bluuebunny/crossref_metadata_2025 huggingface dataset:
P-617 WORK-BREAKS FOR PREVENTING MUSCULOSKELETAL DISORDERS IN HEALTHY WORKERS – A COCHRANE REVIEW UPDATE
Authors: Luger Tessy , Rieger Monika , Steinhilber Benjamin
Published: July 2024

Introduction

Work-related musculoskeletal disorders comprise one of the most common disorders related to occupational sick leave worldwide accounting for about 25% of work absenteeism days. This review focusses on work breaks as a measure of primary prevention, which are a type of organisational intervention. With this review update, we compare the effectiveness of different work-break schedules for preventing work-related musculoskeletal symptoms and disorders in healthy workers, compared to conventional or alternate work-break schedules on potential additional literature.

Methods

We will provide an updated search of the literature (May 2019) for randomized controlled trials that enrolled adult workers free of musculoskeletal symptoms and assessed one or more work-break interventions including changes in frequency, duration and/or type. The primary outcomes are newly diagnosed musculoskeletal disorders, self-reported musculoskeletal pain, discomfort or fatigue, and productivity or work performance. Two review authors will independently screen the literature for additional eligible studies, extract data, perform meta-analyses, assess risk of bias and assess overall quality of the evidence.

Results

At present, six studies (373 workers) investigated different work-break frequencies (five studies) and types (two studies), but none of the comparisons revealed significant influences on the primary outcomes. All studies had high risk of bias and quality of evidence was (very) low.

Conclusion

At present, we concluded that different work-break frequencies and types may not considerably reduce incidence of musculoskeletal disorders. The review update may provide some extra insights, although there still is a need for high-quality studies to assess the effectiveness of different work-break interventions on a larger variety of worker populations.
Diagnosis and Treatment of Presumed Naltrexone-XR–precipitated Opioid Withdrawal in a Patient Chronically Treated With Buprenorphine-XR: A Case Report
Authors: Moore Jessica , Foo Kalvin , Egu Ernest , Gao Xin , Ehrman-Dupre Rachel , Salzman Matthew
Published: July 2024

Naltrexone, buprenorphine, and methadone are Food and Drug Administration–approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment.
Fetal Exposure to Tobacco Metabolites and Depression During Adulthood: Beyond Binary Measures
Authors: Shenassa Edmond D. , Gleason Jessica L. , Hirabayashi Kathryn
Published: July 2024

Background:

Sibling studies of maternal smoking during pregnancy and subsequent risk of depression have produced mixed results. A recent study identified not considering the amount of maternal smoking and age of onset as potentially masking a true association. We examine these issues and also the amount of maternal smoking during pregnancy as a determinant of the severity of depressive symptoms.

Methods:

We analyzed data from the community-based National Longitudinal Survey of Youth (US, 1994–2016). Mothers reported smoking during pregnancy (none, <1 pack/day, ≥1 pack/day). We assessed offspring’s lifetime depression (i.e., ≥8 symptoms) and symptom counts with the Centers for Epidemiologic Studies Depression scale. We estimated the risk of these two outcomes in the full sample (n = 7172) and among siblings (n = 6145) using generalized linear mixed-effects models with random intercepts by family and family-averaged means for sibling analyses.

Results:

Among siblings, we observed dose-dependent elevations for both risk of depression (smoking during pregnancy <1 pack/day adjusted risk ratio [aRR] = 1.18; 95% confidence interval [CI] = 1.07, 1.30; smoking ≥1 aRR = 1.36; 95% CI = 1.19, 1.56) and severity of depressive symptoms (smoking <1 pack/day aRR = 1.12; 95% CI = 1.08, 1.16); smoking ≥1 pack/day aRR = 1.25; 95% CI = 1.18, 1.31). Among both samples, the P for trend was <0.01. In analysis limited to offspring diagnosed before age 18, results for severity were attenuated.

Conclusions:

This evidence supports the existence of an independent association between maternal smoking during pregnancy and both the risk of depression and the severity of depressive symptoms. The results highlight the utility of considering the amount of smoking, severity of symptoms, and age of onset.
The impact of surging transplantation of alcohol-associated liver disease on transplantation for HCC and other indications
Authors: Ayyala-Somayajula Divya , Dodge Jennifer L. , Zhou Kali , Terrault Norah A. , Yuan Liyun
Published: July 2024

Background:

Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications.

Methods:

Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%–37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p).

Results:

Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66–1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96–1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87–1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72–1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67–1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80–1.34]) suggesting a differential impact of ATxV on LT probability.

Conclusions:

The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.
NUAK1 promotes metabolic dysfunction-associated steatohepatitis progression by activating Caspase 6–driven pyroptosis and inflammation
Authors: Sheng Mingwei , Huo Shuhan , Jia Lili , Weng Yiqi , Liu Weihua , Lin Yuanbang , Yu Wenli
Published: July 2024

Background:

lNUAK1 is strongly associated with organ fibrosis, but its causal mechanism for modulating lipid metabolism and hepatic inflammation underlying MASH has not been fully clarified.

Method:

In our study, human liver tissues from patients with MASH and control subjects were obtained to evaluate NUAK1 expression. MASH models were established using C57BL/6 mice. Liver damage and molecular mechanisms of the NUAK1-Caspase 6 signaling were tested in vivo and in vitro.

Results:

In the clinical arm, NUAK1 expression was upregulated in liver samples from patients with MASH. Moreover, increased NUAK1 was detected in mouse MASH models. NUAK1 inhibition ameliorated steatohepatitis development in MASH mice accompanied by the downregulation of hepatic steatosis and fibrosis. Intriguingly, NUAK1 was found to facilitate Caspase 6 activation and trigger pyroptosis in MASH-stressed livers. Disruption of hepatocytes Caspase 6 decreased MASH-induced liver inflammation with upregulated TAK1 but diminished RIPK1. Moreover, we found that NUAK1/Caspase 6 axis inhibition could accelerate the interaction between TAK1 and RIPK1, which in turn led to the degradation of RIPK1.

Conclusions:

In summary, our study elucidates that NUAK1-Caspase 6 signaling controls inflammation activation in MASH through the interaction between TAK1 and RIPK1, which is crucial for controlling pyroptosis and promoting the progression of MASH.
Loss of β-catenin reveals a role for glutathione in regulating oxidative stress during cholestatic liver disease
Authors: Balogun Oluwashanu , Shao Daniel , Carson Matthew , King Thalia , Kosar Karis , Zhang Rong , Zeng Gang , Cornuet Pamela , Goel Chhavi , Lee Elizabeth , Patel Garima , Brooks Eva , Monga Satdarshan P. , Liu Silvia , Nejak-Bowen Kari
Published: July 2024

Background:

Cholestasis is an intractable liver disorder that results from impaired bile flow. We have previously shown that the Wnt/β-catenin signaling pathway regulates the progression of cholestatic liver disease through multiple mechanisms, including bile acid metabolism and hepatocyte proliferation. To further explore the impact of these functions during intrahepatic cholestasis, we exposed mice to a xenobiotic that causes selective biliary injury.

Methods:

α-naphthylisothiocyanate (ANIT) was administered to liver-specific knockout (KO) of β-catenin and wild-type mice in the diet. Mice were killed at 6 or 14 days to assess the severity of cholestatic liver disease, measure the expression of target genes, and perform biochemical analyses.

Results:

We found that the presence of β-catenin was protective against ANIT, as KO mice had a significantly lower survival rate than wild-type mice. Although serum markers of liver damage and total bile acid levels were similar between KO and wild-type mice, the KO had minor histological abnormalities, such as sinusoidal dilatation, concentric fibrosis around ducts, and decreased inflammation. Notably, both total glutathione levels and expression of glutathione-S-transferases, which catalyze the conjugation of ANIT to glutathione, were significantly decreased in KO after ANIT. Nuclear factor erythroid-derived 2-like 2, a master regulator of the antioxidant response, was activated in KO after ANIT as well as in a subset of patients with primary sclerosing cholangitis lacking activated β-catenin. Despite the activation of nuclear factor erythroid-derived 2-like 2, KO livers had increased lipid peroxidation and cell death, which likely contributed to mortality.

Conclusions:

Loss of β-catenin leads to increased cellular injury and cell death during cholestasis through failure to neutralize oxidative stress, which may contribute to the pathology of this disease.
Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction–associated steatotic liver disease
Authors: Kaplan David E. , Teerlink Craig C. , Schwantes-An Tae-Hwi , Norden-Krichmar Trina M. , DuVall Scott L. , Morgan Timothy R. , Tsao Philip S. , Voight Benjamin F. , Lynch Julie A. , Vujković Marijana , Chang Kyong-Mi
Published: July 2024

Background:

Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction–associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, “slope” of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort.

Methods:

In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL.

Results:

FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10−8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10−11; LINC01088, 3.9 × 10−8; and MRC1, 2.9 × 10−9).

Conclusions:

Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.
MULTIMODAL IMAGING OF DIDANOSINE-RELATED RETINOPATHY
Authors: Alexander João Gabriel , Samico Gustavo Albrecht , Ribeiro Lucas Zago , Vasconcelos Júnior Huber Martins
Published: July 2024

Purpose:

To describe multimodal imaging findings in a rare case of didanosine-related retinopathy.

Methods:

Case report.

Results:

55-year-old male patient presenting peripheral visual loss and nyctalopia for the last 8 years in both eyes. Previous medical history of HIV, and use of didanosine for almost 10 years. Fundus examination, autofluorescence, and optical coherence tomography showed bilateral symmetrical peripheral chorioretinal atrophy, sparing the posterior pole. Genetic testing was performed to exclude inherited retinopathies.

Conclusion:

DDI-related chorioretinal toxicity is a rare disease, with few reports in the literature. Multimodal imaging and genetic testing were essential for precise diagnosis. The limitation of this report includes the late presentation of the patient to our clinic, making the evaluation difficult to determine early signs of toxicity and to determine the precise length of DDI treatment and whether or not the degeneration progressed shortly after cessation of the medication.
Intensity, Characteristics, and Factors Associated With Receipt of Care Coordination Among High-Risk Veterans in the Veterans Health Administration
Authors: Govier Diana J. , Hickok Alex , Niederhausen Meike , Rowneki Mazhgan , McCready Holly , Mace Elizabeth , McDonald Kathryn M. , Perla Lisa , Hynes Denise M.
Published: July 2024

Background:

The Veterans Health Administration (VHA) has initiatives underway to enhance the provision of care coordination (CC), particularly among high-risk Veterans. Yet, evidence detailing the characteristics of and who receives VHA CC is limited.

Objectives:

We examined intensity, timing, setting, and factors associated with VHA CC among high-risk Veterans.

Research Design:

We conducted a retrospective observational cohort study, following Veterans for 1 year after being identified as high-risk for hospitalization or mortality, to characterize their CC. Demographic and clinical factors predictive of CC were identified via multivariate logistic regression.

Subjects:

A total of 1,843,272 VHA-enrolled high-risk Veterans in fiscal years 2019-2021.

Measures:

We measured 5 CC variables during the year after Veterans were identified as high risk: (1) receipt of any service, (2) number of services received, (3) number of days to first service, (4) number of days between services, and (5) type of visit during which services were received.

Results:

Overall, 31% of high-risk Veterans in the sample received CC during one-year follow-up. Among Veterans who received ≥1 service, a median of 2 [IQR (1, 6)] services were received. Among Veterans who received ≥2 services, there was a median of 26 [IQR (10, 57)] days between services. Most services were received during outpatient psychiatry (46%) or medicine (16%) visits. Veterans’ sociodemographic and clinical characteristics were associated with receipt of CC.

Conclusions:

A minority of Veterans received CC in the year after being identified as high-risk, and there was variation in intensity, timing, and setting of CC. Research is needed to examine the fit between Veterans’ CC needs and preferences and VHA CC delivery.
Familial Hemophagocytic Lymphohistiocytosis Screening in Neonatal Sepsis
Authors: Kadi Ozan Zuhre , Erduran Erol , Ceylaner Serdar , Aslan Yakup , Bahadir Aysenur , Reis Gokce P. , Mutlu Mehmet
Published: July 2024

Objective:

Neonatal sepsis and familial hemophagocytic lymphohistiocytosis (fHLH) have similar clinical and laboratory symptoms and the possibility of overlooking fHLH diagnosis is high in newborns with sepsis. History of consanguineous marriage and/or sibling death, hepatomegaly/splenomegaly, and hyperferritinemia (>500 ng/mL) are likely to support fHLH in newborns with sepsis. Therefore, in newborns with sepsis in whom at least 2 out of these 3 criteria were detected, genetic variants was investigated for the definitive diagnosed of fHLH. According to the results of genetic examination, we investigated whether these criteria supporting fHLH could be used as a screening test in fHLH.

Materials and Methods:

fHLH-associated genetic variants were investigated in 22 patients diagnosed with neonatal sepsis who fulfilled at least 2 out of the following criteria (1) history of consanguineous marriage and/or sibling death, (2) hepatomegaly/splenomegaly, and (3) hyperferritinemia (>500 ng/mL)

Results:

Heterozygous variants were determined in 6 patients (27.2%): 3 STXBP2, 1 STX11, 1 UNC13D, and 1 PRF1. Polymorphisms associated with the clinical symptoms and signs of HLH were determined in 5 patients (22.7%): 4 UNC13D, 1 PRF1. Two patients were in the heterozygous variants and polymorphism associated with the clinical symptoms and signs of HLH groups. In 12 patients, benign polymorphisms were detected in STXBP2 and UNC13D genes. No change in fHLH associated genes were found in 1 patient.

Conclusion:

Some variants and/or polymorphisms identified in our patients have been previously reported in patients with HLH. Therefore, we recommend further investigation of fHLH in patients with neonatal sepsis who fulfill at least 2 out of the above 3 criteria.
Automatic Segmentation of Heschl Gyrus and Planum Temporale by MRICloud
Authors: Perez-Heydrich Carlos A. , Padova Dominic , Kutten Kwame , Ceritoglu Can , Faria Andreia , Ratnanather J. Tilak , Agrawal Yuri
Published: July 2024

Objectives:

This study used a cloud-based program, MRICloud, which parcellates T1 MRI brain scans using a probabilistic classification based on manually labeled multi-atlas, to create a tool to segment Heschl gyrus (HG) and the planum temporale (PT).

Methods:

MRICloud is an online platform that can automatically segment structural MRIs into 287 labeled brain regions. A 31-brain multi-atlas was manually resegmented to include tags for the HG and PT. This modified atlas set with additional manually labeled regions of interest acted as a new multi-atlas set and was uploaded to MRICloud. This new method of automated segmentation of HG and PT was then compared to manual segmentation of HG and PT in MRIs of 10 healthy adults using Dice similarity coefficient (DSC), Hausdorff distance (HD), and intraclass correlation coefficient (ICC).

Results:

This multi-atlas set was uploaded to MRICloud for public use. When compared to reference manual segmentations of the HG and PT, there was an average DSC for HG and PT of 0.62 ± 0.07, HD of 8.10 ± 3.47 mm, and an ICC for these regions of 0.83 (0.68–0.91), consistent with an appropriate automatic segmentation accuracy.

Conclusion:

This multi-atlas can alleviate the manual segmentation effort and the difficulty in choosing an HG and PT anatomical definition. This protocol is limited by the morphology of the MRI scans needed to make the MRICloud atlas set. Future work will apply this multi-atlas to observe MRI changes in hearing-associated disorders.
How to Disclose Internal Carotid Artery Dehiscence in Patients With Eustachian Tube Dysfunction: Cone Beam Computed Tomography or High-resolution Computed Tomography?
Authors: Holm Niels Højvang , Molnár Balázs , Ovesen Therese
Published: July 2024

Objective:

To compare the prevalence of internal carotid artery dehiscence (ICAD) on high-resolution computed tomography (HRCT) and cone beam computed tomography (CBCT) in patients with Eustachian tube dysfunction (ETD).

Study Design:

A prospective, cohort study.

Setting:

The outpatient clinic at the Department of Otorhinolaryngology, Head and Neck Surgery at Gødstrup Hospital, Denmark (tertiary referral center).

Patients:

Patients >18 years of age diagnosed with long-standing ETD undergoing HRCT and/or CBCT prior to balloon Eustachian tuboplasty.

Intervention(s):

Patients had either initially HRCT and later CBCT performed (HRCT + CBCT group) or solely CBCT (CBCT group).

Main Outcome Measure(s):

Prevalence of ICAD assessed with HRCT and CBCT.

Results:

A total of 23 patients were included in the HRCT + CBCT group and 36 patients in the CBCT group. In the HRCT + CBCT group, ICAD was found in 13 temporal bones (28.3%) with HRCT and 7 temporal bones (15.2%) with CBCT (P = 0.0003). No new cases of ICAD were found with CBCT. In the CBCT group, ICAD was found in 6 temporal bones (8.3%). In both HRCT and CBCT, patients suffered from ETD in 61.5% of the ears where ICAD was found.

Conclusions:

CBCT has a higher specificity than HRCT in diagnosing ICAD in patients with ETD while at the same time using less radiation.
18F-THK5351 Uptake May Not Estimate Neurofibrillary Tangles in In Vivo Images
Authors: Ishibashi Kenji , Tago Tetsuro , Kameyama Masashi , Toyohara Jun , Ishii Kenji
Published: July 2024

Currently, monoamine oxidase B is recognized as the primary target of 18F-THK5351, although 18F-THK5351 was initially developed to target neurofibrillary tangles (NFTs) in Alzheimer disease. When clinically applying 18F-THK5351 PET to visualize ongoing astrogliosis via estimating monoamine oxidase B levels, a crucial concern is how much degree 18F-THK5351 uptake reflects NFTs in in vivo images. To unravel this concern, a head-to-head comparison between 18F-THK5351 and 18F-MK-6240 (estimating NFT) images in the NFT lesion ideally without accompanying astrogliosis is essential. Here, we present such a case suggesting that 18F-THK5351 uptake may not estimate NFTs in in vivo images.
Regression for accurate and sensitive grading of mutations diagnostic of antibiotic resistance inMycobacterium tuberculosis
Authors: Kulkarni Sanjana G. , Laurent Sacha , Miotto Paolo , Walker Timothy M. , Chindelevitch Leonid ,   WHO sequencing network, Nathanson Carl-Michael , Ismail Nazir , Rodwell Timothy C. , Farhat Maha R.
Published: July 2024

Rapid genotype-based drug susceptibility testing for theMycobacterium tuberculosiscomplex (MTBC) relies on a comprehensive knowledgebase of the genetic determinants of resistance. We built a catalog of resistance-associated mutations in MTBC using a novel regression-based approach and benchmarked it against the 2ndedition of the World Health Organization mutation catalog. We trained multivariate logistic regression models on over 50,000 MTBC isolates to associate binary resistance phenotypes for 15 antitubercular drugs with variants extracted from candidate resistance genes. Regression detects 452/457 (99%) resistance-associated variants identified using the existing method (a.k.a,SOLO method) and grades 218 (29%) more total variants than SOLO. The regression-based catalog achieves higher sensitivity on average (+3.2 percentage points, pp) than SOLO with smaller average decreases in specificity (−1.0 pp) and positive predictive value (−1.8 pp). The regression pipeline also detects isoniazid resistance compensatory mutations inahpCand variants linked to bedaquiline and aminoglycoside hypersusceptibility. These results inform the continued development of targeted next generation sequencing, whole genome sequencing, and other commercial molecular assays for diagnosing resistance in MTBC. In addition to grading genetic variants by their associations with phenotype, regression models could potentially provide an accurate and scalable method of predicting antibiotic resistance from bacterial genetic profiles.
Active trachoma among children aged 1-9 years in Ethiopia: A meta-analysis from 2019 to 2024
Authors: Abore Kibruyisfaw Weldeab , Asebot Melat Tesfaye , Kebede Gifty Birhanemeskel , Khasay Robel Tibebu , Akuma Asonya Abera , Dagne Mahlet Minwuyelet , Tesfaye Tewobesta Fesseha , Abebe Mahlet Tesfaye , Fole Estifanos Bekele
Published: July 2024

Background

Trachoma is a leading infectious cause of blindness and of significant public health concern targeted for elimination. This study aimed to systematically summarize the magnitude of active trachoma among children aged 1-9 in Ethiopia from 2019-2024

Methods

Database searches were conducted on Google Scholar, SCOPUS, PubMed, EMBASE, and AJOL for studies published between January 2019 to 31-March-2024 and with restriction to articles published only in English. Data extraction was done using a pre-prepared Excel sheet. STATA version 17 was used to perform the analysis. Heterogeneity between studies was assessed using I2statistics and Cochrane Q. Qualitative synthesis was done to summarize the studies and random effect model was used to estimate the Pooled magnitude of active trachoma with a corresponding 95% confidence interval.

Result

A total of 17 studies with 19793 subjects were included in the meta-analysis. The pooled magnitude of active trachoma among children aged 1-9 years was found to be 18.4% (95% CI: 13.88, 22.91). We found a statistically significant heterogeneity between studies. Among the regions, Southwest region was found to have the highest magnitude (44.1%) (95%CI: 41.8%, 46.4%) and Dire Dawa was found to have the lowest (4.3%) (95%CI: 2.9%, 5.7%).

Conclusion

The magnitude of active trachoma is higher than the WHO target for elimination. There was significant interregional difference in magnitude of active trachoma. Strengthening SAFE strategy and health education and promotion is recommended.
Plasma membrane folding enables constant surface area-to-volume ratio in growing mammalian cells
Authors: Wu Weida , Lam Alice R. , Suarez Kayla , Smith Grace N. , Duquette Sarah M. , Yu Jiaquan , Mankus David , Bisher Margaret , Lytton-Jean Abigail , Manalis Scott R. , Miettinen Teemu P.
Published: July 2024

All cells are subject to geometric constraints, including the surface area-to-volume (SA/V) ratio, which can limit nutrient uptake, maximum cell size, and cell shape changes. Like the SA/V ratio of a sphere, it is generally assumed that the SA/V ratio of cells decreases as cell size increases. However, the structural complexity of the plasma membrane makes studies of the surface area challenging in cells that lack a cell wall. Here, we investigate near-spherical mammalian cells using single-cell measurements of cell mass and plasma membrane proteins and lipids, which allows us to examine the cell size scaling of cell surface components as a proxy for the SA/V ratio. Surprisingly, in various proliferating cell lines, cell surface components scale proportionally with cell size, indicating a nearly constant SA/V ratio as cells grow larger. This behavior is largely independent of the cell cycle stage and is also observed in quiescent cells, including primary human monocytes. Moreover, the constant SA/V ratio persists when cell size increases excessively during polyploidization. This is enabled by increased plasma membrane folding in larger cells, as verified by electron microscopy. We also observe that specific cell surface proteins and cholesterol can deviate from the proportional size scaling. Overall, maintaining a constant SA/V ratio ensures sufficient plasma membrane area for critical functions such as cell division, nutrient uptake, growth, and deformation across a wide range of cell sizes.
Mesolimbic local field potentials are modulated by motor control
Authors: Mann Leah G , Qian Helen , Hughes Natasha Cindy , Zhao Zixiang , Singh Balbir , Wang Zhengyang , Johnson Graham W. , Fulton Jenna N. , Yan Bailu , Kang Hakmook , Li Rui , Dawant Benoit M. , Englot Dario J. , Constantinidis Christos , Roberson Shawniqua Williams , Claassen Daniel O. , Bick Sarah K.
Published: July 2024

Background and Objectives

While historically cortico-basal ganglia-thalamocortical loops were believed to process limbic and sensorimotor data in parallel, there is now evidence to suggest that the two information streams can be processed in a single open loop. However, the limbic-motor interface remains insufficiently characterized. We sought to further investigate how extrastriatal regions may regulate motor output by examining electrophysiological activity in these areas during a response inhibition paradigm.

Methods

We recorded local field potentials (LFPs) from epilepsy patients implanted with intracranial depth electrodes for seizure localization purposes. Participants performed the stop-signal task, during which they made speeded choice reactions to “go” stimuli and occasionally inhibited their reactions in the incident of a “stop” signal. To compare power during movement and the absence of movement, we applied a Wilcoxon signed-rank test. Additionally, we performed a linear mixed-effects model to relate power in limbic regions to power in the motor cortex. Finally, we implemented exploratory analyses to identify power differences for correct go versus correct stop trials and for correct stop versus incorrect stop trials using cluster-based permutation testing.

Results

14 patients participated. A comparison between movement and baseline fixation revealed that motor response is associated with reduced beta (15-35 Hz) power in the amygdala, hippocampus, and motor cortex and reduced gamma (35-100 Hz) power in the amygdala and hippocampus. Moreover, average beta and gamma power in the amygdala and hippocampus during motor execution were positively associated with average beta and gamma power in the motor cortex. Additionally, we identified significant differences between correct go and stop trials in delta (1-4 Hz) power for all three regions and in theta (4-8 Hz) power for the amygdala and motor cortex. Likewise, we identified significant differences between correct and incorrect stop trials in delta power for the hippocampus and motor cortex, in theta power for the motor cortex, in alpha (8-15 Hz) and beta power for the amygdala and motor cortex, and in gamma power for all three areas.

Discussion

These correlations between neural oscillations in the hippocampus and amygdala and movement strengthen the notion of mesolimbic modulation of motor activity.
Detecting Delta and Omicron co-infection cases in the Philippines from SARS-CoV-2 genomic surveillance
Authors: Realingo Adeliza Mae L. , Polotan Francisco Gerardo M. , Abulencia Miguel Francisco B. , Pantoni Roslind Anne R. , Capin Jessel Babe G. , Sotelo Gerald Ivan , Corpuz Maria Carmen A. , Yabut Neil Tristan M. , Rojas Saul M. , Nicolasora Amalea Dulcene , Tujan Ma. Angelica , Tomas Karen Iana , Dolor Ardiane Ysabelle , Celis Czarina Christelle Alyannah , Ortia Stephen Paul , Melo Ezekiel , Reyes Chelsea Mae , Flores Elijah Miguel P. , Alpino Anne Pauline A. , Penales Aldwin Kim A. , Medina Kathlene Mae C. , Manalo Joanna Ina , Dizon Timothy John R. , Hampson Katie , Kasaragod Sandeep , Hughes Joseph , Brunker Kirstyn
Published: July 2024

Co-infection with multiple SARS-CoV-2 variants, though rare, may have clinical and public health implications, including facilitating variant recombination. Early detection of co-infections is therefore crucial. In this study, we report two probable cases of co-infection identified during routine genomic surveillance. Initially suspected as cross-contamination due to the presence of private mutations and nucleotide mixtures flagged by Nextclade and bammix, the samples were re-extracted and resequenced after workspace decontamination, yet the anomalies persisted. To investigate further, we developed a bioinformatics pipeline incorporating tools such as Pangolin, Nextclade, and bammix, which consistently revealed lineage inconsistencies and nucleotide mixtures in both samples. Lineage abundance results from Freyja supported the presence of multiple variants within each sample, while VirStrain confirmed the inconsistent lineage assignment. We also visualised the alternative allele fractions for each lineage-defining mutation and amplicon, which revealed evidence of two variants — Delta and Omicron — co-existing within a single amplicon, indicative of co-infection. Amplicon sorting effectively separated the reads corresponding to the two variants, and the resulting consensus sequences aligned with their respective lineage assignments. These findings suggest that the first sample, PH-RITM-1395, involved a Delta-Omicron co-infection, while the second sample, PH-RITM-4146, was a recombinant case. To further support the second sample’s recombinant nature, we employed sc2rf, which identified breakpoints consistent with Delta-Omicron recombination. Retrospective analysis of 1,078 samples from July 2021 to July 2022, encompassing the period of co-circulation of different variants in the Philippines, flagged four additional co-infection cases, including Delta-Omicron and Beta-Omicron suggesting a lower bound co-infection rate of 0.27%, and 0.19%, respectively. Our findings underscore the critical importance of real-time genomic surveillance and advanced bioinformatics pipelines in detecting SARS-CoV-2 co-infections and variant recombination. Such insights are vital to anticipating shifts in viral evolution, offering insights for public health preparedness.
Inherited infertility - mapping loci associated with impaired female reproduction
Authors: Ruotsalainen Sanni , Karjalainen Juha , Kurki Mitja , Lahtela Elisa , Pirinen Matti , Riikonen Juha , Ritari Jarmo , Tammi Silja , Partanen Jukka , Laivuori Hannele ,   FinnGen, Palotie Aarno , Heyne Henrike , Daly Mark , Widen Elisabeth
Published: July 2024

Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15-30% of cases. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 controls from the Finnish population cohort FinnGen, we unveil a unique landscape of genetic factors associated with the disease. Our recessive analysis identified a low-frequency stop-gained mutation inTBPL2(p.Arg331Ter; minor allele frequency (MAF) = 1.2%) with an impact comparable to highly penetrant monogenic mutations (OR = 650, p = 4.1 ×10-25). While previous studies have linked the homologous gene to anovulation and sterility in knockout mice, the severe consequence of the p.Arg331Ter mutation was evidenced by homozygous carriers having significantly fewer offspring (average of 0.16) compared to women belonging to the other genotype groups (average of 1.75 offspring, p = 1.4×10-15). Notably, all homozygous women who had given birth had received infertility therapy. Moreover, our age-stratified analyses identified three additional genome-wide significant loci. Two loci were associated with early-onset disease (infertility diagnosed before age 30), located nearCHEK2and within the major histocompatibility complex (MHC)-region. The third locus, associated with late-onset disease, had its lead SNP located in an intron of a lncRNA gene. Taken together, our data highlight the significance of rare recessive alleles in shaping female infertility risk. The results further provide evidence supporting specific age-dependent mechanisms underlying this complex disorder.
Aging promotes lung cancer metastasis through epigenetic ATF4 induction
Authors: Patel Angana A.H. , Dzanan Jozefina , Ali Kevin X. , Eklund Ella A. , Alvarez Samantha W. , Altinönder Ilayda , Raj Dorota , El Zowalaty Ahmed Ezat , Sayin Sama I. , Dankis Martin , Schwarz Maria , Jonasson Emma , Gal Kristell Le , Albatrok Heba , Bagge Roger Olofsson , Härtlova Anetta , Ståhlberg Anders , Hallqvist Andreas , Wiel Clotilde , Sayin Volkan I.
Published: July 2024

Lung cancer is primarily a disease of the elderly. Despite shared molecular changes between aging and cancer1– such as permissive chromatin states and deregulated protein homeostasis – studies on physiologically aged models of human lung cancer are lacking. Here, we show that aging alters the progression of KRAS-driven non-small cell lung cancer (NSCLC), promoting metastasis while suppressing primary lung tumor growth. Clinically, a multicenter analysis of all consecutively diagnosed NSCLC cases in Western Sweden over a 3-year period confirmed increased metastasis and smaller primary tumor size with age in KRAS-driven NSCLC. In addition, primary lung tumor cultures derived from older mice demonstrated an increased metastatic phenotype. Unbiased transcriptomic and epigenomic analyses identified ATF4, a major arm of the unfolded protein response (UPR), as a driver of aging-induced lung cancer metastasis. Furthermore, we found that the age-associated increase in ATF4 fuels metastatic dissemination through metabolic rewiring, including increased glutaminolysis. Finally, we report that pharmacological inhibition of glutaminase effectively suppressed aging-induced metastasis. Our findings suggest a novel adjuvant therapy for human lung cancer by targeting aging-induced metabolic plasticity, highlighting the need to consider the biology of aging in the development of cancer therapy.
Dicarbonyl stress enhances tumor intravasation
Authors: Kumar Nilesh , Samanta Bidita , Jyothsna KM , Raghunathan Varun , Sen Prosenjit , Bhat Ramray
Published: July 2024

Metastasis of cancer is a multi-step process that involves the migration of transformed cells from their native organ into a vascular channel, followed by their dissemination to prospective sites of colonization. The entry of tumor cells into blood or lymph, known as intravasation involves their breaching the stromal and endothelial extracellular matrix (ECM) and the endothelial barriers. How the kinetics of these cell-ECM interactions are confounded by chronic inflammatory stresses seen in comorbid risk factors of cancer such as diabetes and aging remain ill-investigated. Here, we construct and deploy a histopathology-motivated, imaging-tractable, microfluidic multi-organ-on-chip platform, that seamlessly integrates two tissue environments: that of a breast tumor and a vascular channel, to study the problem. The former comprises invasive triple-negative MDA-MB-231 breast cancer cells embedded within a three-dimensional fibrillar Collagen I milieu. The latter consists of a monolayer of TeloHAEC, immortalized human aortic endothelial cells arranged on laminin-rich basement membrane ECM, both of which concentrically line a hollow channel, wherein unidirectional fluid flows are implemented. The chip showcases the complexity of intravasation, wherein tumor cells and endothelia cooperate to form anastomotic structures. The formation of such structures is regulated by fluid flow in the vascular channel and is associated with cancer cell migration and entry into the vascular channel. Disseminated cancer cells are observed to enter, get adhered within, and flow through the vascular channel. Exposure to methylglyoxal (MG), a mediator of dicarbonyl stress associated with diabetic circulatory milieu, leads to greater cancer cell intravasation and flow through the vascular channel. This could be driven not just by MG-induced endothelial senescence and shedding, but also by the effect of MG on the chip ECM: we demonstrate it can degrade basement membrane and pathologically crosslink Collagen I, diminishing their cell adhesiveness. Our results thus show how dicarbonyl stress may attenuate homoeostatic barriers to cancer intravasation, exacerbating metastasis.
Wild-type and single-O-antigen repeat outer-membrane vesicles induce equivalent protection against homologous and heterologousSalmonellachallenge
Authors: Alshayea Areej , Jossi Sian Emily , Marcial-Juárez Edith , Pérez-Toledo Marisol , Persaud Ruby , Schager Anna Elizabeth , Larsen Daniel Nyberg , Gutishvili Gvantsa , Pillaye Jamie , Escobar-Riquelme Fernanda , Aksu Kubra , Bryant Jack A. , Horsnell William G. , Banzhaf Manuel , Kaczmarek Jakub Zbigniew , Højrup Peter , Gumbart James C. , Henderson Ian Robert , Bavro Vassiliy N. , López-Macías Constantino , Cunningham Adam F.
Published: July 2024

Lipopolysaccharide O-antigen is an immunodominant target of protective antibodies. Variation in O-antigen structures limits antibody-mediated cross-protection between closely-related pathogens includingSalmonellaTyphimurium (STm) andS. Enteritidis (SEn). Bacterial outer membrane vesicles (OMV) are vaccine platforms presenting surface antigens in their natural conformations. To assess how O-antigen lengths impact antibody responses and control of homologous or heterologous infection, mice were immunized with STm-OMV containing wild-type O-antigen unit repeats (wt-OMV), ≤1 O-antigen unit (wzy-OMV), or no O-antigen units (wbaP-OMV) respectively and challenged with either STm or SEn. Unexpectedly, anti-STm LPS IgG and protection to STm were comparable after immunization with either wt-OMV or wzy-OMV. Anti-porin responses were elevated after immunization with wzy-OMV and wbaP-OMV. A single immunization with any OMV induced minimal cross-protection against SEn, except in blood. In contrast, boosting with O-antigen-expressing OMV enhanced control of SEn infections by >10-fold. These results suggest that i) Antibody to single or variable-length O-antigen units are comparably protective againstSalmonella; ii) Antigens other than immunodominant O-antigens may be targets of cross-reactive antibodies that moderate bacterial burdens; iii) Boosting can enhance the level of cross-protection against relatedSalmonellaserovars and iv) High tissue burdens ofSalmonellacan be present in the absence of detectable bacteraemia.
Microgravity stimulates network activity of 3D neuronal spheroids in an acoustic trap
Authors: Pierre-Ewen Lecoq , Guillaume Viraye , Chloé Dupuis , Xavier Benoit-Gonin , Jean-Luc Aider , Jean-Michel Peyrin
Published: July 2024

Among biological models, cell culture constitutes an important paradigm that allows rapid examination of cell phenotype and behavior. While cell cultures are classically grown on a 2D substrate, the recent development of organoid technologies represents a paradigmatic shift in biological experimentation as they pave the way for the reconstruction of minimalist organs in 3D. Manipulating these 3D cell assemblies represents a considerable challenge. While there is growing interest in studying the behavior of cells and organs in the space environment, manipulating 3D cultures in microgravity remains a challenge. But with cellular research underway aboard the International Space Station (ISS), optimizing techniques for handling 3D cellular assemblies is essential. Here, in order to cultivate 3D models of spheroids in microgravity, we developed and used an acoustic bioreactor to trap levitating cellular organoids in a liquid cell culture medium. Indeed, in a Bulk Acoustic Wave (BAW) resonator, spherical objects, such as cells, can be maintained in an equilibrium position, inside a resonant cavity, away from the walls. In the acoustic levitation plane, gravity is counterbalanced by the acoustic radiation force (ARF) making it possible to maintain an object even in weightlessness. A dedicated setup was designed and built to perform live calcium imaging during parabolic flights. During a parabolic flight campaign, we were able to monitor the calcium activity of 3D neural networks trapped in an acoustic field during changes in gravity during different parabolas. Our results clearly indicate a change in calcium activity associated with variations in gravity.
Basal Cambrian soft-bodied segmented bilaterians preserved as microbial pseudomorphs
Authors: Yang Xiaoguang , Wang Deng , Zhang Zhiliang , Wang Xing , Sun Jie , Hao Wenjing , Liu Yiqun , Uesugi Kentaro , Komiya Tsuyoshi , Han Jian
Published: July 2024

Before Cambrian Stage 3, unambiguous body fossils of segmented bilaterians were rare, severely hampering our understanding of the early history of such important animals. Here we report a variety of microfossils with quintessential features such as paired appendages, dorsoventral and anteroposterior differentiations from the basal Cambrian Fortunian of South China, representing the earliest known three-dimensional body fossils of segmented bilaterians. These fossils were all microbial pseudomorphs built up by secondarily phosphatized bacteria aggregations, testifying microbial pseudomorph could serve as a novel and important pathway to preserve tiny, fragile bilaterian progenitors. This finding unveils a diversified segmented bilaterian world at the very beginning of Cambrian and would arouse a more comprehensive perspective on the early evolution of bilaterian body plans.
Intravital imaging reveals glucose-dependent cilia movement in pancreatic isletsin vivo
Authors: Melnyk Olha , Guo Jeff Kaihao , Li Zipeng Alex , Hughes Jing W. , Linnemann Amelia K.
Published: July 2024

Pancreatic islet cells harbor primary cilia, small sensory organelles that detect environmental changes to regulate hormone secretion and intercellular communication. While the sensory and signaling capacity of primary cilia are well-appreciated, it is less recognized that these organelles also possess active motility, including in dense multicellular tissues such as the pancreatic islet. In this manuscript, we use transgenic cilia reporter mice and an intravital imaging approach to quantitate primary cilia dynamics as it occurs in live mouse pancreatic islets. We validate this imaging workflow as suitable for studying islet cilia motion in real timein vivoand demonstrate that glucose stimulation corresponds to a change in cilia motility, which may be a physiologic measure of nutrient-dependent fluxes in islet cell function.
Lost in the woods: shifting habitats can lead phylogeography astray
Authors: Neher Richard A.
Published: July 2024

Continuous phylogeographic inference is a popular method to reconstruct the spatial distribution of ancestral populations and estimate parameters of the dispersal process. While the underlying probabilistic models can be complex and their parameters are often computationally demanding to infer, these models typically ignore that replication and population growth are tightly coupled to spatial location: populations expand into fertile uninhabited areas and contract in regions with limited resources. Here, I first investigate the sampling consistency of popular summary statistics of dispersal and show that estimators of “lineage velocities” are ill-defined. I then use simulations to investigate how local density regulation or shifting habitats perturb phylogeographic inference and show that these can result in biased and overconfident estimates of ancestral locations and dispersal parameters. These, sometimes dramatic, distortions depend in complicated ways on the past dynamics of habitats and underlying population dynamics and dispersal processes. Consequently, the validity of phylogeographic inferences, in particular when involving poorly sampled locations or extrapolations far into the past, is hard to assess and confidence can be much lower than suggested by the inferred posterior distributions.