bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous perforation of the common bile duct in adults presenting as biliary peritonitis: a case report and literature review
Authors: Bouzid Ahmed , Fendri Sami , Rejab Haitham , Trigui Ayman , Mejdoub Youssef , Boujelbene Salah
Published: March 2023

Introduction:

Spontaneous perforation of the common bile duct (SPCBD) is an exceptional disease, especially in adults. The cause is often idiopathic once trauma and choledochal cyst are excluded. Early diagnosis is often difficult because of its often-misleading appearance.

Case presentation:

The authors report the case of a 54-year-old man, a known case of type 2 diabetes mellitus, who presented to our emergency department for acute abdominal pain that had evolved for 2 days.

Clinical findings and investigations:

On physical examination, the patient had a fever of up to 38.5°C, and the abdomen was distended and generally tight. The abdominal computerized tomography scan confirms the presence of free fluid. In addition, the thickness of the gallbladder wall had increased in contrast with a resolved gallbladder distention. Because exploration failed to demonstrate the cause of ascites, the authors performed a diagnostic paracentesis, which revealing ascites with a dark yellow-green color, which implied bile leakage.

After initial resuscitation, an emergent exploratory laparotomy was performed. The authors found biliary peritonitis secondary to SPCBD. After peritoneal lavage, the perforation was repaired over a T-tube. The postoperative course was uneventful. Histological findings were consistent with ulcerous acalculous cholecystitis. The patient was disease-free after a 3-month follow-up.

Discussion:

SPCBD is an uncommon condition in adults, and it is rarely reported in the literature. The pathogenesis of this disease is not clear and may be related to single or multiple factors. Usually, this disease is diagnosed in the postmortem. Early diagnosis and optimal surgical treatment are challenging.

Conclusion:

This present case highlighted the preoperative diagnostic difficulties of the SPCBD. Emergent surgical management should be instituted in the shortest time possible to reduce the high mortality.
Breast Cancer Survivors’ Experiences of Acceptance Following Recurrence
Authors: Matbouei Mahsa , Samsami Majid , Soleimani Mohsen
Published: March 2023

Background

Breast cancer recurrence is a traumatic event for patients, and its treatment depends on the patient’s ability to accept the circumstances.

Objective

The aim of this study was to explore how patients experience breast cancer recurrence and go through a process of negotiating acceptance.

Methods

This study explored the experiences of 16 patients with breast cancer recurrence regarding the acceptance of recurrence in a hospital in Tehran, Iran. Purposive sampling with maximum diversity was used. Data were collected through semistructured telephone interviews from November 2020 to November 2021 and analyzed using the qualitative content analysis.

Results

Four themes emerged that described the process of accepting cancer recurrence: (1) response to recurrence (emotional reactions and loss of trust); (2) psychological preparedness (confirmation of medical diagnosis and acceptance of fate); (3) mobilizing supports (using spiritual capacities, utilizing supportive resources, and seeking relationships to promote knowledge); and (4) return to the path of treatment (rebuilding trust and continuation of treatment).

Conclusions

The acceptance of breast cancer recurrence is a process that begins with emotional reactions and ends with returning to the treatment path. The patient’s psychological preparation, support systems, behavior of healthcare providers, and rebuilding trust are the determining factors in acceptance of recurrence.

Implications for Practice

Nurses can compensate for the failures created in the primary treatment of breast cancer by spending time with patients and paying attention to their concerns, providing effective education, strengthening communication between patients with similar conditions and using the spiritual capacities of patients, and mobilizing the support of family and relatives.
Adolescent and Caregiver Perspectives on Living With a Limb Fracture
Authors: Bharadia Manisha , Golden-Plotnik Stevi , van Manen Michael , Sivakumar Mithra , Drendel Amy L. , Poonai Naveen , Moir Mackenzie , Ali Samina
Published: March 2023

Background

Fractures occur in up to half of children by age 16 years. After initial emergency care for a fracture, function is universally impaired in children, and impacts extend to the immediate family. Knowledge of expected functional limitations is key to providing proper discharge instructions and anticipatory guidance to families.

Objectives

The primary objective of this study was to understand how changes in functional ability impact youth with fractures.

Methods

We conducted individual, semistructured interviews from June 2019 to November 2020 with adolescents and their caregivers 7 to 14 days following their initial visit to a pediatric emergency department. We used qualitative content analysis methodology; recruitment proceeded until thematic saturation was achieved. Coding and analysis were concurrent with recruitment and interviews. The interview script was modified in an iterative process, to reflect emerging themes.

Results

Twenty-nine interviews were completed. The most frequently affected functions were (a) showering and hygiene (requiring the most caregiver support), (b) sleep (due to pain and cast-related discomfort), and (c) exclusion from sports/activities. Many adolescents experienced disruptions to social activities and gatherings. Youth valued independence and took more time to complete tasks, regardless of inconvenience. Both adolescents and caregivers reported feelings of frustration from day-to-day impacts of the injury. Generally, caregivers' perspectives were in keeping with the experiences that adolescents described for themselves. Notable family impacts included “sibling burden,” or conflicts that arose when a sibling had to take on extra chores/tasks.

Conclusions

Overall, caregivers' perspectives were congruent with the self-described experiences of adolescents. Key messages for optimized discharge instructions include pain and sleep management, allowing extra time to complete tasks independently, considering impact on siblings, preparing for changes in activities and social dynamics, and normalizing frustration. These themes highlight an opportunity to better tailor discharge instructions for adolescents with fractures.
Building Public Health Emergency Preparedness, Response, and Recovery Capabilities Through Disaster Citizen Science: Perspectives From Local Health Department, Academic, and Community Representatives
Authors: Siddiqi Sameer M. , Kareddy Vishnupriya , Uscher-Pines Lori , Chari Ramya
Published: March 2023

Context:

Disaster citizen is the use of scientific methods by the public to address preparedness, response, or recovery needs. Disaster citizen science applications with public health relevance are growing in academic and community sectors, but integration with public health emergency preparedness, response, and recovery (PHEPRR) agencies is limited.

Objective:

We examined how local health departments (LHDs) and community-based organizations have used citizen science to build public health preparedness and response (PHEP) capabilities. The purpose of this study is to help LHDs make use of citizen science to support PHEPRR.

Design:

We conducted semistructured telephone interviews (n = 55) with LHD, academic, and community representatives engaged or interested in citizen science. We used inductive and deductive methods to code and analyze interview transcripts.

Setting:

US and international community-based organizations and US LHDs.

Participants:

Participants included 18 LHD representatives reflecting diversity in geographic regions and population sizes served and 31 disaster citizen science project leaders and 6 citizen science thought leaders.

Main Outcomes:

We identified challenges LHDs and academic and community partners face in using citizen science for PHEPRR as well as strategies to facilitate implementation.

Results:

Academic and community-led disaster citizen science activities aligned with many PHEP capabilities including community preparedness, community recovery, public health surveillance and epidemiological investigation, and volunteer management. All participant groups discussed challenges related to resources, volunteer management, collaborations, research quality, and institutional acceptance of citizen science. The LHD representatives noted unique barriers due to legal and regulatory constraints and their role in using citizen science data to inform public health decisions. Strategies to increase institutional acceptance included enhancing policy support for citizen science, increasing volunteer management support, developing best practices for research quality, strengthening collaborations, and adopting lessons learned from relevant PHEPRR activities.

Conclusions:

There are challenges to overcome in building PHEPRR capacity for disaster citizen science but also opportunities for LHDs to leverage the growing body of work, knowledge, and resources in academic and community sectors.
Recommendations to Improve the Nature and Extent of Relationships Among Organizations Within a Network to Enhance Supports for Transgender Survivors of Sexual Assault
Authors: Du Mont Janice , Coelho Madelaine , Lebel Nicholas , Friedman Burley Joseph , Kosa Sarah Daisy , Macdonald Sheila
Published: March 2023

Context:

To enhance the provision of comprehensive supports to transgender (trans) survivors of sexual assault, a structurally marginalized group with complex care needs, we developed an intersectoral network of trans-positive health care and community organizations in Ontario, Canada.

Objective:

As a baseline evaluation of the network, we conducted a social network analysis to determine the extent and nature of collaboration, communication, and connection among members.

Design:

Relational data (eg, activities of collaboration) were collected from June to July 2021, and analyzed using a validated survey tool, Program to Analyze, Record, and Track Networks to Enhance Relationships (PARTNER). We shared findings in a virtual consultation session with key stakeholders and facilitated discussion to generate action items. Consultation data were synthesized into 12 themes through conventional content analysis.

Setting:

An intersectoral network in Ontario, Canada.

Participants:

Of the 119 representatives of trans-positive health care and community organizations invited to participate in this study, 78 (65.5%) completed the survey.

Main Outcome Measures:

Proportion/count of organizations collaborating with other organizations. Network scores for value and trust.

Results:

Almost all (97.5%) invited organizations were listed as collaborators, representing 378 unique relationships. The network achieved a value score of 70.4% and trust score of 83.4%. The most prominent themes were “Communication and knowledge exchange channels,” “Clearer roles and contributions,” “Indicators of success,” and “Client voices at the centre.”

Conclusion:

As key antecedents of network success, high value and trust indicate that network member organizations are well positioned to further foster knowledge sharing, define their roles and contributions, prioritize the integration of trans voices in all activities, and, ultimately, achieve common goals with clearly defined outcomes. There is great potential to optimize network functioning and advance the network's mission to improve services for trans survivors by mobilizing these findings into recommendations.
Epidemiology of Culture-Negative Pulmonary Tuberculosis—Alameda County, 2010-2019
Authors: Chen Jennie , Marusinec Rachel , Brown Robert , Shiau Rita , Jaganath Devan , Chitnis Amit S.
Published: March 2023

Context:

Patients with culture-negative pulmonary TB (PTB) can face delays in diagnosis that worsen outcomes and lead to ongoing transmission. An understanding of current trends and characteristics of culture-negative PTB can support earlier detection and access to care.

Objective:

Describe epidemiology of culture-negative PTB.

Design, Setting, Participants:

We utilized Alameda County TB surveillance data from 2010 to 2019. Culture-negative PTB cases met clinical but not laboratory criteria for PTB per US National Tuberculosis Surveillance System definitions. We calculated trends in annual incidence and proportion of culture-negative PTB using Poisson and weighted linear regression, respectively. We further compared demographic and clinical characteristics among culture-negative versus culture-positive PTB cases.

Results:

During 2010-2019, there were 870 cases of PTB, of which 152 (17%) were culture-negative. The incidence of culture-negative PTB declined by 76%, from 1.9/100 000 to 0.46/100 000 (P for trend <.01), while the incidence of culture-positive PTB reduced by 37% (6.5/100 000 to 4.1/100 000, P for trend =.1). Culture-negative PTB case-patients were more likely than culture-positive PTB case-patients to be younger (7.9% were children <15 years old vs 1.1%; P < .01), recent immigrants within 5 years of arrival (38.2% vs 25.5%; P < .01), and have a TB contact (11.2% vs 2.9%; P < .01). Culture-negative PTB case-patients were less likely than culture-positive PTB case-patients to be evaluated because of TB symptoms (57.2% vs 74.7%; P < .01) or have cavitation on chest imaging (13.1% vs 38.8%; P < .01). At the same time culture-negative PTB case-patients were less likely to die during TB treatment (2.0% vs 9.6%; P < .01).

Conclusions:

The incidence of culture-negative PTB disproportionately declined compared with culture-positive TB and raises concern for gaps in detection. Expansion of screening programs for recent immigrants and TB contacts and greater recognition of risk factors may increase detection of culture-negative PTB.
Comparing State-Level and Facility-Based Review to Assess Quality of Severe Maternal Morbidity Reviews
Authors: Garland Caitlin E. , Craemer Katherine A. , Koch Abigail R. , Locher Stephen , Geller Stacie E.
Published: March 2023

Objective:

To compare results from facility-level and state-level severe maternal morbidity (SMM) reviews in Illinois.

Design:

We report descriptive characteristics about SMM cases and compare the results of both review processes, including the primary cause, assessment of preventability, and factors that contributed to the severity of the SMM cases.

Setting:

All birthing hospitals in Illinois.

Participants:

A total of 81 SMM cases were reviewed by a facility-level committee and the state-level review committee. SMM was defined as any intensive care or critical care unit admission and/or transfusion of 4 or more units of packed red blood cells from conception to 42 days postpartum.

Results:

Among the cases reviewed by both committees, hemorrhage was the primary cause of morbidity, with 26 (32.1%) and 38 (46.9%) hemorrhage cases identified by the facility-level and state-level committees, respectively. Both committees identified infection/sepsis (n = 12) and preeclampsia/eclampsia (n = 12) as the next most common causes of SMM. State-level review found more cases potentially preventable (n = 29, 35.8% vs n = 18, 22.2%) and more cases not preventable but improvement in care needed (n = 31, 38.3% vs n = 27, 33.3%). State-level review found more provider and system opportunities to alter the SMM outcome and fewer patient opportunities than facility-level review.

Conclusion:

State-level review found more SMM cases potentially preventable and identified more opportunities to improve care than facility-level review. State-level review has the potential to strengthen facility-level reviews by identifying opportunities to improve the review process and develop recommendations and tools to aid facility-level reviews.
Effectiveness of an External Urinary Device for Female Anatomy and Trends in Catheter-Associated Urinary Tract Infections
Authors: Beeson Terrie , Pittman Joyce , Davis Carmen R.
Published: March 2023

PURPOSE:

The purpose of this study was to examine the effectiveness of an external female urinary management system (external urinary device for female anatomy [EUDFA]) in critically ill women unable to self-toilet and to identify rates of indwelling catheter use, catheter-associated urinary tract infections (CAUTIs), urinary incontinence (UI), and incontinence-associated dermatitis (IAD) before and after the introduction of the EUDFA.

DESIGN:

Prospective, observational, and quasi-experimental design.

SUBJECTS AND SETTING:

The sample comprised 50 adult female patients in 4 critical/progressive care units using an EUDFA at a large academic hospital in the Midwestern United States. All adult patients in these units were included in the aggregate data.

METHODS:

Prospective data collected from the adult female patients over 7 days included urine diverted from the device to a canister and total leakage. Aggregate unit rates of indwelling catheter use, CAUTIs, UI, and IAD were retrospectively examined during 2016, 2018, and 2019. Means and percentages were compared using t tests or chi-square tests.

RESULTS:

The EUDFA successfully diverted 85.5% of patients' urine. Indwelling urinary catheter use was significantly lower in 2018 (40.6%) and 2019 (36.6%) compared with 2016 (43.9%) (P < .01). The rate of CAUTIs was lower in 2019 than in 2016, but not significantly (1.34 per 1000 catheter-days vs 0.50, P = .08). The percentage of incontinent patients with IAD was 69.2% in 2016 and 39.5% in 2018-2019 (P = .06).

CONCLUSIONS:

The EUDFA was effective in diverting urine from critically ill female incontinent patients and indwelling catheter utilization.
Whole-genome sequencing-based characterization of Streptomyces sp. 6(4): focus on natural product
Authors: Borba Marcela Proença , Witusk João Paulo , Cunha Débora Marchesan , de Lima-Morales Daiana , Martins Andreza Francisco , Van Der Sand Sueli
Published: March 2023

We have sequenced the whole genome of

Streptomyces

sp. 6(4) isolated from tomato roots that presents antifungal activity against phytopathogenic fungi, mainly Bipolaris sorokiniana. The genome has almost 7 Mb and 3368 hypothetical proteins that were analysed and characterized in Uniprot with the emphasis on biological compounds. Multilocus sequence typing (MLST) analyses were performed in an effort to characterize and identify this isolate, resulting in a new sequence type (ST), classified as ST64. Phenetic and phylogenetic trees were constructed to investigate

Streptomyces

sp. 6(4) evolution and sequence similarity, and the isolate is a strain closer to

Streptomyces prasinus

and

Streptomyces viridosporus

. It is known that the genus

Streptomyces

possess huge metabolic capacity with the presence of cryptic genes. These genes are usually present in clusters, which are responsible for the production of diverse natural products, mainly antibiotics. In addition, 6(4) showed 11 biosynthetic gene clusters through antiSMASH, including 3 polyketide synthase (PKS) and non-ribosomal peptide synthase (NRPS) type clusters.
Microbial communities in freshwater used for hydraulic fracturing are unable to withstand the high temperatures and pressures characteristic of fractured shales
Authors: Nixon Sophie L , Plominsky Alvaro M , Hernandez-Becerra Natali , Boothman Christopher , Bartlett Douglas H
Published: March 2023

Natural gas is recovered from shale formations by hydraulic fracturing, a process known to create microbial ecosystems in the deep subsurface. Microbial communities that emerge in fractured shales include organisms known to degrade fracturing fluid additives and contribute to corrosion of well infrastructure. In order to limit these negative microbial processes, it is essential to constrain the source of the microorganisms responsible. Previous studies have identified a number of potential sources, including fracturing fluids and drilling muds, yet these sources remain largely untested. Here, we apply high pressure experimental approaches to assess whether the microbial community in synthetic fracturing fluid made from freshwater reservoir water can withstand the temperature and pressure conditions of hydraulic fracturing and the fractured shale environment. Using cell enumerations, DNA extraction and culturing, we show that the community can withstand high pressure or high temperature alone, but the combination of both is fatal. These results suggest that initial freshwater-based fracturing fluids are an unlikely source of microorganisms in fractured shales. These findings indicate that potentially problematic lineages, such as sulfidogenic strains of Halanaerobium that have been found to dominate fractured shale microbial communities, likely derive from other input sources into the down well environment, such as drilling muds.
A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
Authors: Walker Romy , Mahmood Khalid , Joo Jihoon E. , Clendenning Mark , Georgeson Peter , Como Julia , Joseland Sharelle , Preston Susan G. , Antill Yoland , Austin Rachel , Boussioutas Alex , Bowman Michelle , Burke Jo , Campbell Ainsley , Daneshvar Simin , Edwards Emma , Gleeson Margaret , Goodwin Annabel , Harris Marion T. , Henderson Alex , Higgins Megan , Hopper John L. , Hutchinson Ryan A. , Ip Emilia , Isbister Joanne , Kasem Kais , Marfan Helen , Milnes Di , Ng Annabelle , Nichols Cassandra , O’Connell Shona , Pachter Nicholas , Pope Bernard J. , Poplawski Nicola , Ragunathan Abiramy , Smyth Courtney , Spigelman Allan , Storey Kirsty , Susman Rachel , Taylor Jessica A. , Warwick Linda , Wilding Mathilda , Williams Rachel , Win Aung K. , Walsh Michael D. , Macrae Finlay A. , Jenkins Mark A. , Rosty Christophe , Winship Ingrid M. , Buchanan Daniel D. ,   the Family Cancer Clinics of Australia
Published: March 2023

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) andMLH1promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primaryMLH1epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumorMLH1methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternateMLH1methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
Differential cognitive effects of unilateral left and right subthalamic nucleus deep brain stimulation for Parkinson disease
Authors: Del Bene Victor A , Martin Roy C. , Brinkerhoff Sarah A. , Olson Joseph W. , Nelson Matthew J. , Marotta Dario , Gonzalez Christopher L. , Mills Kelly A. , Kamath Vidyulata , Bentley J. Nicole , Guthrie Barton L. , Knight Robert T. , Walker Harrison C.
Published: March 2023

Objective

To investigate hemispheric effects of directional versus ring subthalamic nucleus (STN) deep brain stimulation (DBS) surgery on cognitive function in patients with advanced Parkinson’s disease (PD).

Methods

We examined 31 PD patients (Left STN n = 17; Right STN n = 14) who underwent unilateral subthalamic nucleus (STN) DBS as part of a NIH-sponsored randomized, cross-over, double-blind (ring vs directional) clinical trial. Outcome measures were tests of verbal fluency, auditory-verbal memory, and response inhibition. First, all participants were pooled together to study the effects of directional versus ring stimulation. Then, we stratified the groups by surgery hemisphere and studied the longitudinal changes in cognition post-unilateral STN DBS.

Results

Relative to pre-DBS cognitive baseline performances, there were no group changes in cognition following unilateral DBS for either directional or ring stimulation. However, assessment of unilateral DBS by hemisphere revealed a different pattern. The left STN DBS group had lower verbal fluency than the right STN group (t(20.66 = -2.50,p= 0.02). Over a period of eight months post-DBS, verbal fluency declined in the left STN DBS group (p= 0.013) and improved in the right STN DBS group over time (p< .001). Similarly, response inhibition improved following right STN DBS (p= 0.031). Immediate recall did not significantly differ over time, nor was it affected by implant hemisphere, but delayed recall equivalently declined over time for both left and right STN DBS groups (left STN DBSp= 0.001, right STN DBS differ from left STN DBSp= 0.794).

Conclusions

Directional and ring DBS did not differentially or adversely affect cognition over time. Regarding hemisphere effects, verbal fluency decline was observed in those who received left STN DBS, along with the left and right STN DBS declines in delayed memory. The left STN DBS verbal fluency decrement is consistent with prior bilateral DBS research, likely reflecting disruption of the basal-ganglia-thalamocortical network connecting STN and inferior frontal gyrus. Interestingly, we found an improvement in verbal fluency and response inhibition following right STN DBS. It is possible that unilateral STN DBS, particularly in the right hemisphere, may mitigate cognitive decline.
Combining models to generate a consensus effective reproduction numberRfor the COVID-19 epidemic status in England
Authors: Manley Harrison , Park Josie , Bevan Luke , Sanchez-Marroquin Alberto , Danelian Gabriel , Bayley Thomas , Bowman Veronica , Maishman Thomas , Finnie Thomas , Charlett André , Watkins Nicholas A , Hutchinson Johanna , Riley Steven ,   Nowcasts Model Contributing Group, Panovska-Griffiths Jasmina
Published: March 2023

The effective reproduction numberRwas widely accepted as a key indicator during the early stages of the COVID-19 pandemic. In the UK, theRvalue published on the UK Government Dashboard has been generated as a combined value from an ensemble of epidemiological models via a collaborative initiative between academia and government. In this paper we outline this collaborative modelling approach and illustrate how, by using an established combination method, a combinedRestimate can be generated from an ensemble of epidemiological models. We analyse theRvalues calculated for the period between April 2021 and December 2021, to show that thisRis robust to different model weighting methods and ensemble size, and that using heterogeneous data sources for validation increases its robustness and reduces the biases and limitations associated with a single source of data. We discuss howRcan be generated from different data sources and is therefore a good summary indicator of the current dynamics in an epidemic.
Burden and risk factors for Achilles tendinopathy in the military population from 2006 to 2015. A retrospective cohort study
Authors: Sullivan Christopher K , Janney Cory F. , Fraser John J.
Published: March 2023

Background

Ankle-foot conditions are ubiquitous in the US Military. The objective of this study was to evaluate the burden and associated factors of Achilles tendinopathy (AT).

Methods

The Defense Medical Epidemiology Database was used to identify all diagnosed AT in military personnel from 2006 to 2015. Prevalence of AT was calculated and compared by year, service branch, and military rank. Unadjusted and adjusted assessment of injury risk were calculated.

Results

Officers incurred 37,939 episodes at a prevalence of 17.65 per 1000 (male officers: 18.20 per 1000; female officers: 14.80 per 1000). Among enlisted personnel, there were 116,122 episodes of AT that occurred in 12.22 per 1000 (male enlisted: 12.07 per 1000; female enlisted: 13.22 per 1000). All officer specialties had significantly higher risk of AT episodes compared to the ground and naval gunfire officers (PR: 1.04-1.43), with aviation demonstrating a significant protective effect (PR: 0.65). Among enlisted specialties, maritime/naval specialties had reduced risk (PR: 0.82), with all specialties (except aviation) having increased risk of AT compared to infantry (PR: 1.07-1.71). There were multiple associated factors identified, to include sex, age, rank, military occupation, and service branch.

Conclusions

AT was ubiquitous in the US military, with a progressive increase in prevalence during the study epoch. There were multiple associated factors identified, to include sex, age, rank, military occupation, and service branch. These findings highlight both the need for prophylactic interventions and identification of the populations with the greatest need.
Condensate-driven interfacial forces reposition DNA loci and measure chromatin viscoelasticity
Authors: Strom Amy R. , Kim Yoonji , Zhao Hongbo , Orlovsky Natalia , Chang Yi-Che , Košmrlj Andrej , Storm Cornelis , Brangwynne Clifford P.
Published: March 2023

Biomolecular condensates assemble in living cells through phase separation and related phase transitions. An underappreciated feature of these dynamic molecular assemblies is that they form interfaces with cellular structures, including membranes, cytoskeleton, DNA and RNA, and other membraneless compartments. These interfaces are expected to give rise to capillary forces, but there are few ways of quantifying and harnessing these forces in living cells. Here, we introduce VECTOR (ViscoElasticChromatinTethering andORganization), which uses light-inducible biomolecular condensates to generate capillary forces at targeted DNA loci. VECTOR can be utilized to programmably reposition genomic loci on a timescale of seconds to minutes, quantitatively revealing local heterogeneity in the viscoelastic material properties of chromatin. These synthetic condensates are built from components that naturally form liquid-like structures in living cells, highlighting the potential role for native condensates to generate forces and do work to reorganize the genome and impact chromatin architecture.
Topology recapitulates ontogeny of dendritic arbors
Authors: Liao Maijia , Bird Alex D. , Cuntz Hermann , Howard Jonathon
Published: March 2023

Branching of dendrites and axons allows neurons to make synaptic contacts with large numbers of other neurons, facilitating the high connectivity of the nervous system. Neurons have geometric properties, such as the lengths and diameters of their branches, that change systematically throughout the arbor in ways that are thought to minimize construction costs and to optimize the transmission of electrical signals and the intracellular transport of materials. In this work, we investigated whether neuronal arbors also have topological properties that reflect the growth and/or functional properties of their dendritic arbors. In our efforts to uncover possible topological rules, we discovered a function that depends only on the topology of bifurcating trees such as dendritic arbors:the tip-support distribution, which is the average number of branches that supportndendrite tips. We found that for many, but not all, neurons from a wide range of invertebrate and vertebrate species,the tip-support distributionfollows a power law with slopes ranging from -1.4 and -1.8 on a log-log plot. The slope is invariant under iterative trimming of terminal branches and under random ablation of internal branches. We found that power laws with similar slopes emerge from a variety of iterative growth processes including the Galton-Watson (GW) process, where the power-law behavior occurs after the percolation threshold. Through simulation, we show the slope of the power-law increases with the branching probability of a GW process, which corresponds to a more regular tree. Furthermore, the inclusion of postsynaptic spines and other terminal processes on branches causes a characteristic deviation of thetip-support distributionfrom a power law. Therefore, the tip-support function is a topological property that reflects the underlying branching morphogenesis of dendritic trees.
Haplotype phasing ofCYP2D6: an allelic ratio method using Agena MassARRAY data
Authors: Thamilselvan Megana , Mather Cheryl , Wang Yabing , Aitchison Katherine J.
Published: March 2023

Pharmacogenomics aims to use the genetic information of an individual to personalize drug prescribing. There is evidence that pharmacogenomic testing before prescription may prevent adverse drug reactions, increase efficacy, and reduce cost of treatment.CYP2D6is a key pharmacogene of relevance to multiple therapeutic areas. Indeed, there are prescribing guidelines available for medications based on CYP2D6 enzyme activity as deduced fromCYP2D6genetic data. The Agena MassARRAY system is a cost-effective method of detecting genetic variation that has been clinically applied to other genes. However, its clinical application toCYP2D6has to date been limited by weaknesses such as the inability to determine which haplotype was present in more than one copy for individuals with more than two copies of theCYP2D6gene. We report application of a new protocol forCYP2D6haplotype phasing of data generated from the Agena MassARRAY system. For samples with more than two copies of theCYP2D6gene for which the prior consensus data specified which one was present in more than one copy, our protocol was able to conductCYP2D6haplotype phasing resulting in 100% concordance with the prior data. In addition, for three reference samples known to have more than two copies ofCYP2D6but for which the exact number ofCYP2D6genes was unknown, our protocol was able to resolve the number for two out of the three of these, and estimate the likely number for the third. In addition, we demonstrate that our method is applicable toCYP2D6hybrid tandem configurations.
Activation of prefrontal parvalbumin interneurons ameliorates treatment-resistant working memory deficit even under continuous antipsychotic treatment in a mouse model of schizophrenia
Authors: Arime Yosefu , Saitoh Yoshito , Ishikawa Mikiko , Kamiyoshihara Chikako , Uchida Yasuo , Fujii Kazuki , Takao Keizo , Akiyama Kazufumi , Ohkawa Noriaki
Published: March 2023

BACKGROUND

One of the critical unmet medical needs in schizophrenia is a remedy for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. In addition, despite the patients with schizophrenia cannot stop taking antipsychotics due to a high rate of discontinuation-induced relapse, previous studies using animal models of schizophrenia have not considered these clinical situations.

METHODS

Here, we employ multi-dimensional approaches, including histological analysis in the prelimbic cortex, LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotic drugs, in vivo calcium imaging and behavioral analyses of mice using chemogenetic manipulation, to investigate neural mechanisms and potential therapeutic interventions for working memory deficit in a mouse model with chronic phencyclidine (PCP) administration that resembles the schizophrenia symptomatology.

RESULTS

Chronic PCP administration led to abnormalities in excitatory and inhibitory synapses, including dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons, in layer 2–3 of the prelimbic cortex. Continuous olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not affect these synaptic abnormalities and working memory deficit in the PCP-treated mice. We found that the selective prelimbic PV activation, using hM3D(Gq)-DREADD system confirmed by in vivo calcium imaging, restored working memory deficit, even under continuous olanzapine treatment.

CONCLUSIONS

Our study raises a possibility that intervention in prefrontal PV neurons leads to an add-on therapy to antipsychotics targeting amelioration of treatment-resistant cognitive deficits in schizophrenia.
Radiobiological analysis of the response of prostate cancer to different fractionations
Authors: Pardo-Montero Juan , González-Crespo Isabel , Gómez-Caamaño Antonio , Gago-Arias Araceli
Published: March 2023

Purpose

To investigate the response of prostate cancer to different radiotherapy schedules, including hypofractionation, and to evaluate potential departures from the linear-quadratic (LQ) response. To obtain best-fitting parameters for low (LR), intermediate (IR), and high risk (HR) prostate cancer.

Methods and Materials

We have constructed a dataset of dose-response containing 87 entries (35 LR, 32 IR, 20 HR), with doses per fraction ranging from 1.8 to 10 Gy. These data were fitted to tumor control probability models based on the LQ model, linear-quadratic-linear (LQL), and a modification of the LQ (LQmod) accounting for increasing radiosensitivity at large doses. Fits were performed with the maximum likelihood expectation methodology, and the Akaike-Information-Criterion (AIC) was used to compare models.

Results

The AIC shows that the LQ model is superior to the LQL and LQmod for all risks, except for IR where the LQL outperforms the other models. The analysis shows a low α/β for all risks: 2.01 Gy for LR (95% confidence interval 1.74-2.26), 3.44 Gy for IR (2.99-4.02), and 2.78 Gy for HR (1.43-4.18). Best-fits do not show proliferation for LR, and only moderate proliferation for IR/HR.

Conclusions

In general, the LQ model describes the response of prostate cancer better than the alternative models. Only for IR the LQL outperforms the LQ. This study confirms a lowα/βfor all risks, with doses per fraction ranging from <2 Gy up to 10 Gy.
An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis
Authors: Jörgensen Sara K. M. , Karnošová Alena , Mazzaferro Simone , Rowley Oliver , Chen Hsiao-Jou Cortina , Robbins Sarah J. , Christofides Sarah , Merkle Florian T. , Maletínská Lenka , Petrik David
Published: March 2023

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, Diet Induced Obesity (DIO) by High Fat Diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR. In the HFD context, LiPR rescued survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. In addition, LiPR rescued reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.
How is Emotional Evidence from Multiple Sources Used in Perceptual Decision Making?
Authors: Ngai Hilary H.T. , Hsiao Janet H. , Luhmann Christian , Mohanty Aprajita , Jin Jingwen
Published: March 2023

Judging the emotional nature of a scene requires us to deliberately integrate pieces of evidence with varying intensity of emotion. Our existing knowledge about emotion-related perceptual decision making is largely based on paradigms using single stimulus and, when involving multiple stimuli, rapid decisions. Consequently, it remains unclear how we sample and integrate multiple pieces of emotional evidence deliberately to form an overall judgment. Findings from non-emotion rapid decision-making studies show humans down-sample and downweight extreme evidence. However, deliberate decision making may rely on a different attention mode than in rapid decision making; and extreme emotional stimuli are inherently salient. Given these critical differences, it is imperative to directly examine the deliberate decision-making process about multiple emotional stimuli. In the current study, human participants (N=33) viewed arrays of faces with expressions ranging from extremely fearful to extremely happy freely with their eye movement tracked. They then decided whether the faces were more fearful or happier on average. In contrast to conclusions drawn from non-emotion and rapid decision-making studies, eye movement measures revealed that participants attentionally sampled extreme emotional evidence more than less extreme evidence. Computational modeling results showed that even though participants exhibited biased attention distribution, they weighted various emotional evidence equally. These findings provide novel insights into how people sample and integrate multiple pieces of emotional evidence, contribute to a more comprehensive understanding of emotion-related decision making, and shed light on the mechanisms of pathological affective decisions.
Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation
Authors: Harris Rebecca J. , Heer Maninder , Levasseur Mark D. , Cartwright Tyrell N. , Weston Bethany , Mitchell Jennifer L. , Coxhead Jonathan M. , Gaughan Luke , Prendergast Lisa , Rico Daniel , Higgins Jonathan M.G.
Published: March 2023

Histone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where particular combinations of modifications specify unique downstream functions, is widely accepted and can be demonstratedin vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognise trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me3 during mitosis. We find that H3K4me3 hinders adjacent H3T3ph deposition in cells, and that the PHD domain of TAF3 can bind H3K4me3 in mitotic chromatin despite the presence of H3T3ph. Unlikein vitro, H3K4 readers are displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.
Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
Authors: Niemi Natalie M. , Serrano Lia R. , Muehlbauer Laura K. , Balnis Catie , Kozul Keri-Lyn , Rashan Edrees H. , Shishkova Evgenia , Schueler Kathryn L. , Keller Mark P. , Attie Alan D. , Pagan Julia , Coon Joshua J. , Pagliarini David J.
Published: March 2023

Pptc7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lackingPptc7exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss ofPptc7in adult mice causes marked reduction in mitochondrial mass concomitant with elevation of the mitophagy receptors Bnip3 and Nix. Consistently,Pptc7-/-mouse embryonic fibroblasts (MEFs) exhibit a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs— including multiple sites on Bnip3 and Nix. These data suggest thatPptc7deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that Pptc7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for Pptc7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
Liver-specific Inflammatory Signatures Predict Clinically Significant Liver Damage
Authors: Chua Conan , Mahamed Deeqa , Nkongolo Shirin , Mehrotra Aman , Wong David K.H. , Chung Raymond T. , Feld Jordan J. , Janssen Harry L.A. , Gehring Adam J.
Published: March 2023

Background and Aims

Inflammation drives progression of chronic liver disease. However, the triggers of inflammation remain undefined during chronic hepatitis B (CHB) because hepatic flares are spontaneous and difficult to capture. We used nucleoside analogue (NA) withdrawal to investigate early inflammatory events because liver damage after stopping therapy occurs in a predictable time frame. 11 CHB patients underwent 192 weeks of NA therapy before a protocol defined stop. Liver fine-needle aspirates (FNAs) were collected at baseline and 4-weeks post-withdrawal and analyzed using flow cytometry and single-cell RNA sequencing (scRNA-seq). Intrahepatic mononuclear cells (IHMCs) from uninfected livers were used to validate transcriptomic findings. At 4 weeks post NA-withdrawal, HBV DNA rebounded but alanine aminotransferase (ALT) levels remained normal, 7/11 patients developed ALT elevations (>2xULN) at later timepoints. There were no changes in cell frequencies between baseline and viral rebound. ScRNA-seq revealed upregulation of IFN stimulated genes (ISGs) and pro-inflammatory cytokineMIFupon viral rebound. In vitro experiments confirmed the type I IFN-dependent ISG profile whereasMIFwas induced primarily by IL-12. MIF exposure further amplified inflammatory cytokine production by myeloid cells. Our data show that innate immune activation is detectable in the liver before clinically-significant liver damage is detectable in the serum.
Cryo-EM-guided engineering of T-box-tRNA modules with enhanced selectivity and sensitivity in translational regulation
Authors: Jia Xinyu , Zhang Chong , Luo Bingnan , Frandsen Jane K. , Watkins Andrew M. , Li Kaiyu , Zhang Minghua , Wei Xiawei , Yang Yang , Henkin Tina M. , Su Zhaoming
Published: March 2023

Riboswitches are non-coding RNA elements that play vital roles in regulating gene expression. Their specific ligand-dependent structural reorganization facilitates their use as templates for design of engineered RNA switches for therapeutics, nanotechnology and synthetic biology. T-box riboswitches bind tRNAs to sense aminoacylation and control gene expression via transcription attenuation or translation inhibition. Here we determine the cryo-EM structure of the wild-typeMycobacterium smegmatis ileST-box in complex with its cognate tRNAIle. This structure shows a very flexible antisequestrator region that tolerates both 3’-OH and 2’,3’-cyclic phosphate modification at the 3’ end of tRNAIle. Elongation of one helical turn (11-base pair) in both the tRNA acceptor arm and T-box Stem III maintains T-box-tRNA complex formation and increases the selectivity for tRNA 3’ end modification. Moreover, elongation of Stem III results in ∼6-fold tighter binding to tRNA, which leads to increased sensitivity of downstream translational regulation indicated by precedent translation. Our results demonstrate that cryo-EM can guide RNA engineering to design improved riboswitch modules for translational regulation, and potentially a variety of additional functions.