bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuberculous Osteomyelitis of the Fifth Metatarsal Treated Using the Induced Membrane Technique: A Case Report
Authors: Bellil Mehdi , Ben Tekaya Aicha , Souissi Mariem , Chrif Kammoun , Kooli Mondher , Ben Salah Mohamed
Published: November 2022

Tuberculous osteomyelitis of the foot, an uncommon and rare entity, accounts for <0.01% of all tuberculous localizations. Osteomyelitis secondary to tuberculosis is difficult to diagnose and treat, requiring a high suspicion index. We report a case of tuberculous osteomyelitis of the fifth metatarsal bone treated with the induced membrane technique. Here, we report the case of a 40-year-old woman with a history of immunosuppressive treatment presented with a complaint of painful swelling of the left foot. Radiographs showed osteolytic lesions of the fifth metatarsal bone. Initial biopsy suggested tuberculosis. She was surgically treated with the induced membrane technique. Histology confirmed tuberculous osteomyelitis and antituberculous treatment was initiated. Full weight-bearing was allowed after 8 months. At 24 months follow-up, all symptoms were resolved. The radiographs showed an integrated graft. In conclusion, the presence of osteolytic lesions on a plain film should rise high suspicious for a possible infection requiring biopsy, and if confirmed, mandates surgical debridement and reconstruction. The induced membrane technique offers a mean to treat infectious bone defects.

Level of Evidence: Level 4.
Alcohol and Atrial Fibrillation: A Pathophysiologic Perspective
Authors: Kaul Risheek , Kaul Ridhima , Paul Pradipta , Maksymiuk Victoria , Frishman William H. , Aronow Wilbert S.
Published: November 2022

Atrial fibrillation (AF) is the most common cardiac arrhythmia responsible for significant morbidity and mortality. Its burden on patients and the health care system is only expected to increase. Several studies have established a dose-response relationship between the amount and frequency of alcohol consumption and the incidence of new onset AF independent of sex, age, and other risk factors. This causal relationship is mediated by the impact alcohol consumption has on conduction properties of the atrium, structural and cellular effect on cardiac myocytes, and dysregulation of the autonomic nervous system. This article reviews the current literature supporting the link between alcohol consumption and AF while attempting to provide an insight into pathophysiological mechanisms.
Use of the DASH Diet and Coronary Artery Disease
Authors: McMaster Matthew W. , Sharma Dikshya , Kafle Paritosh , Frishman William H. , Aronow Wilbert S.
Published: November 2022

Initial dietary approach to stop hypertension (DASH) diet feeding trials showed blood pressure (BP)-lowering effects that corresponded to higher degrees of concordance with the diet. These results popularized the idea that adherence to a DASH diet could reduce coronary artery disease (CAD) risk for patients. Recent evidence shows that the impact of DASH on CAD incidence and risk is less clear. While many studies show that the DASH diet impacts CAD risk factors, others suggest that these effects do not remain when important confounders are controlled. Also, the evidence from meta-analyses that the DASH diet impacts incident CAD is still inconclusive. Reassessment of the DASH diet, and the search for an ideal diet to prevent CAD will require a better understanding of the mechanisms through which the DASH diet works. Proposed mechanisms for its benefit include preventing inflammation and atherosclerosis progression as well as providing a heathy balance of dietary sodium and potassium intake.
Measurement of Disease Activity of Pouchitis
Authors: Chis Roxana S. , Silverberg Mark S.
Published: November 2022

BACKGROUND:

Pouchitis is the most common inflammatory complication in ulcerative colitis patients undergoing postoperative construction of an IPAA. Pouchitis refers to a spectrum of diseases, and as such, it lacks a universally accepted definition as well as validated instruments to measure disease activity and treatment response. Assessing pouchitis activity is challenging, and methods for diagnosis and classification of severity of pouchitis are not universally agreed upon.

CLINICAL FEATURES:

Pouchitis is characterized by a constellation of clinical symptoms, including increased stool frequency, urgency, incontinence, bleeding, and rarely constitutional symptoms such as malaise and low-grade fever. However, these symptoms are subjective, and similar symptoms can be caused by noninflammatory conditions including anal sphincter dysfunction, anastomotic strictures, occult leaks, pouch inlet obstruction, and cuffitis. Objective scores that include endoscopic and histologic criteria have been developed for subjects with an IPAA. However, these instruments are not validated for measuring pouchitis disease activity and are associated with a number of challenges. In addition, the clinical components of the scores correlate poorly with endoscopic and histologic findings.

CONCLUSION AND FUTURE DIRECTIONS:

There is a need for prospective studies to facilitate the development and validation of novel instruments that are valid, reliable, and responsive to change that would facilitate the development of therapeutic agents for the treatment of pouchitis.
What Parameters Influence the Effect of Cold-Water Immersion on Muscle Soreness? An Updated Systematic Review and Meta-Analysis
Authors: Batista Natanael P. , de Carvalho Flávia A. , Machado Aryane F. , Micheletti Jéssica K. , Pastre Carlos M.
Published: November 2022

Objective:

Our objective was to determine the efficacy of cold-water immersion (CWI) on the management of muscle soreness to identify the impact of immersion time, water temperature, CWI protocol, and type of exercise on this outcome.

Design:

Intervention systematic review and meta-analysis.

Setting:

MEDLINE/PubMed, Embase, Central, and SPORTDiscus databases were searched from their earliest record to July 30, 2020. Only randomized controlled trials that assessed muscle soreness comparing CWI and control were included. Studies were pooled in different subgroups regarding the used protocol: water temperature (severe or moderate cold), immersion time (short, medium, or longer time), CWI protocol (intermittent or continuous application), and type of exercise (endurance or resistance exercise). Data were pooled in a meta-analysis and described as weighted mean difference (95% confidence interval, P < 0.05).

Participants:

Athletes and nonathletes.

Interventions:

Cold-water immersion and control condition.

Main Outcome Measures:

Muscle soreness.

Results:

Forty-four studies were included. For immediate effects, CWI was superior to control regardless of water temperature and protocol, and for short and medium immersion times and endurance exercises. For delayed effects, CWI was superior to control in all subgroups except longer immersions time.

Conclusions:

This study suggests that CWI is better than control for the management of muscle soreness and water temperature and CWI protocol do not influence this result, but only short and medium immersions times presented positive effects. Aiming immediate effects, the best results suggest CWI application only after endurance exercises, while delayed effect CWI was superior both after endurance and resistance exercises.
Fatal Retroperitoneal Bleeding in Neurofibromatosis Type 1
Authors: Voudouri Mariana , Chambers Meagan , Baker Michael L. , Kerr Darcy A.
Published: November 2022

Neurofibromatosis type 1 (NF1) is a common, autosomal dominant neurocutaneous syndrome. The most frequent clinical manifestations include multiple neurofibromas, café-au-lait spots, dystrophic scoliosis, benign and malignant peripheral nerve sheath tumors, and paragangliomas. Neurofibromatosis type 1 vasculopathy is a less well-recognized constellation of vascular pathologies that can cause significant medical complications in patients with NF1. A rare manifestation of this process is neurofibroma infiltration of vasculature with resultant bleeding. The case presented herein illustrates a rare example of a massive fatal hemorrhage due to disruption of a large paraspinal artery in the setting of a diffuse, infiltrative neurofibroma. This case highlights the potential of benign neurofibromas to infiltrate major blood vessels, leading to extensive bleeding and death.
Using Routine Chest Computed Tomography to Diagnose Pulmonary Embolism
Authors: Chan Jason , Ho Bianca , Ye Kenny , Haramati Linda B. , Jain Vineet R.
Published: November 2022

Objective

This study investigated the use of routine contrast-enhanced chest computed tomography (CT) to diagnose unsuspected pulmonary embolism (PE).

Methods

All adult routine contrast-enhanced chest CTs performed at Montefiore in 2018 were included. Pulmonary artery enhancement was measured by placing regions of interest in the pulmonary vasculature. Adequate enhancement was defined as 200 Hounsfield units (HU) or greater. Presence or absence of PE was noted. Descriptive statistics and logistic regression analysis were performed.

Results

A total of 3164 CTs were evaluated (55.8% women; mean age, 63.2 years). Main pulmonary enhancement was highly correlated with peripheral enhancement. Of all cases, 28.7% (907 of 3164) reached the 200 HU threshold. Greater enhancement was associated with female sex, older age, outpatients, and contrast amount administered. Pulmonary embolism–positive cases comprised 1.8% (58 of 3164) of total cases. Furthermore, 39.7% (23 of 58) of PE-positive cases reached the 200 HU threshold.

Conclusions

Over one quarter of routine contrast-enhanced chest CT scans met the 200 HU threshold indicative of adequate pulmonary artery enhancement, including nearly half of the 2% of examinations positive for PE.
Blunt pancreatic trauma: A Western Trauma Association critical decisions algorithm
Authors: Moren Alexis M. , Biffl Walter L. , Ball Chad G. , de Moya Marc , Brasel Karen J. , Brown Carlos V.R. , Hartwell Jennifer L. , Inaba Kenji , Ley Eric J. , Moore Ernest E. , Peck Kimberly A. , Rizzo Anne G. , Rosen Nelson G. , Sperry Jason L. , Weinberg Jordan A. , Coimbra Raul , Shatz David V. , Martin Matthew J.
Published: November 2022

BACKGROUND

The Western Trauma Association (WTA) has undertaken publication of best practice clinical practice guidelines on multiple trauma topics. These guidelines are based on scientific evidence, case reports, and best practices per expert opinion. Some of the topics covered by this consensus group do not have the ability to have randomized controlled studies completed because of complexity, ethical issues, financial considerations, or scarcity of experience and cases. Blunt pancreatic trauma falls under one of these clinically complex and rare scenarios. This algorithm is the result of an extensive literature review and input from the WTA membership and WTA Algorithm Committee members.

METHODS

Multiple evidence-based guideline reviews, case reports, and expert opinion were compiled and reviewed.

RESULTS

The algorithm is attached with detailed explanation of each step, supported by data if available.

CONCLUSION

Blunt pancreatic trauma is rare and presents many treatment challenges.
Hemodialysis Access Outcomes for Patients with Unstable Housing
Authors: Sung Eric , Levin Scott R , Kariveda Rohith , Farber Alik , King Elizabeth G , Cheng Thomas W , Siracuse Jeffrey J
Published: November 2022

Background:

End stage renal disease has traditionally been noted to disproportionately affect patients with fewer resources. Our goal was to assess practice patterns and outcomes in patients with unstable housing undergoing permanent hemodialysis access creation.

Study design:

A retrospective, single center review of patients with unstable housing was conducted. Perioperative and long-term outcomes were assessed. Univariable and multivariable analysis as well as Kaplan Meier analysis were performed.

Results:

There were 144 patients (63% male) identified with a mean age of 57 years. There were 33% of patients that had no current permanent residence and 81% had at least 3 addresses the year prior to operation. Access type included brachiocephalic (48%), brachiobasilic (19%), radiocephalic fistulas (11%) and prosthetic grafts (19%). Thirty-day readmission was seen in 27.8% of patients. Kaplan-Meier analysis showed that 1-year and 4-year patient survival were 94.4% and 80.6%, respectively. Multivariable analysis demonstrated that newly formed access (OR 3.66, 95% CI 1.02-13.16, P=.05), absence of a permanent residence (OR 2.92, 95% CI 1.15-7.44, P=.03), and female gender (OR 2.86, 95% CI, 1.18-7.14, P=.02) were associated with 90-day readmission. Multivariable analysis of mortality revealed that previous stroke (HR 7.15, 95% CI 1.93-26.5, P=.003), history of alcohol use disorder (HR 4.55, 95% CI 1.22-16.99, P=.024), and age (HR 1.10, 95% CI, 1.02-1.18, P=.017) were associated with four-year mortality; housing instability was not associated with decreased survival. Prior TDC (HR 1.63, 95% CI 1.02-2.61, P=.04) was associated with four-year reintervention and frequent address change (HR .47, 95% CI .27-.81, P=.01) was found to be a protective factor against long-term reintervention.

Conclusion:

Poor outcomes in patients with unstable housing were primarily driven by comorbidities. Lack of permanent residence was significantly associated with readmission.
Regulatoryde novomutations underlying intellectual disability
Authors: De Vas Matias G , Boulet Fanny , Joshi Shweta S , Garstang Myles G , Khan Tahir N. , Atla Goutham , Parry David , Moore David , Cebola Inês , Zhang Shuchen , Cui Wei , Lampe Anne K , Lam Wayne W ,   Genomics England Research Consortium, Ferrer Jorge , Pradeepa Madapura M , Atanur Santosh S
Published: November 2022

The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown.De novomutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents (trio). Additionally, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific and human-gained enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the pre-frontal cortex, have been previously implicated in ID or related disorders, and exhibit intolerance to loss of function mutations. Moreover, we found that highly interacting regulatory regions from intermediate progenitor cells of the developing human cortex were strongly enriched for ID DNMs. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1, OLFM1, andPOU3F3). The majority of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that regulatory elements harbouring DNMs indeed function as enhancers and DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.
Association between the Epigenetic Lifespan Predictor GrimAge and History of Suicide Attempt in Bipolar Disorder
Authors: de Carvalho Lima Camila N. , Kovács Emese H.C. , Mirza Salahudeen , Del Favero-Campbell Alexandra , Diaz Alexandre Paim , Quevedo Joao , Argue Benney M.R. , Richards Jenny Gringer , Williams Aislinn , Wemmie John A. , Magnotta Vincent A. , Fiedorowicz Jess G. , Soares Jair C. , Gaine Marie E. , Fries Gabriel R.
Published: November 2022

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n=50), BD individuals with (n=77, BD/SA) and without (n=67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n=48) and BD/non-SA (n=47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F=5.424,p=0.005), with the highest GrimAgeAccel in BD/SA (p=0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p=0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population.
Efficacy of the wild-type/Omicron BA.1 bivalent vaccine as the second booster dose against Omicron BA.2 and BA.5
Authors: Kawasuji Hitoshi , Morinaga Yoshitomo , Tani Hideki , Saga Yumiko , Yamada Hiroshi , Yoshida Yoshihiro , Takegoshi Yusuke , Kaneda Makito , Murai Yushi , Kimoto Kou , Ueno Akitoshi , Miyajima Yuki , Nagaoka Kentaro , Ono Chikako , Matsuura Yoshiharu , Niimi Hideki , Yamamoto Yoshihiro
Published: November 2022

Introduction

In addition to the original monovalent vaccines available for SARS-CoV-2, bivalent vaccines covering wild-type (WT) and Omicron BA.1 are also available. However, there is a lack of real-world data on the effectiveness of bivalent vaccines as second boosters on the dominant Omicron sublineages, including BA.2 and BA.5.

Methods

This prospective longitudinal cohort study was conducted at Toyama University Hospital, a tertiary medical center in Japan. Participants (n = 565) who received the first booster vaccination were followed up until 2 weeks after the second booster dose of the monovalent mRNA-1273 (WT group, n = 168) and bivalent BNT162b2 (WT+BA.1 group, n = 23) vaccines. Participants with previous SARS-CoV-2 infections were excluded from the study. Anti-receptor-binding domain (RBD) antibody levels and neutralizing activity were measured. Vaccine-related symptoms were also assessed using a questionnaire after the second booster dose.

Results

The anti-RBD antibody levels after the second booster dose in the WT and WT+BA.1 group were similar (median [inter quartile], 26262.0 [16951.0–38137.0] U/mL vs. 24840.0 [14828.0–41460.0] U/mL, respectively). Although the neutralization activity of the pooled sera of the WT+BA.1 group was the lowest against BA.5, the activities against BA.2 and BA.5 were higher than those of the WT group in both pseudotyped and live virus assays. Vaccine-related symptoms, including systemic and local symptoms, were strongly correlated with anti-RBD antibody levels and neutralizing titers with significant differences.

Conclusion

The second booster dose of the bivalent (WT/Omicron BA.1) vaccine induced higher neutralizing activity against BA.2 and BA.5 than that of the original monovalent vaccine.
Magnitude and causes of under-five mortality in the North Shewa Zone, Ethiopia
Authors: Bekele Delayehu , Wang-Cendejas Ruoqing R. , Goddard Frederick G. B. , Hunegnaw Bezawit M. , Haneuse Sebastien , Bitye Tefera , Muleta Hemen , Mohammed Yahya , Zeleke Mesfin , Wickle Kimiko Van , Bekele Chalachew , Chan Grace J.
Published: November 2022

Introduction: Globally around 5 million children under the age of 5 years die every year. Ethiopia is one of five countries that contribute to more than half of these deaths. In the absence of a national vital registry system in Ethiopia, there is a lack of high-quality data regarding causes of death. Methods: We conducted a verbal autopsy study among under-five deceased children at the Birhan health and demographic site (HDSS) located in the North Shewa zone, Ethiopia. All deaths of under five children, which occurred in the time period from March 1, 2019 to February 29, 2020 at the Birhan HDSS, were identified. The under-five mortality rate (U5MR) was computed using a Kaplan-Meier approach. The world health organization verbal autopsy questionnaire was administered to mothers or caregivers of the deceased child after a minimum mourning period of 42 days. The causes of death were then determined by the InterVA-5 algorithm. Results: There were 90 under-five deaths resulting in an estimated U5MR of 45.3 per 1000 live births. The majority (62.2%) of deaths occurred during the neonatal period. The leading causes of death in under-five children were birth asphyxia (20, 27.0%), prematurity (19, 25.7%) and meningitis and encephalitis (8, 10.8%) while leading causes of neonatal deaths were birth asphyxia (19, 38.0%), prematurity (18, 36.0%) and neonatal sepsis (6, 12.0%). Conclusions: There is a high under-five mortality rate at the study site, with most deaths occurring in the neonatal period. Birth asphyxia and prematurity contributed to more than half of the under-five deaths suggesting that follow-up and management during pregnancy, labor and delivery should be strengthened to avert a significant proportion of under-five deaths.
Organ Finder – a new AI-based organ segmentation tool for CT
Authors: Edenbrandt Lars , Enqvist Olof , Larsson Måns , Ulén Johannes
Published: November 2022

Background

Automated organ segmentation in computed tomography (CT) is a vital component in many artificial intelligence-based tools in medical imaging. This study presents a new organ segmentation tool called Organ Finder 2.0. In contrast to most existing methods, Organ Finder was trained and evaluated on a rich multi-origin dataset with both contrast and non-contrast studies from different vendors and patient populations.

Approach

A total of 1,171 CT studies from seven different publicly available CT databases were retrospectively included. Twenty CT studies were used as test set and the remaining 1,151 were used to train a convolutional neural network. Twenty-two different organs were studied. Professional annotators segmented a total of 5,826 organs and segmentation quality was assured manually for each of these organs.

Results

Organ Finder showed high agreement with manual segmentations in the test set. The average Dice index over all organs was 0.93 and the same high performance was found for four different subgroups of the test set based on the presence or absence of intravenous and oral contrast.

Conclusions

An AI-based tool can be used to accurately segment organs in both contrast and non-contrast CT studies. The results indicate that a large training set and high-quality manual segmentations should be used to handle common variations in the appearance of clinical CT studies.
Founder effects arising from gathering dynamics systematically bias emerging pathogen surveillance
Authors: Taylor Bradford P , Hanage William P
Published: November 2022

Models of infectious disease transmission have shown the importance of heterogeneous contact networks for epidemiology; the most connected individuals are most likely to be infected early. Yet it is cumbersome to parameterize and incorporate such networks into simple models. We introduce an alternative model framework that explicitly includes attendance at and disease transmission within gatherings of different sizes, which disaggregates sequential epidemics moving from the most to least social subpopulations that underly the overall, single-peaked infection curve. This can systematically bias initial estimates of the growth rate for emerging variants and their severity, if vulnerable populations avoid large gatherings. Finally, we show that how often similarly social individuals preferentially interact (i.e., homophily, or assortative mixing) tunes the magnitude and duration of these biases. Together, we provide a simple framework for incorporating socialization and behavior in epidemic models, which can help contextualize surveillance of emerging infectious agents.
Selective prediction for extracting unstructured clinical data
Authors: Swaminathan Akshay , Lopez Ivan , Wang William , Srivastava Ujwal , Tran Edward , Bhargava-Shah Aarohi , Wu Janet Y , Ren Alexander , Caoili Kaitlin , Bui Brandon , Alkhani Layth , Lee Susan , Mohit Nathan , Seo Noel , Macedo Nicholas , Cheng Winson , Liu Charles , Thomas Reena , Chen Jonathan H. , Gevaert Olivier
Published: November 2022

Electronic health records represent a large data source for outcomes research, but the majority of EHR data is unstructured (e.g. free text of clinical notes) and not conducive to computational methods. While there are currently approaches to handle unstructured data, such as manual abstraction, structured proxy variables, and model-assisted abstraction, these methods are time-consuming, not scalable, and require clinical domain expertise. This paper aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction. We trained selective prediction models to identify the presence of four distinct clinical variables in free-text pathology reports: primary cancer diagnosis of glioblastoma (GBM, n = 659), resection of rectal adenocarcinoma (RRA, n = 601), and two procedures for resection of rectal adenocarcinoma: abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601). Data were manually abstracted from pathology reports and used to train L1-regularized logistic regression models using term-frequency-inverse-document-frequency features. Data points that the model was unable to predict with high certainty were manually abstracted. All four selective prediction models achieved a test-set sensitivity, specificity, positive predictive value, and negative predictive value above 0.91. The use of selective prediction led to sizable gains in automation (anywhere from 57% to 95% reduction in manual abstraction of charts across the four outcomes). For our GBM classifier, the selective prediction model saw improvements to sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier. Selective prediction using utility-based probability thresholds can facilitate unstructured data extraction by giving “easy” charts to a model and “hard” charts to human abstractors, thus increasing efficiency while maintaining or improving accuracy.
PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation
Authors: Truong Brittany T. , Shull Lomeli C. , Lencer Ezra , Bend Eric G. , Field Michael ,   University of Washington Center for Mendelian Genomics (UW-CMG), Everman David , Schwartz Charles E. , Flanagan-Steet Heather , Artinger Kristin B.
Published: November 2022

Split Hand/Foot Malformation (SHFM) is a rare limb abnormality with clefting of the fingers and/or toes. For many patients, the genetic etiology is unknown. Through whole exome and targeted sequencing, we detected three novel variants in a transcription factor,PRDM1that arosede novoin families with SHFM or segregated with the phenotype. PRDM1 is required for limb development; however, its role is not well understood, and it is unclear how thePRDM1variants affect protein function. Using transient and stable overexpression rescue experiments in zebrafish, we show that the variants, which disrupt the proline/serine-rich and DNA-binding zinc finger domains have reduced function compared to wildtypePRDM1. Through gene expression assays, RNA-seq, and CUT&RUN in isolated pectoral fin cells, we demonstrate that Prdm1a directly binds to and regulates genes required for limb induction, outgrowth, and anterior/posterior patterning, such asfgfr1a, dlx5a, dlx6a, andsmo. Together, these results improve our understanding of the role of PRDM1 in the limb gene regulatory network and demonstrate the pathogenicity ofPRDM1variants in humans.

SUMMARY STATEMENT

PRDM1 proline/serine and zinc finger domains are required to regulate limb induction, outgrowth, and anterior/posterior patterning. Variants in PRDM1 are shown to cause Split Hand/Foot Malformation in humans.
Effect of COVID-19 pandemic on essential health care services and mitigation strategies implemented in Benishangul gumuz: An emerging region of Ethiopia
Authors: Amaya Alemayehu Assefa
Published: November 2022

Health systems of low-to-middle-income countries may have fewer buffering resources and capacity against shocks from a pandemic. This study assessed the effects of COVID-19 on essential health care services and its mitigation strategies employed in Benishangul Gumuz Region in the Assosa district of western Ethiopia. Institutional based cross-sectional study design with multilevel triangulated mixed approach was used. Purposively selected health facilities and key informant or in-depth interviewee from different facilities were involved. Document review from health facilities reports and case registration logs were used to access the service utilizations per- and -post the pandemic. The study showed that there was a significant decrement in antenatal care (ANC) visits, family planning new acceptors, family planning repeated acceptors, skilled delivery, and in postnatal care within 7 days of delivery during the COVID-19 pandemic. There was an increase in home delivery, teenage pregnancy and still births. There was also a significant reduction in the vaccination coverage for almost all vaccines. During the pandemic, children treated for diarrheal disease and the number of people screened for human immunodeficiency virus (HIV), new HIV-positive individuals, and new HIV-positive individuals receiving antiretroviral therapy have decreased significantly. There has been a statistically significant increase in the number of people with elevated blood sugar during the pandemic. The COVID-19 pandemic has had a significant negative impact on essential health services, most notably in Benishangul Gumuz Region. Groups of individuals considered to be at higher risks of morbidity and mortality are the most significantly affected. Mitigation strategies have been implemented to address the indirect effects of the COVID-19 pandemic and improve health care delivery in the region’s highly affected areas. Urgent and comprehensive action is needed to mitigate the future (long-term) impact of Covid-19 on the health of community in the region.
Altered spreading of neuronal avalanches in temporal lobe epilepsy relates to cognitive performance: a resting-state hdEEG study
Authors: Duma Gian Marco , Danieli Alberto , Mento Giovanni , Vitale Valerio , Opipari Raffaella Scotto , Jirsa Viktor , Bonanni Paolo , Sorrentino Pierpaolo
Published: November 2022

Objective

Large aperiodic bursts of activations named neuronal avalanches have been used to characterize whole-brain activity, as their presence typically relates to optimal dynamics. Epilepsy is characterized by alterations of large-scale brain network dynamics. Here, we exploited neuronal avalanches to characterize differences in the electroencephalography (EEG) basal activity, free from seizures and/or interictal spikes, between patients with temporal lobe epilepsy (TLE) and matched controls.

Method

We defined neuronal avalanches as starting when the z-scored source-reconstructed EEG signals crossed a specific threshold in any region and ending when all regions went back to baseline. This technique avoids data manipulation or assumptions of signal stationarity, focusing on the aperiodic, scale-free components of the signals. We computed individual avalanche transition matrices, to track the probability of avalanche spreading across any two regions, compared them between patients and controls, and related them to memory performance in patients.

Results

We observed a robust topography of significant edges clustering in regions functionally and structurally relevant for the TLE, such as the entorhinal cortex, the inferior parietal and fusiform area, the inferior temporal gyrus, and the anterior cingulate cortex. We detected a significant correlation between the centrality of the entorhinal cortex in the transition matrix and the long-term memory performance (delay recall Rey figure test).

Significance

Our results show that the propagation patterns of large-scale neuronal avalanches are altered in TLE during resting state, suggesting a potential diagnostic application in epilepsy. Furthermore, the relationship between specific patterns of propagation and memory performance supports the neurophysiological relevance of neuronal avalanches.

Key Points

Investigation of the brain dynamics during resting-state activity in patients with TLE using neuronal avalanches (i.e., large scale patterns of activation)

We found higher transition probabilities in patients with TLE in the entorhinal cortex, inferior temporal and fusiform gyri, and anterior cingulate cortex

We found higher eigenvector centrality of the left entorhinal cortex in the avalanche transition matrix, which was related to reduced long term memory performance

Discussion of the potential application of the avalanche transition matrix as diagnostic tool in presurgical evaluations and epilepsy types differentiation
Development of prediction models for antenatal care attendance in Amhara region, Ethiopia
Authors: Wilder Bryan , Pons-Duran Clara , Goddard Frederick G. B. , Hunegnaw Bezawit Mesfin , Haneuse Sebastien , Bekele Delayehu , Chan Grace J.
Published: November 2022

Background

In low-resource settings, coverage of at least four antenatal care (ANC) visits remains low. As a first step towards enhancing ANC attendance, this study aims to develop a series of predictive models to identify women who are at high risk of failing to attend ANC in a rural setting in Ethiopia.

Methods

This is a cohort study conducted in the Birhan field site, Amhara region. Using data of a surveillance system and a pregnancy cohort, we developed and internally validated a series of logistic regressions with regularization (LASSO), and ensembles of decision trees.

Discrimination was estimated using the area under the receiving operator characteristic curve (AUC). Three prediction time points were considered: conception, and gestational weeks 13 and All models were internally validated using 5-fold cross validation to avoid overfitting.

Results

The study sample size was 2195. Mean age of participants was 26.8 years (Standard Deviation (SD) 6.1) and mean gestational age at enrolment was 25.5 weeks (SD 8.8). A total of 582 women (26.5%) failed to attend ANC during cohort follow-up. We observed AUC in the range of 0.61-0.70, with higher values for models predicting at weeks 13 and 24. All AUC values were similar with slightly higher performance for the ensembles of decision trees.

Conclusion

This study presents a series of prediction models for ANC attendance with modest performance. The developed models may be useful to identify women at high risk of missing their ANC visits to target interventions to improve attendance rates. This study opens the possibility to develop and validate easy-to-use tools to predict health-related behaviors in settings with scarce resources.

SUMMARY BOX

No published studies to date have developed risk prediction models for ANC attendance.

The presented models show modest performance, but may be useful to identify pregnancies at a high risk of not initiating ANC.

This type of models could be used by countries with strong community health programs to identify high-risk women to target specific interventions aiming to improve ANC attendance rates, increasing feasibility and cost-effectiveness of those interventions.

Our models were internally validated using cross-validation to avoid overfitting, and despite not being tested in other populations, they are useful to inform local and regional health authorities.

This study demonstrates that it is possible to develop predictive models for behavioral outcomes using data from surveillance systems and pregnancy cohorts in settings with scarcity of resources.
High Throughput Transcriptomics to Understand Chemical Drivers of Aggressive Breast Cancer Subtypes
Authors: Sala-Hamrick Kimberley E. , Tapaswi Anagha , Polemi Katelyn M. , Nguyen Vy. K , Colacino Justin A.
Published: November 2022

Background

The impact of chemical exposures on breast cancer progression is poorly characterized and may influence the development of more severe and aggressive subtypes.

Objectives

There is a suite of toxicants, including metals, pesticides, and personal care product compounds, which are commonly detected at high levels in US Center for Disease Control’s National Health and Nutrition Examination Survey (NHANES) chemical biomarker screens. To characterize the impact of these toxicants on breast cancer pathways, we performed high throughput dose-response transcriptomic analysis of toxicant exposed breast cells.

Methods

We treated non-tumorigenic mammary epithelial cells, MCF10A, with 21 chemicals at four doses (25nM, 250nM, 2.5µM, 25µM) for 48 hours. We conducted RNA-sequencing for these 408 samples, adapting the PlexWell plate-based RNA-sequencing method to analyze changes in gene expression resulting from these exposures. For each chemical, we calculated gene and biological pathway specific benchmark doses using BMDExpress2, identifying differentially expressed genes and generating the best fit benchmark dose models for each gene. We employed enrichment testing to test whether each chemical’s upregulated or downregulated genes were over-represented in a biological process or pathway. We contextualized benchmark doses relative to human population biomarker concentrations in NHANES.

Results

Overall, significant changes in gene expression varied across doses of each chemical and benchmark dose modeling revealed dose-responsive alterations of thousands of different genes. Comparison of benchmark data to NHANES chemical biomarker concentrations indicated an overlap between actual exposure levels and levels sufficient to cause a gene expression response. Enrichment and cell deconvolution analyses showed benchmark dose responses correlated with changes in cancer and breast cancer related pathways, including induction of basal-like characteristics for some chemicals, including p,p’-DDE, lead, copper, and methyl paraben.

Discussion

These analyses revealed that these 21 chemicals induce significant changes in pathways involved in breast cancer initiation and progression at human exposure relevant doses.
A deep residual model for characterization of 5D spatiotemporal network dynamics reveals widespread spatiodynamic changes in schizophrenia
Authors: Kazemivash Behnam , VanErp Theo GM , Kochunov Peter , Calhoun Vince D.
Published: November 2022

Schizophrenia is a severe brain disorder with serious symptoms including delusions, disorganized speech, and hallucinations that can have a long-term detrimental impact on different aspects of a patient’s life. It is still unclear what the main cause of schizophrenia is, but a combination of altered brain connectivity and structure may play a role. Neuroimaging data has been useful in characterizing schizophrenia, but there has been very little work focused on voxel-wise changes in multiple brain networks over time, despite evidence that functional networks exhibit complex spatiotemporal changes over time within individual subjects. Recent studies have primarily focused on static (average) features of functional data or on temporal variations between fixed networks; however, such approaches are not able to capture multiple overlapping networks which change at the voxel level.

In this work, we employ a deep residual convolutional neural network (CNN) model to extract 53 different spatiotemporal networks each of which captures dynamism within various domains including subcortical, cerebellar, visual, sensori-motor, auditory, cognitive control, and default mode. We apply this approach to study spatiotemporal brain dynamism at the voxel level within multiple functional networks extracted from a large functional magnetic resonance imaging (fMRI) dataset of individuals with schizophrenia (N=708) and controls (N=510). Our analysis reveals widespread group level differences across multiple networks and spatiotemporal features including voxel-wise variability, magnitude, and temporal functional network connectivity in widespread regions expected to be impacted by the disorder. We compare with typical average spatial amplitude and show highly structured and neuroanatomically relevant results are missed if one does not consider the voxel-wise spatial dynamics. Importantly, our approach can summarize static, temporal dynamic, spatial dynamic, and spatiotemporal dynamics features, thus proving a powerful approach to unify and compare these various perspectives.

In sum, we show the proposed approach highlights the importance of accounting for both temporal and spatial dynamism in whole brain neuroimaging data generally, shows a high-level of sensitivity to schizophrenia highlighting global but spatially unique dynamics showing group differences, and may be especially important in studies focused on the development of brain-based biomarkers.
The relationships between children’s motor competence, physical activity, perceived motor competence, physical fitness and weight status in relation to age
Authors: den Uil Anne Rosalinde , Janssen Mirka , Busch Vincent , Kat Ilse T , Scholte Ron H.J.
Published: November 2022

Objective: The goal of this cross-sectional study was to further explore the relationships between motor competence, physical activity, perceived motor competence, physical fitness and weight status in different age categories of Dutch primary school children. Methods: Participants were 2068 children aged 4 to 13 years old, divided over 9 age groups. During physical education classes, they completed the 4-Skills Test, a physical activity questionnaire, versions of the Self-Perception Profile for Children, Eurofit test and anthropometry measurements. Results: Results show that all five factors included in the analyses are related to each other and that a tipping point exists at which relations emerge or strengthen. Physical fitness is related to both motor competence and physical activity and these relationships strengthen with age. A relationship between body mass index and the other four factors emerges in middle childhood. Interestingly, at a young age, motor competence and perceived motor competence are weakly related, but neither one of these have a relation with physical activity. In middle childhood, both motor competence and perceived motor competence are related to physical activity. Conclusion: Our findings show that children in late childhood who have higher perceived motor competence are also more physically active, have higher physical fitness, higher motor competence and lower body mass index. Our results indicate that targeting motor competence at a young age might be a feasible way to ensure continued participation in physical activities throughout childhood and adolescence.
TimiGP: inferring inter-cell functional interactions and clinical values in the tumor immune microenvironment through gene pairs
Authors: Li Chenyang , Zhang Baoyi , Schaafsma Evelien , Reuben Alexandre , Zhang Jianjun , Cheng Chao
Published: November 2022

Determining how immune cells functionally interact in the tumor microenvironment and identifying their biological roles and clinical values are critical for understanding cancer progression and developing new therapeutic strategies. Here we introduce TimiGP, a computational method to infer inter-cell functional interaction networks and annotate the corresponding prognostic effect from bulk gene expression and survival statistics data. When applied to metastatic melanoma, TimiGP overcomes the prognostic bias caused by immune co-infiltration and identifies the prognostic value of immune cells consistent with their anti- or pro-tumor roles. It reveals the functional interaction network in which the interaction X→Y indicates a more positive impact of cell X than Y on survival. This network provides immunological insights to facilitate the development of prognostic models, as evidenced by our computational-friendly, biologically interpretable, independently validated models. By leveraging single-cell RNA-seq data for specific immune cell subsets, TimiGP has the flexibility to delineate the tumor microenvironment at different resolutions and is readily applicable to a wide range of cancer types.
Dietary fiber controls blood pressure and cardiovascular risk by lowering large intestinal pH and activating the proton-sensing receptor GPR65
Authors: Xie Liang , Muralitharan Rikeish R. , Dinakis Evany , Antonacci Simona , Leung Kwan Charmaine , McArdle Zoe , Mirabito Colafella Katrina , Nakai Michael , Paterson Madeleine , Peh Alex , Jama Hamdi , Salimova Ekaterina , Anderson Dovile , Ang Caroline , Alam Md Jahangir , Yap Yu-Anne , Creek Darren , Robert Remy , O’Donnell Joanne A. , Mackay Charles R. , Marques Francine Z.
Published: November 2022

High blood pressure (BP) is the most common cause of death globally, due to increasing the risk of cardiovascular diseases. Dietary fiber regulates BP through gut microbial production of acidic metabolites known as short-chain fatty acids (SCFAs). The specific mechanisms of how SCFAs regulate BP are still emerging. In a phenome-wide association study, we identified that the proton-sensing G-protein-coupled receptorGPR65gene is associated with hypertension and its associated end-organ damage phenotypes. We hypothesized that acidic metabolites produced from the gut microbiota may activate GPR65, thus conferring BP regulating effects. We found that dietary fiber levels determined the luminal and interstitial tissue pH in the large intestine through production of SCFAs by the gut microbiota. We identified that low pH produced by high fiber intake, acting via GPR65 signaling, increased cAMP production and phosphorylation of CREB, and restricted the production of hypertension-promoting inflammatory cytokines by CD8+T cells.Gpr65−/−mice spontaneously developed higher BP, cardiac and renal hypertrophy and fibrosis. We showed that the benefits of a diet high in fiber, which prevented hypertension and associated end-organ damage, were decreased inGpr65−/−mice. Finally, adoptive transfers revealed that GPR65 deficiency in CD8+T cells causally explained this phenotype. In conclusion, we showed that pH sensing by GPR65 in CD8+ T cells mediates much of the cardiovascular benefits of dietary fiber. pH sensing represents a novel gene-by-environment interaction of gut microbiota-to-host biological effects and may form the basis for new therapeutic strategies for hypertension.