Zhao , Saipuljumri Eka Norfaishanty , Indajang Jonathan , Lim Kah Leong , Zeng Jialiu
Published: April 2024

Parkinson’s disease (PD) is an age-related neurodegenerative disease characterized by histopathological hallmarks of Lewy bodies formed by accumulation of α-synuclein (αSyn) and progressive loss of dopaminergic neurons in the substantia nigrapars compactaof the midbrain, with clinical symptoms of motor deficits. Toxic protein accumulation of αSyn in PD is associated with autolysosomal acidification dysfunction that contributes to defective autophagy-lysosomal degradation system. While lysosome-acidifying nanoparticles have been applied as therapeutics to ameliorate dopaminergic neurodegeneration in neurotoxin mediated or αSyn aggregates induced mouse model of sporadic PD, lysosome-targeted approach has not yet been applied in synucleinopathy models of familial PD. Here, we report the first application of the new poly(ethylene tetrafluorosuccinate-co-succinate) (PEFSU)-based acidic nanoparticles (AcNPs) in A30P αSyn overexpressing SH-SY5Y cells andDrosophilamodels of PD. In the cellular model, we showed that AcNPs restore lysosomal acidification, promote autophagic clearance of αSyn, improve mitochondrial turnover and function, and rescue A30P αSyn induced death in SH-SY5Y cells. In theDrosophilamodel, we demonstrated that AcNPs enhance clearance of αSyn and rescue dopaminergic neuronal loss in fly brains and improve their locomotor activity. Our results highlight AcNPs as a new class of lysosome-acidifying therapeutic for treatment of PD and other proteinopathies in general.
Spherical Phenotype Clustering
Authors: Nightingale Luke , Tuersley Joseph , Cairoli Andrea , Howes Jacob , Shand Cameron , Powell Andrew , Green Darren , Strange Amy , Warchal Scott , Howell Michael
Published: April 2024

Phenotypic screening experiments comprise many images of the same cells perturbed in different ways, with biologically significant variation often subtle or difficult to see by eye. The specialized nature of the morphological changes and the fact that large quantities of data can be produced quickly makes training new machine learning models attractive. A byproduct of the experimental setup is knowledge of which well an image originated from and the treatment applied. We propose a geometrically inspired variant of contrastive learning incorporating this metadata. The method is tested on the BBBC021 benchmark dataset and in datasets of HaCaT cells perturbed chemically or genetically. On BBBC021 we attain higher NSC and NSCB scores than existing unsupervised (or weakly supervised) methods. In the HaCaT cells we find consistent quantitative gains and qualitative clustering reflecting underlying biology, including alignment of chemical and genetic perturbations.
Dzip1 is dynamically expressed in the vertebrate germline and regulates the development ofXenopusprimordial germ cells
Authors: Turgeon Aurora , Fu Jia , Divyanshi  , Ma Meng , Jin Zhigang , Hwang Hyojeong , Li Meining , Qiao Huanyu , Mei Wenyan , Yang Jing
Published: April 2024

Primordial germ cells (PGCs) are the precursors of sperms and oocytes. Proper development of PGCs is crucial for the survival of the species. In many organisms, factors responsible for PGC development are synthesized during early oogenesis and assembled into the germ plasm. During early embryonic development, germ plasm is inherited by a few cells, leading to the formation of PGCs. While germline development has been extensively studied, how components of the germ plasm regulate PGC development is not fully understood. Here, we report that Dzip1 is dynamically expressed in vertebrate germline and is a novel component of the germ plasm inXenopusand zebrafish. Knockdown of Dzip1 impairs PGC development inXenopusembryos. At the molecular level, Dzip1 physically interacts with Dazl, an evolutionarily conserved RNA-binding protein that plays a multifaced role during germline development. We further showed that the sequence between amino acid residues 282 and 550 of Dzip1 is responsible for binding to Dazl. Disruption of the binding between Dzip1 and Dazl leads to defective PGC development. Taken together, our results presented here demonstrate that Dzip1 is dynamically expressed in the vertebrate germline and plays a novel function duringXenopusPGC development.
Models optimized for real-world tasks reveal the task-dependent necessity of precise temporal coding in hearing
Authors: Saddler Mark R. , McDermott Josh H.
Published: April 2024

Neurons encode information in the timing of their spikes in addition to their firing rates. Spike timing is particularly precise in the auditory nerve, where action potentials phase lock to sound with sub-millisecond precision, but its behavioral relevance remains uncertain. We optimized machine learning models to perform real-world hearing tasks with simulated cochlear input, assessing the precision of auditory nerve spike timing needed to reproduce human behavior. Models with high-fidelity phase locking exhibited more human-like sound localization and speech perception than models without, consistent with an essential role in human hearing. However, the temporal precision needed to reproduce human-like behavior varied across tasks, as did the precision that benefited real-world task performance. These effects suggest that perceptual domains incorporate phase locking to different extents depending on the demands of real-world hearing. The results illustrate how optimizing models for realistic tasks can clarify the role of candidate neural codes in perception.
Mind the gap: the relevance of the genome reference to resolve rare and pathogenic inversions
Authors: Bilgrav Saether Kristine , Eisfeldt Jesper , Bengtsson Jesse , Lun Ming Yin , Grochowski Christopher M. , Mahmoud Medhat , Chao Hsiao-Tuan , Rosenfeld Jill A. , Liu Pengfei , Schuy Jakob , Ameur Adam ,   Undiagnosed Diseases Network, Hwang James Paul , Sedlazeck Fritz J. , Bi Weimin , Marom Ronit , Nordgren Ann , Carvalho Claudia M.B. , Lindstrand Anna
Published: April 2024

Both long-read genome sequencing (lrGS) and the recently published Telomere to Telomere (T2T) reference genome provide increased coverage and resolution across repetitive regions promising heightened structural variant detection and improved mapping. Inversions (INV), intrachromosomal segments which are rotated 180° and inserted back into the same chromosome, are a class of structural variants particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage sensitive genesin cis.

Here we remapped the genome data from six individuals carrying unsolved cytogenetically detected inversions. An INV6 and INV10 were resolved using GRCh38 and T2T-CHM13. Finally, an INV9 required optical genome mapping,de novoassembly of lrGS data and T2T-CHM13. This inversion disrupted intron 25 ofEHMT1,confirming a diagnosis of Kleefstra syndrome 1 (MIM#610253).

These three inversions, only mappable in specific references, prompted us to investigate the presence and population frequencies of differential reference regions (DRRs) between T2T-CHM13, GRCh37, GRCh38, the chimpanzee and bonobo, and hundreds of megabases of DRRs were identified.

Our results emphasize the significance of the chosen reference genome and the added benefits of lrGS and optical genome mapping in solving rearrangements in challenging regions of the genome. This is particularly important for inversions and may impact clinical diagnostics.
Robust prediction of relative binding energies for protein-protein complex mutations using free energy perturbation calculations
Authors: Sampson Jared M. , Cannon Daniel A. , Duan Jianxin , Epstein Jordan C. K. , Sergeeva Alina P. , Katsamba Phinikoula S. , Mannepalli Seetha M. , Bahna Fabiana A. , Adihou Hélène , Guéret Stéphanie M. , Gopalakrishnan Ranganath , Geschwindner Stefan , Rees D. Gareth , Sigurdardottir Anna , Wilkinson Trevor , Dodd Roger B. , De Maria Leonardo , Mobarec Juan Carlos , Shapiro Lawrence , Honig Barry , Buchanan Andrew , Friesner Richard A. , Wang Lingle
Published: April 2024

Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.

Graphical Abstract

Highlights

Reliable calculation of relative binding free energy changes for most protein mutations to within ∼1 kcal/mol.

Automated Protein FEP+ Groups treatment of alternate protonation states for titratable residues.

Application of FEP+ methodology to “real-world” protein design projects.
Cortical tracking of hierarchical rhythms orchestrates the multisensory processing of biological motion
Authors: Shen Li , Li Shuo , Tian Yuhao , Wang Ying , Jiang Yi
Published: April 2024

When observing others’ behaviors, we continuously integrate their movements with the corresponding sounds to enhance perception and develop adaptive responses. However, how the human brain integrates these complex audiovisual cues based on their natural temporal correspondence remains unclear. Using electroencephalogram (EEG), we demonstrated that rhythmic cortical activity tracked the hierarchical rhythmic structures in audiovisually congruent human walking movements and footstep sounds. Remarkably, the cortical tracking effects exhibit distinct multisensory integration modes at two temporal scales: an additive mode in a lower-order, narrower temporal integration window (step-cycle) and a super-additive enhancement in a higher-order, broader temporal window (gait-cycle). Furthermore, while neural responses at the lower-order timescale reflect a domain-general audiovisual integration process, cortical tracking at the higher-order timescale is exclusively engaged in the integration of biological motion cues. In addition, only this higher-order, domain-specific cortical tracking effect correlates with individuals’ autistic traits, highlighting its potential as a neural marker for autism spectrum disorder. These findings unveil the multifaceted mechanism whereby rhythmic cortical activity supports the multisensory integration of human motion, shedding light on how neural coding of hierarchical temporal structures orchestrates the processing of complex, natural stimuli across multiple timescales.
Optimised proteomic analysis of insulin granules from MIN6 β-cells identifies Scamp3, a novel regulator of insulin secretion and content
Authors: Norris Nicholas , Yau Belinda , Famularo Carlo , Thomas Helen E. , Larance Mark , Senior Alistair M. , Kebede Melkam A.
Published: April 2024

Pancreatic β-cells in the islets of Langerhans are key to maintaining glucose homeostasis, by secreting the peptide hormone insulin. Insulin is packaged within vesicles named insulin secretory granules (ISGs), that have recently been considered to have intrinsic structures and proteins that regulate insulin granule maturation, trafficking, and secretion. Previously, studies have identified a handful of novel ISG-associated proteins using different separation techniques. Here, this study combines an optimized ISG isolation technique and mass spectrometry-based proteomics, with an unbiased protein correlation profiling and targeted machine learning approach to uncover 211 ISG-associated proteins. Five of these proteins: Syntaxin-7, Synaptophysin, Synaptotagmin-13, Zinc transporter ZIP8 and SCAMP3 have not been previously ISG-associated. Through colocalization analysis of confocal imaging we validate the association of these proteins to the ISG in MIN6 and human β-cells. We further validate the role for one (SCAMP3) in regulating insulin storage and secretion from β-cells for the first time. SCAMP3 knock-down INS-1 cells show a reduction in insulin content and dysfunctional insulin secretion. These data provide the basis for future investigation into β-cell biology and the regulation of insulin secretion.

Article Highlights

Why did we undertake this study?

We undertook this study to optimize insulin granule isolation techniques alongside enhanced proteomics analyses to establish the first published murine insulin granule proteome.

What is the specific question(s) we wanted to answer?

We aimed to specifically answer and investigate what proteins are present on insulin granules from MIN6 cells to further our understanding of insulin granule biogenesis, trafficking, and secretion.

What did we find?

We find and validate the presence of 5 novel insulin granule-associated proteins.

What are the implications of our findings?

An extensive proteomics analysis of MIN6 insulin granules and implicate Scamp3 as a novel protein that regulates insulin content and secretion in beta-cells.
Beyond the Smoke: A Phenomenological Study of Health and Social Implications of Kush Use Among Sierra Leonean Youths
Authors: Bangura Ronald Abu , Mayei Alhassan , Fatoma Patrick , Bunting-Graden Joseph Anderson , Kaisam John Paul , Ansumana Rashid
Published: April 2024

Background

The rising use of “Kush” among Sierra Leone’s youth is a public health concern. Kush, a concoction of Cannabis indica and synthetic substances, symbolizes the broader issue of drug misuse in low-income settings. This study explored the intricacies of Kush use among young Sierra Leoneans, highlighting the gravity of the crisis.

Methods

The research employed a phenomenological method, gathering insights through Focus Group Discussions (FGDs), Key Informant Interviews (KIIs), and In-Depth Interviews (IDIs) to understand the motivations and repercussions of Kush consumption. Selecting participants from diverse socio-demographic groups, the study included habitual users and those in vulnerable situations. Ten interviews were analyzed thematically, facilitated by NVivo software and Concept maps, to distill information.

Results

Findings identified numerous reasons for Kush use, from managing stress and trauma to seeking social belonging and economic necessity. Users experienced severe health issues, economic instability, and productivity loss. The effects varied by Kush strain, underscoring its heterogeneous nature. Despite a strong will to quit, influenced by health, family, and aspirations, youths faced hurdles like withdrawal symptoms, peer pressure, and scarce support systems.

Conclusion

Kush consumption in Sierra Leonean youths is entwined with socioeconomic and post-conflict factors, leading to significant adverse effects. Effective intervention requires a multifaceted strategy, focusing on underlying drug abuse causes and providing robust support systems. This study calls for tailored measures and policies that acknowledge the complex motivations behind Kush use and its impacts, aiming to foster an environment conducive to youth empowerment and health.
Evaluating the impact of the Mellow Babies group-based parenting programme for supporting at-risk mothers in Tajikistan
Authors: Duncan Natalie , Jones Ailsa , Tainsh Rachel , Muhamedjonova Nazira , Ibrahim Raquib , MacBeth Angus
Published: April 2024

Parental mental health has a long-lasting impact on developmental outcomes for infants and children through its impact on the family environment. Targeted parenting interventions should address both parental health and parenting skills. However, data is limited on how interventions perform in Central Asian populations.

Using routine evaluation data from n=194 participants, we modelled the effectiveness of the Mellow Babies (MB) programmes, delivered to mothers from Tajikistan and their children as part of a community support approach. Pre-post intervention changes were measured on depression, anxiety, parenting stress, quality of life, and child behaviour outcomes. Demographics were modelled as covariates.

Participation in MB was associated with improvements in maternal mental health, parenting stress, quality of life and child behaviour. Demographic factors moderated interactions between pre and post intervention outcomes, including urban/rural differences, parental employment, marital status and child disability status. Our findings suggest that MB is acceptable, effective and potentially scalable as a parenting intervention in Tajikistan. Future replication using implementation designs and replication of MB in other global settings is merited.
Primary health facility readiness to care for infants under six months at risk of poor growth and development: A HHFA-based survey
Authors: van Immerzeel Tabitha D. , Ba Abou , Diagne Maty , Deme-Ly Indou , Murungi Amanda E. , Penzias Rebecca , Seck Daouda , Diallo Abdallah , Grijalva-Eternod Carlos S. , Kerac Marko , Day Louise T.
Published: April 2024

Malnutrition in infants under six months of age (u6m) is poorly identified and managed in many countries, increasing these children’s risk of poor growth and development and preventable mortality and morbidity. New 2023 WHO malnutrition guidelines recommend assessment, classification and treatment at primary health care level. This study aimed to assess primary health facility availability and readiness for WHO-recommended nutritional care in infants u6m.

We adapted the WHO Harmonized Health Facility Assessment (HHFA) with additional items forManagement of small and nutritionallyAt-risk Infants u6m and theirMothers (MAMI): the HHFA-MAMI tool. Methods included survey of health care providers, direct observation and data extraction from routine registers to calculate mean percentages of a set of items for different readiness areas. We assessed 15 primary health facilities in Senegal, focusing on the five contact points for infants u6m: delivery and postnatal care, immunization programmes, sick child clinics and community health care.

The HHFA-MAMI mean scores (n=15) were: general service availability 51%, general service readiness 69%, management & finance 50%, clinical quality of care 47%. MAMI availability scored 48% and readiness 35%, MAMI infrastructure scored 72%, health workforce 61%, assess MAMI 54%, classify MAMI 15% and treat MAMI 38%, equipment 33% and guidelines & training 22%. Service utilization was highest in postnatal care and immunization contact points, MAMI availability & readiness was highest in delivery and postnatal care.

We conclude that primary health facilities in Senegal have potential to care for infants u6m at risk of poor growth and development with high general PHC readiness and frequent use of care contact points for infants u6m. MAMI availability and readiness require improvements to provide WHO-recommended care.
Assessment of Donated Medications and their Use in Tikur Anbessa Specialized Hospital: Promoting Green Health and Circular Economy
Authors: Alemaw Elbethel Getinet , Demisse Bezawit Negash
Published: April 2024

Introduction

Despite the increased access to medicine, developing countries receive large amounts of medicines from donations. Donated medication could save lives and alleviate suffering but they could also cause deleterious effects on recipients. These effects can lead to the disposal of harmful drugs, affecting health infrastructure and causing negative. Organizations donate drugs for various reasons, including charitable, publicity, or humanitarian reasons. Despite the need for donated drugs, drug dumping remains a prevalent issue in Sub-Saharan Africa.

The volume of pharmaceutical waste that accumulates worldwide is now a major concern. The idea of a sustainable, circular bioeconomy on a global scale is appealing. It prioritizes environmental sustainability and human well-being atop economic recovery.

The primary objective of this study was to evaluate the status of donated medicines in Tikur Anbessa Specialized Hospital (TASH) and develop suggestions. Medicines donated from April 2022 up to May 2022 were included in this study

Materials and Methods

A cross-sectional survey conducted at an institutional level employed both quantitative and qualitative research methodologies. The study was conducted from April 2022 to May 2022, focusing on pharmaceuticals donated to Tikur Anbessa Specialized Hospital (TASH) between November 2021 and March 2022. For the qualitative part, employees of Tikur Anbessa Specialized Hospital (TASH) working at different dispensary units, and pharmaceutical stores constituted the source population.

Results and recommendations

A total of six donors contributed a combined value of 11,715,389 Ethiopian birr worth of medicines, supplies, and equipment. The donated items comprised 45 product categories and a total of 160 individual products. Among these, the most prevalent product categories included Opioids (27.48%), ASRVI (10.22%), PDE-5 Inhibitors (7.70%), Antihemophilic agents (7.34%), Antibiotics (7.02%), Anticonvulsants (5.67%), and Antifungals (3.36%). Management of medicines, supplies, and equipment at Tikur Anbessa Specialized Hospital (TASH) is facilitated through the Pharmaceutical Management Information System (PMIS), similar to other medication management processes. The acquisition of donated medications primarily occurs through both recipient requests and donor initiatives. Delivery of drugs near expiry, too small amount, discontinuation, disposal cost and push pull scenario were among the problems. Simple effective communication among donors and the hospital can uplift these problems and enhance the positive impacts of donations. Furthermore, the hospital needs to update its policy on donation and schedule donations to optimize the effects of donations; as a result promoting sustainability.
The impact of COVID vaccination on incidence of long COVID and healthcare resource utilisation in a primary care cohort in England, 2021-2022
Authors: Yang Jingyan , Rai Kiran K. , Alfred Tamuno , Massey Lucy , Massey Olivia , McGrath Leah , Andersen Kathleen M. , Tritton Theo , Tsang Carmen , Butfield Rebecca , Reynard Charlie , Mendes Diana , Nguyen Jennifer L
Published: April 2024

Background

Long COVID, a diverse set of symptoms that persist after a minimum of 4 weeks from the initial SARS-CoV-2 infection, has posed substantial burden to healthcare systems. There is some evidence that COVID-19 vaccination may be associated with lower risk of long COVID. However, little is known about the association between vaccination status and long COVID-associated healthcare resource utilisation (HCRU) and costs.

Methods

We conducted a cohort study using primary care electronic health record data in England from the Clinical Practice Research Datalink (CPRD) Aurum dataset linked to Hospital Episode Statistics where applicable. Adult (≥18 years) patients were indexed on a COVID-19 diagnosis between 1stMarch 2021 and 1stDecember 2021. Vaccination status was assessed at index: unvaccinated or completed primary series (two doses for immunocompetent and three doses for immunocompromised patients). Covariate balance was conducted using entropy balancing. Weighted multivariable Poisson regression was used to estimate the incidence rate ratio (IRR) for incident long COVID, and separately long COVID primary care resource use, by vaccination status. Patients were followed up to a maximum of 9-months post index.

Results

A total of 35,713 patients who had completed primary series vaccination, and 75,522 unvaccinated patients were included. The weighted and adjusted IRR for long COVID among patients vaccinated with the primary series compared to being unvaccinated was 0.81 (95% CI: 0.77-0.86) in the overall cohort, 0.83 (95% CI: 0.78-0.88) in the immunocompetent cohort and 0.28 (95% CI: 0.13-0.58) in the immunocompromised cohort. Among those with long COVID, there was no association between the rate of primary care consultations and vaccination status in the overall and immunocompetent cohorts. Cost of primary care consultations was greater in the unvaccinated group than for those who completed primary series.

Conclusion

Vaccination against COVID-19 may reduce the risk of long COVID in both immunocompetent and immunocompromised patients. However, no association was found between frequency of primary care visits and vaccination among patients diagnosed in 2021. Future studies with larger sample size, higher vaccine uptake, and longer study periods during the pandemic are needed to further quantify the impact of vaccination on long COVID.
Initial treatment choices for long term remission of insomnia disorder in adults: a systematic review and network meta-analysis
Authors: Furukawa Yuki , Sakata Masatsugu , Furukawa Toshi A. , Efthimiou Orestis , Perlis Michael
Published: April 2024

Background

Cognitive behavioral therapy for insomnia (CBT-I), pharmacotherapy and their combination are effective for insomnia. However, it remains unclear which treatment is more likely to lead to favorable long-term outcomes when used as the initial treatment. We aimed to evaluate the comparative efficacy and acceptability of CBT-I, pharmacotherapy, and their combination in the long- and short-terms among adults with insomnia disorder.

Methods

We searched PubMed, CENTRAL, PsycINFO and WHO ICTRP from database inception to Dec 27, 2023, to identify published and unpublished randomized controlled trials. We included trials in hypnotic-free adults with insomnia disorder comparing at least two of the following: CBT-I with at least one effective component (sleep restriction, stimulus control, cognitive restructuring, and third wave components), pharmacotherapy, or their combination. We assessed the confidence in evidence using CINeMA. The primary outcome was long-term remission (longest follow-up between 3 to 12 months). Secondary outcomes included all-cause dropout and self-reported sleep continuity measures at long-term follow-up, and the same outcomes at the end of the acute treatment phase. We performed frequentist random-effects network meta-analyses. We used odds ratio (OR) for dichotomous outcomes and mean difference for continuous outcomes, expressed in minutes and percent. This study is registered in PROSPERO (CRD42024505519).

Findings

We identified 13 trials, including 823 randomized participants (mean age, 47.8 years, 60% women). Results suggested that CBT-I was more beneficial than pharmacotherapy in the long-term (remission OR 1.82 [95% Confidence Interval (CI), 1.15 to 2.87; certainty of evidence: high]), while there was weaker evidence of benefit of combination against pharmacotherapy (OR 1.71 [95%CI, 0.88 to 3.30: moderate]) and no clear evidence of difference of CBT-I against combination (OR 1.07 [95%CI, 0.63 to 1.80: moderate]). CBT-I was associated with less dropouts than pharmacotherapy in the long-term. Short-term outcomes also favored CBT-I over pharmacotherapy except total sleep time. Given the average long-term remission rate in the pharmacotherapy-initiating arms of 28%, CBT-I resulted in a long-term remission rate of 41% (95% CI: 31% to 53%) and combination 40% (95% CI: 25% to 56%).

Interpretation

This study found that starting with CBT-I for the treatment of adults with chronic insomnia leads to better outcomes than starting with pharmacotherapy. Combination therapy may be better than pharmacotherapy alone, but unlikely to be worth the additional burden over CBT-I alone.

Funding

None.