bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Conceptions of Instrumental Thought
Authors: O’Connell Rory
Published: September 2023

According to a dominant assumption the truth of instrumental thoughts—thoughts in which one action is identified as a means to another—are not affected by agents’ normative conceptions of their ends. Agents could in principle grasp these thoughts, and thereby the correct means to their ends, without consulting any conception they may have as to the pursuit-worthiness of those ends. I argue this assumption (the ‘Theoretical Conception’) prevents us from explaining how agents can identify means to their ends. I sketch an alternative account according to which the contents of instrumental thoughts are directly determined by agent's reasons for acting. This is explained by the fact that an agent's reasons for action reveal what they take the good of their ends to be. Ultimately, I argue, agents must have a conception of their final ends as intrinsically good if they are to successfully specify means to them.
Why Must Incompatibility Be Symmetric?
Authors: Simonelli Ryan
Published: September 2023

Why must incompatibility be symmetric? An odd question, but recent work in the semantics of non-classical logic, which appeals to the notion of incompatibility as a primitive and defines negation in terms of it, has brought this question to the fore. Francesco Berto proposes such a semantics for negation argues that, since incompatibility must be symmetric, double negation introduction must be a law of negation. However, he offers no argument for the claim that incompatibility really must be symmetric. Here, I provide such an argument, showing that, insofar as we think of incompatibility in normative pragmatic terms, it can play its basic pragmatic function only if it is symmetric. The upshot is that we can vindicate Berto’s claim about the symmetry of incompatibility but only if we, pace Berto, think about incompatibility, in the first instance, as a pragmatic relation between acts rather than a semantic relation between contents.
Vagus Nerve Stimulation Paired With Mobility Training in Chronic Ischemic Stroke: A Case Report
Authors: Kimberley Teresa J , Prudente Cecília N , Engineer Navzer D , Dickie David Alexander , Bisson Teresa A , Van de Winckel Ann
Published: September 2023

Objective

The purpose of this case report is to describe pairing vagus nerve stimulation (VNS) with mobility training in an individual after stroke.

Methods

A 53-year-old man with left hemiparesis 14.2 months after an ischemic stroke participated in a pilot study investigating the safety and feasibility of VNS paired with upper limb rehabilitation. In addition to upper limb impairment, the participant had impaired gait and wanted to improve his mobility. A single-subject design investigation of VNS paired with self-directed mobility training was conducted. Following the conclusion of the pilot study, the participant was instructed to complete daily sessions of self-activated VNS paired with walking or stationary biking. The 10-Meter Walk Test and timed distance (6-Minute Walk Test) were assessed at 4 baseline points and at 3 to 41 months after mobility training.

Results

The participant had stable baseline values and was classified as a household ambulator with a quad cane. After VNS-paired mobility training, statistically significant improvements were observed in all measures, with the greatest improvements at 9 months exceeding the minimal detectable change: self-selected gait speed from 0.34 (standard deviation [SD] = 0.01) to 0.60 meters/second, fast gait speed from 0.37 (SD = 0.03) to 0.79 meters/second, and 6-Minute Walk Test distance from 106.91 (SD = 6.38) to 179.83 meters. The participant reported increased confidence and balance when walking. No falls or adverse events were reported.

Conclusion

The participant demonstrated improved gait speed and timed distance after VNS-paired mobility training. Randomized, blinded trials are needed to determine treatment efficacy.

Impact

This is the first documented case of VNS-paired mobility training in an individual with chronic poststroke gait impairments. VNS paired with mobility training may improve poststroke gait impairments.
New Insights and Approach Toward the Genetic Diversity and Strain Typing of Erwinia pyrifoliae Based on rsxC, an Electron Transport Gene
Authors: Ham Hyeonheui , Park Dong Suk
Published: September 2023

Erwinia pyrifoliae, a causal agent of black shoot blight in apple and pear trees, is a plant pathogenic bacterium first reported in South Korea. The symptoms of black shoot blight are very similar to those of the fire blight disease in apple and pear trees caused by E. amylovora, as E. pyrifoliae has a genetically very close relationship with E. amylovora. Recently, there have been reports that E. pyrifoliae causes disease in European strawberries, resulting in severe fruit loss that aroused great concern about its spread, distribution, and host range. Therefore, it is essential to establish a trustworthy approach to understanding the distribution patterns of E. pyrifoliae based on the genetic background to strengthen the barrier of potential spreading risks, although advanced methods have been provided to accurately detect E. pyrifoliae and E. amylovora. Consequently, this study discovered a noble and noteworthy gene, rsxC, capable of providing the pathogen genotype by comparing E. pyrifoliae genomic sequences in the international representative genome archive. Different numbers of 40-unit amino acid repeats in this gene among the strains induced intraspecific traits in RsxC. By comparing their repeat pattern, E. pyrifoliae isolates were divided into two main groups, branching into several clades via sequence alignment of 35 E. pyrifoliae isolates from various apple orchards from 2020 to 2021 in South Korea. The newly discovered quadraginta amino acid repeat within this gene would be a valuable genetic touchstone for determining the genotype and distribution pattern of E. pyrifoliae strains, ultimately leading to exploring their evolution. The function of amino acid repeats and the biological significance of strains need to be elucidated further.
Treating acute migraine with ubrogepant
Authors: Schoenfuss Erin S.
Published: September 2023

Acute migraine affects millions of people and is one of the most common primary care complaints in the United States. Available first-line abortive treatments are limited and vary in efficacy. Newer medications such as calcitonin gene-related peptide (CGRP) receptor antagonists may be a useful alternative. This article describes the use of ubrogepant, a new CGRP receptor antagonist, in a patient with contraindications to traditional medications used for acute migraine.
How to avoid pitfalls when referring patients to otolaryngology
Authors: Dey Dennis
Published: September 2023

Delayed, faulty, incomplete, or misdiagnosed referrals to otolaryngology (also called ear, nose, and throat, or ENT) can result in physical and monetary harm to the patient and time spent by clinicians in reordering the appropriate diagnostic tests. This article describes how to refer patients to ENT in the most time- and cost-effective ways, and addresses initial management in primary care.
CBD oil
Authors: Felker Lori
Published: September 2023

Cannabinoid (CBD) oil is a trend in self-care management. In this digital age, patients have access to products from across the globe, and these products may not be regulated. Healthcare providers must be at the forefront of the latest trends in medicine and alternative therapies to better serve patients' needs. This article reviews various medical conditions for which CBD oil already is being used, its other medicinal uses, major adverse reactions, and what patients should know before they decide to consume CBD oil.
Maximizing patient safety when prescribing opioids for pain management
Authors: Judy Megan , Sams David , Poulton Stephon
Published: September 2023

Cytochrome P450 enzyme metabolism is altered by environmental and genetic factors, which can affect the efficacy and safety of opioids. This article describes CYP polymorphisms and how pharmacogenetic testing could be used to help clinicians make safer decisions about opioid use in patients.
Heterozygous and homozygous gene knockout of the 5-HT1B receptor have different effects on methamphetamine-induced behavioral sensitization
Authors: Moriya Yuki , Kasahara Yoshiyuki , Ishihara Kana , Hall Frank Scott , Hagino Yoko , Hen René , Ikeda Kazutaka , Uhl George R. , Sora Ichiro
Published: September 2023

The psychostimulant drug methamphetamine (METH) causes euphoria in humans and locomotor hyperactivity in rodents by acting on the mesolimbic dopamine (DA) pathway and has severe abuse and addiction liability. Behavioral sensitization, an increased behavioral response to a drug with repeated administration, can persist for many months after the last administration. Research has shown that the serotonin 1B (5-HT1B) receptor plays a critical role in the development and maintenance of drug addiction, as well as other addictive behaviors. This study examined the role of 5-HT1B receptors in METH-induced locomotor sensitization using 5-HT1B knockout (KO) mice. To clarify the action of METH in 5-HT1B KO mice the effects of METH on extracellular levels of DA (DAec) and 5-HT (5-HTec) in the caudate putamen (CPu) and the nucleus accumbens (NAc) were examined. Locomotor sensitization and extracellular monoamine levels were determined in wild-type mice (5-HT1B +/+), heterozygous 5-HT1B receptor KO (5-HT1B +/−) mice and homozygous 5-HT1B receptor KO mice (5-HT1B −/−).

Behavioral sensitization to METH was enhanced in 5-HT1B −/− mice compared to 5-HT1B +/+ mice but was attenuated in 5-HT1B +/− mice compared to 5-HT1B +/+ and 5-HT1B −/− mice. In vivo, microdialysis demonstrated that acute administration of METH increases DAec levels in the CPu and NAc of 5-HT1B KO mice compared to saline groups. In 5-HT1B +/− mice, METH increased 5-HTec levels in the CPu, and DAec levels in the NAc were higher than in others.5-HT1B receptors play an important role in regulating METH-induced behavioral sensitization.
Methodological approach: using a within-subjects design in the marble burying assay
Authors: Partridge Kaitlyn J. , Olson Ruth , Hillhouse Todd M.
Published: September 2023

In 2016, the National Institutes of Health mandated the use of both male and female mice in funded research. The use of both sexes is an important variable to consider; however, it comes with negative consequences such as increased animal expenses. One way to combat these negatives is to explore the option of using a within-subjects design (repeated measures) in behavioral assays that historically use a between-subjects design. Our study aimed to determine if a within-subjects design can be utilized in the marble burying assay. The marble burying assay is used as a tool for screening putative anxiolytic compounds as the assay is thought to measure obsessive-compulsive disorder- or anxiety-like behaviors. First, we compared the effects of sex and digging medium (corn cob or Sani Chip) on the number of marbles buried using CD-1 mice. Second, we determined if mice would continue to bury marbles after repeated exposures to the test arena. Lastly, we tested three positive controls (buspirone, ketamine, and fluoxetine). We found that mice buried significantly more marbles within Sani Chip digging medium, and no sex differences were observed. Next, the number of marbles buried and locomotor activity remained consistent across four test sessions. The positive controls buspirone (3.2-10 mg/kg) ketamine (32 mg/kg), and fluoxetine (10 mg/kg) decreased the number of marbles buried using the within-subjects design. These data suggest that a within-subjects design is optimal for the marble burying assay as it will reduce the number of animals and increase statistical power.
Preoperative optimization and rapid discharge after coronary artery bypass grafting
Authors: Ponnambalam Menaka , Alex Rozen M.
Published: September 2023

Purpose of review

This review discusses current guidelines and evidence-based care for the preoperative optimization of patients who are undergoing coronary artery bypass grafting (CABG) and for enabling rapid discharge after surgery.

Recent findings

Since the Enhanced Recovery After Cardiac Surgery Society (ERAS Cardiac) issued guidelines for perioperative care, in 2019, there has been a significant body of research that has added to and provided further guidance regarding preoperative optimization and accelerated recovery after CABG.

A review of the current literature provides a framework for a pragmatic approach to preoperative optimization, utilizing the time from referral to surgery to mitigate multiple aspects of the patient condition, leading to improved patient outcomes and reduced length of stay and cost to the healthcare system.
Social and Health Care Utilization Factors Associated With Ophthalmic Visit Nonadherence in Glaucoma: An All of Us Study
Authors: Wu Jo-Hsuan , Varkhedi Varsha , Radha Saseendrakumar Bharanidharan , Acuff Kaela , Weinreb Robert N. , Baxter Sally L.
Published: September 2023

Précis:

In a diverse nationwide cohort, lower education and income levels, cost saving on medications, fewer past-year medical/specialist visits, and concerns regarding dissimilarity with health care providers were risk factors for ophthalmic visit nonadherence among glaucoma patients.

Purpose:

The purpose of this study was to characterize social and health care utilization factors associated with nonadherence with ophthalmic visits among patients with glaucoma.

Materials and Methods:

Glaucoma patients in the All of Us database who completed the Healthcare Access and Utilization Survey were included and categorized into “visit” and “nonvisit” groups based on visit adherence, defined by self-reported past-year encounters with eyecare providers (yes/no). Data regarding potential factors affecting ophthalmic visit adherence, including past-year medical visits, inabilities to afford health care, and self-reported reasons for delayed care, were extracted. χ2 tests and logistic regression were used to compare the 2 groups. Odds ratios (ORs) of visit adherence were analyzed for potential risk factors.

Results:

Of 5739 glaucoma patients, 861 (15%) were in the nonvisit group. More participants in the visit group reported past-year general doctor/specialist visits (94%/65%; vs. nonvisit group: 89%/49.3%; P<0.05). The nonvisit group reported greater difficulty in affording medical care and learning about medical conditions, and higher rates of delayed/missed health care access for various concerns (P<0.05). Older age (OR=1.02, 1.01–1.03), higher education (OR=1.25, 1.13–1.40), and income level (OR=1.06, 1.01–1.11), not employed for wages (OR=1.28, 1.08–1.53), and higher health care utilization in general medical/specialist visits (ORs range:1.08–1.90) were associated with visit adherence (P<0.05). Visit nonadherence was associated with cost saving on medication (OR=0.62, 0.40–0.97) and delaying/avoiding seeing health care providers because of dissimilarity (OR=0.84, 0.71–0.99) (P<0.05).

Conclusions:

This study builds on prior literature by identifying potentially modifiable factors associated with visit nonadherence and underutilization of eyecare in glaucoma. These may inform strategies to improve real-world ophthalmic visit adherence and identify patients who might benefit from additional support.
Clinical Relevance of RSV and SARS-CoV-2 Coinfections in Infants and Young Children
Authors: Rodriguez-Fernandez Rosa , González-Martínez Felipe , Perez-Moreno Jimena , González-Sánchez María Isabel , Toledo del Castillo Blanca , Mingueza de la Paz Irene , Diaz Pozo Laura , Mejias Asuncion , Ramilo Octavio
Published: September 2023

We analyzed the frequency, clinical impact and severity of respiratory syncytial virus (RSV) and SARS-CoV-2 coinfections in a single pediatric center between March 2020 and January 2023. Compared to single RSV infections, RSV/SARS-CoV-2 coinfections were uncommon (2.1%), occurred more frequently during circulation of omicron, and were associated with increased disease severity as defined by longer hospitalization and increased need for high-flow nasal cannula.
Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine KCONVAC in Chinese Children: Randomized, Double-blind, Placebo-controlled Phase 1 and 2 Trials
Authors: Liu Jiankai , Huang Baoying , Li Guifan , Huang Tao , Wang Danni , Zhang Li , Deng Yao , Chang Xianyun , Liu Yafei , Li Weiqi , Zhang Siyuan , Huang Weijin , Tan WenJie , Gao Lidong
Published: September 2023

Background:

It is important to extend the indication of severe acute respiratory syndrome coronavirus 2 vaccine to children to improve the vaccine intake rate and reduce infection in this population.

Methods:

In 2 phase 1 and phase 2 randomized, double-blind and placebo-controlled trials, 84 and 480 Chinese healthy children 3 to 17 years old were enrolled, respectively, and randomized in 3:1 ratio to receive 2 doses of a severe acute respiratory syndrome coronavirus 2 inactivated vaccine, KCONVAC or placebo. The 2 doses were given 28 days apart. Adverse events (AEs) were recorded through Day 28 after each dosing. Live virus neutralizing antibody and receptor binding domain antibody (RBD-IgG) were tested before vaccination and after the second dose.

Results:

Two doses of the vaccine, KCONVAC, elicited geometric mean titers of 142–150 for neutralizing antibody and 4154–4253 for RBD-IgG 28 days after the second dose. Seroconversion rates were 100% after 2 doses for both antibodies in both trials. The predominant AEs were injection-site pain, cough and fever. Most AEs were grade 1 or 2 in intensity. Five participants reported 6 vaccination-unrelated serious AEs in the phase 2 trial.

Conclusions:

Two doses of this study vaccine, KCONVAC, were well tolerated and immunogenic in children 3 to 17 years of age.
Prevalence and Prognostic Significance of PIK3CA Mutation and CNV Status and Phosphorylated AKT Expression in Patients With Cervical Cancer Treated With Primary Surgery
Authors: Martell Kevin , McIntyre John B. , Abedin Tasnima , Kornaga Elizabeth N. , Chan Angela M.Y. , Enwere Emeka , Köbel Martin , Dean Michelle L. , Phan Tien , Ghatage Prafull , Lees-Miller Susan P. , Doll Corinne M.
Published: September 2023

Currently, there are limited and conflicting reports on the prognostic utility of PIK3CA and associated pathway markers for cervical cancers treated with primary surgical management. Moreover, current studies are lacking complete characterization of adjuvant treatment with RT and/or chemotherapy. We aimed to document the prevalence, clinicopathologic, adjuvant treatment details, and prognostic value of PI3K/AKT pathway mutations and copy number variation and phosphorylated AKT status in patients with cervical cancers treated with primary surgery. A clinicopathologic review was performed on a retrospective cohort of 185 patients with cervical cancer, treated with primary surgery at a single tertiary institution. Next-generation sequencing and digital PCR was used to determine PI3K/AKT pathway mutational status and PIK3CA copy number variation, respectively, and fluorescent immunohistochemistry measured phosphorylated AKT expression. In all, 179 of 185 (96.8%) of tumors were successfully sequenced; 48 (26.8%) were positive for PI3K/AKT pathway mutations—the majority (n=37, 77.1%) PIK3CA mutations. PIK3CA mutation was associated with pathologically positive lymph nodes [12 (32%) vs. 22 (16%); P=0.022] and indication for postoperative chemoradiotherapy [17 (45.9%) vs. 32 (22.5%); P=0.004]. On multivariable analysis, PIK3CA status was not associated with overall survival (P=0.103) or progression-free survival (P=0.240) at 5 yrs, nor was PIK3CA copy number variation status. phosphorylated AKT ≤ median significantly predicted for progression-free survival [multivariable hazard ratio 0.39 (0.17–0.89; P=0.025)] but not overall survival (P=0.087). The correlation of PIK3CA with pathologic positive lymph node status yet lack of association with survival outcomes may be due to the use of adjuvant postoperative therapy. PIK3CA assessment before radical hysterectomy may help identify patients with a higher risk of node-positive disease.
Brent Technique of Repair Versus Nagata Auricular Reconstruction for Microtia Reconstruction: A Systematic Review and Meta-Analysis
Authors: Yturralde Kylee J. , Le Paulina B. , Martinez O. Parker , Chen Elliott
Published: September 2023

Background:

Up to 17.4 in every 10,000 births are affected by microtia, but no consensus exists on a gold standard technique for autogenous repair. In this study, the authors compare 2 common methods—the Brent and Nagata autogenous costal cartilage ear reconstruction techniques. A systematic review of the literature and a quantitative meta-analysis to compare the outcomes of these 2 approaches were performed. The outcomes analyzed included rates of infection, necrosis, cartilage exposure, cartilage resorption, hematoma, wire extrusion, and hypertrophic scar.

Methods:

A MEDLINE database systematic review with the following keywords: microtia, Brent, and Nagata was performed. Case reports and articles without original data or patient outcomes were excluded. Inclusion methods for study selection are outlined in Supplemental Digital Content 1, http://links.lww.com/SCS/F461, below. The prevalence of outcomes for each study was analyzed through meta-analysis of proportions using Stata.

Results:

A total of 536 potential studies were retrieved for review. Twelve of these studies met inclusion criteria. Four studies utilized the Brent method of repair with the inclusion of 563 ear reconstructions. Nine studies implemented the Nagata technique in 2304 reconstructions. Two studies directly compared the Brent (327 ears) and Nagata (471 ears) techniques. The calculated rate and 95% confidence intervals are summarized in Supplemental Digital Content 2, http://links.lww.com/SCS/F461. There were no statistically significant differences in complication rates between the Brent and Nagata microtic reconstruction techniques identified in this study.

Conclusions:

The Brent and Nagata microtia reconstruction techniques have no difference in the risk of infection, necrosis, cartilage exposure, cartilage resorption, hematoma, wire extrusion, or hypertrophic scars.
Trocar Site Location in Laparoscopic Appendectomy—A Prospective Randomized Study
Authors: Gundogan Ersin , Carkit Sedat , Cinar Olcay , Azar Ramazan , Donder Yunus , Karaagac Mustafa , Ertan Tamer
Published: September 2023

Introduction:

Laparoscopic appendectomy has been used in the treatment of appendicitis, which is among the most common emergency pathologies worldwide. There is no consensus on the best trocar entry sites. The purpose of the present study was to compare various trocar entry sites in the literature and to find the localization with the optimal usage area.

Methods:

Patients who underwent laparoscopic appendectomy between 2021 and 2022 were randomized into 4 groups and included in the study. The demographic data, perioperative, and postoperative findings of the patients were evaluated.

Results:

A total of 200 patients participated in the study and 73% were male. No differences were detected between the groups in terms of demographic data, preoperative findings, length of stay, and complications of the patients. However, when the mean surgery times of the groups were examined (47.2±26.9, 58.4±23.1, 54.5±18.3, 55.8±18.6 min), it was observed that this period was less in Group 1 (P=0.02). When the postoperative Visual Analogue Scale values were analyzed (4.8±2.2, 6.2±1.7, 5.5±2.0, and 5.8±1.9), Group 1 was found to be less painful (P=0.00001).

Conclusion:

When the surgical procedure is optimized and environmental factors are homogenized, Group 1 trocar entry sites seem advantageous for the procedure in terms of postoperative patient pain scale and operation times.
Mid-term Outcomes of Nissen Fundoplication Versus Roux-en-y Gastric Bypass for Primary Management of Gastroesophageal Reflux Disease in Patients With Obesity
Authors: Colvin Jennifer S. , Jalilvand Anahita D. , Um Phoebe , Noria Sabrena F. , Needleman Bradley J. , O’Neill Sean M. , Perry Kyle A.
Published: September 2023

Introduction:

The efficacy and outcomes of laparoscopic Nissen fundoplication (LNF) in patients with obesity is controversial. Specifically, concerns regarding long-term outcomes and recurrence in the setting of obesity has led to interest in laparoscopic Roux-en-Y gastric bypass (RYGB).

Methods:

In this retrospective cohort study, we studied patients with obesity who underwent either LNF or RYGB for gastroesophageal reflux disease. Baseline demographics, clinical variables, operative outcomes, and symptom severity scores were compared.

Results:

Baseline demographics, operative outcomes, and quality-of-life scores were similar. Proton pump inhibitor usage, quality-of-life, symptom severity scores, and satisfaction with the operation were similar between groups at mid-term follow-up.

Discussion:

RYGB and LNF produced similar improvements in disease-specific quality of life with similar rates of complications, side effects, and need for reoperation. This demonstrates that RYGB and LNF represent possible options for surgical management of gastroesophageal reflux disease in obese patients.
Concomitant Hiatal Hernia Repair With Sleeve Gastrectomy: Impact on Gastroesophageal Reflux?
Authors: Kumar Arun , Madhav Jarapala V. , Singla Vitish , Monga Sukhda , Aggarwal Sandeep
Published: September 2023

Background:

Hiatal hernia (HH), whenever encountered during sleeve gastrectomy (SG), needs to be addressed because of its strong association with gastroesophageal reflux disease (GERD). However, the mid-term to long-term effects of hiatal hernia repair (HHR) on GERD remain unclear.

Methods:

This was a cross-sectional observational analysis of patients who underwent SG + HHR and had completed at least 1 year of follow-up. The preoperative data were retrieved from a prospectively maintained database. Of the 590 patients who underwent SG, 63 patients (10.7%) with concomitant HHR were assessed for the use of proton pump inhibitors (PPIs) and symptoms of GERD using the GERD-Q questionnaire.

Results:

Of the 63 patients, 11 were lost to follow-up, and one underwent Roux-en-Y gastric bypass for HH recurrence and severe reflux. The remaining 51 patients were assessed at a mean follow-up of 3.7±2.0 years. Of these, 51% (26/51) patients had preoperative reflux symptoms. On follow-up, 69.2% (18/26) had complete resolution with significant improvement in their GERD-Q scores (9.8±3.1 to 6.5±2.1; P=0.001), while 76.2% (16/21) of patients were off the PPIs. The incidence of de novo GERD was found in 20% (5/25) of the patients.

Conclusions:

In patients of morbid obesity with HH, concomitant HHR with SG leads to improvement of the reflux symptoms in more than two-thirds of the patients, besides alleviating the use of PPIs.
Clonal expansion and rapid characterization of Klebsiella pneumoniae ST1788, an otherwise uncommon strain spreading in Wales, UK
Authors: Mentasti Massimo , David Sophia , Turton Jane , Morgan Mari , Turner Luke , Westlake Joseph , Jenkins Jonathan , Williams Catie , Rey Sara , Watkins Joanne , Daniel Victoria , Mitchell Shanine , Forbes Gavin , Wootton Mandy , Jones Lim
Published: September 2023

A multidrug-resistant strain of

Klebsiella pneumoniae

(Kp) sequence type (ST) 1788, an otherwise uncommon ST worldwide, was isolated from 65 patients at 11 hospitals and 11 general practices across South and West Wales, UK, between February 2019 and November 2021. A collection of 97 Kp ST1788 isolates (including 94 from Wales) was analysed to investigate the diversity and spread across Wales and to identify molecular marker(s) to aid development of a strain-specific real-time PCR. Whole genome sequencing (WGS) was performed with Illumina technology and the data were used to perform phylogenetic analyses. Pan-genome analysis of further Kp genome collections was used to identify an ST1788-specific gene target; a real-time PCR was then validated against a panel of 314 strains and 218 broth-enriched screening samples. Low genomic diversity was demonstrated amongst the 94 isolates from Wales. Evidence of spread within and across healthcare facilities was found. A yersiniabactin locus and the KL2 capsular locus were identified in 85/94 (90.4 %) and 94/94 (100 %) genomes respectively; bla
SHV-232, bla
TEM-1, bla
CTX-M-15 and bla
OXA-1 were simultaneously carried by 86/94 (91.5 %) isolates; 4/94 (4.3 %) isolates also carried bla
OXA-48 carbapenemase. Aminoglycoside and fluoroquinolone resistance markers were found in 94/94 (100 %) and 86/94 (91.5 %) isolates respectively. The ST1788-specific real-time PCR was 100 % sensitive and specific. Our analyses demonstrated recent clonal expansion and spread of Kp ST1788 in the community and across healthcare facilities in South and West Wales with isolates carrying well-defined antimicrobial resistance and virulence markers. An ST1788-specific marker was also identified, enabling rapid and reliable preliminary characterization of isolates by real-time PCR. This study confirms the utility of WGS in investigating novel strains and in aiding proactive implementation of molecular tools to assist infection control specialists.
A Systematic Literature Review and Meta-Analysis of the Effects of Lockdowns on COVID-19 Mortality II
Authors: Herby Jonas , Jonung Lars , Hanke Steve H.
Published: September 2023

The purpose of this systematic review and meta-analysis is to determine the effect of lockdowns on COVID-19 mortality based on available empirical evidence. Lockdowns are defined as the imposition of at least one compulsory, non-pharmaceutical intervention (NPI). We employ a systematic search and screening procedure in which 19,646 studies are identified that could potentially address the purpose of our study. After three levels of screening, 32 studies qualified. Of those, estimates from 22 studies could be converted to standardized measures for inclusion in the meta-analysis. They are separated into three groups: lockdown stringency index studies, shelter-in-place-order (SIPO) studies, and specific NPI studies. Stringency index studies find that the average lockdown in Europe and the United States in the spring of 2020 only reduced COVID-19 mortality by 3.2%. This translates into approximately 6,000 avoided deaths in Europe and 4,000 in the United States. SIPOs were also relatively ineffective in the spring of 2020, only reducing COVID-19 mortality by 2.0%. This translates into approximately 4,000 avoided deaths in Europe and 3,000 in the United States. Based on specific NPIs, we estimate that the average lockdown in Europe and the United States in the spring of 2020 reduced COVID-19 mortality by 10.7%. This translates into approximately 23,000 avoided deaths in Europe and 16,000 in the United States. In comparison, there are approximately 72,000 flu deaths in Europe and 38,000 flu deaths in the United States each year. When checked for potential biases, our results are robust. Our results are also supported by the natural experiments we have been able to identify. The results of our meta-analysis support the conclusion that lockdowns in the spring of 2020 had little to no effect on COVID-19 mortality. This result is consistent with the view that voluntary changes in behavior, such as social distancing, did play an important role in mitigating the pandemic.
Imaging of existing and newly translated proteins elucidates mechanisms of sarcomere turnover
Authors: Douvdevany Guy , Erlich Itai , Haimovich-Caspi Lilac , Mashiah Tomer , Prondzynski Maksymilian , Pricolo Maria Rosaria , Alegre-Cebollada Jorge , Linke Wolfgang A. , Carrier Lucie , Kehat Izhak
Published: September 2023

Background

How the sarcomeric complex is continuously turned-over in long-living cardiomyocytes is unclear. According to the prevailing model of sarcomere maintenance, sarcomeres are maintained by cytoplasmic soluble protein pools with free recycling between pools and sarcomeres.

Methods

We imaged and quantified the turnover of expressed and endogenous sarcomeric proteins, including the giant protein titin, in cardiomyocytes in culture and in vivo, at the single cell and at the single sarcomere level using pulse-chase labeling of Halo-tagged proteins with covalent ligands.

Results

We disprove the prevailing ‘protein pool’ model and instead show an ordered mechanism in which only newly translated proteins enter the sarcomeric complex while older ones are removed and degraded. We also show that degradation is independent of protein age, and that proteolytic extraction is a rate limiting step in the turnover. We show that replacement of sarcomeric proteins occurs at a similar rate within cells and across the heart and is slower in adult cells.

Conclusions

Our findings establish a ‘unidirectional replacement’ model for cardiac sarcomeres subunit replacement and identify their turnover principles.
Black women in medical education publishing: Bibliometric and testimonio accounts using intersectionality methodology
Authors: Seide Witzard , Maggio Lauren A. , Artino Anthony R. , Leroux Todd , Konopasky Abigail
Published: September 2023

Background

Black women in academic medicine experience racial and gender discrimination, all while being tasked with improving a flawed system. Representation of Black women in medicine remains low, yet they bear the burden of fostering diversity and mentoring trainees, exacerbating their minority tax and emotional labor, and negatively impacting career progression.

Objective

To complement qualitative accounts of Black women authors in the medical education literature with a quantitative account of their representation.

Design

An intersectional methodology employing bibliometric analysis and testimonio reflection.

Subjects

US-based authors of journal articles published in medical education journals between 2000 and 2020.

Main measures

Author race was determined using a probability-based algorithm incorporating US Census data, and author gender was ascribed using Social Security Administration records. We conducted two negative binomial generalized linear models by first and last author publications. Metadata for each article was retrieved from Web of Science and PubMed to include author names, country of institutional affiliation, and Medical Subject Headings (MeSH). Results were contextualized via the “testimonio” account of a Black woman author.

Key Results

Of 21,945 unique authors, Black women (and other racially minoritized groups) published far fewer first and last authors papers than white women and men. In addition, major MeSH terms used by Black women authors reveal little overlap of highly ranked medical education topics. The testimonio further narrated struggles with belonging and racial identity.

Conclusion

Black women are underrepresented in medical education publishing and feel a lack of belonging. We believe that dismantling oppressive structures in the publishing ecosystem and the field is imperative for achieving equity. Additionally, further experiential accounts are needed to contextualize this quantitative account and understand oppression in medical education publishing.
The Egg-Counter: A novel microfluidic platform for characterization ofCaenorhabditis elegansegg-laying
Authors: Banse Stephen A. , Jarrett Cody M. , Robinson Kristin J. , Blue Benjamin W. , Shaw Emily L. , Phillips Patrick C.
Published: September 2023

Reproduction is a fundamental process that shapes the demography of every living organism yet is often difficult to assess with high precision in animals that produce large numbers of offspring. Here, we present a novel microfluidic research platform for studyingCaenorhabditis elegans’egg-laying. The platform provides higher throughput than traditional solid-media assays while providing a very high degree of temporal resolution. Additionally, the environmental control enabled by microfluidic animal husbandry allows for experimental perturbations difficult to achieve with solid-media assays. We demonstrate the platform’s utility by characterizingC. elegansegg-laying behavior at two commonly used temperatures, 15 and 20°C. As expected, we observed a delayed onset of egg-laying at 15°C degrees, consistent with published temperature effects on development rate. Additionally, as seen in solid media studies, egg laying output was higher under the canonical 20°C conditions. While we validated the Egg-Counter with a study of temperature effects in wild-type animals, the platform is highly adaptable to any nematode egg-laying research where throughput or environmental control needs to be maximized without sacrificing temporal resolution.
A pan-MHC reference graph with 246 fully contiguous phased sequences
Authors: Huijse Liza , Adams Solomon M. , Burton Joshua N. , David Julianne K. , Julian Russell S. , Meshulam-Simon Galit , Mickalide Harry , Tafesse Bersabeh D. , Calonga-Solís Verónica , Wolf Ivan Rodrigo , Morrison Ashby J. , Augusto Danillo G. , Endlich Solomon
Published: September 2023

The major histocompatibility complex (MHC) is a region of the human genome that is key to immune system function but sometimes refractory to genomic analyses due to extreme polymorphism and structural variation. We performed targeted long-read sequencing andde novoassembly of MHC to create 246 highly accurate, fully contiguous, and phased full-length sequences, mostly from data provided by the Human Pangenome Reference Consortium (HPRC). We identified alleles at high resolution across 39 loci including the class I and II HLA (human leukocyte antigen) genes, discovering 1,246 putative novel allele sequences. We identified copy number variation in theC4AandC4Bgenes and found significant linkage disequilibrium betweenC4A∼C4Bhaplotypes and 14 MHC loci. We build our sequences into a novel “pan-MHC” reference graph, and we demonstrate that this improves the accuracy of short-read variant calling. Our haplotypes and graph contain significantly more population diversity than preexisting MHC sequences, thus improving the prospects for global health equity in this clinically important genomic region.
Intervertebral Disc Elastography to Relate Shear Modulus and Relaxometry in Compression and Bending
Authors: Davis Zachary R. , Gossett Paull C. , Wilson Robert L. , Kim Woong , Mei Yue , Butz Kent D. , Emery Nancy C. , Nauman Eric A. , Avril Stéphane , Neu Corey P. , Chan Deva D.
Published: September 2023

Intervertebral disc degeneration is the most recognized cause of low back pain, characterized by the decline of tissue structure and mechanics. Image-based mechanical parameters (e.g., strain, stiffness) may provide an ideal assessment of disc function that is lost with degeneration but unfortunately remains underdeveloped. Moreover, it is unknown whether strain or stiffness of the disc may be predicted by MRI relaxometry (e.g.T1orT2), an increasingly accepted quantitative measure of disc structure. In this study, we quantifiedT1andT2relaxation times and in-plane strains using displacement-encoded MRI within the disc under physiological levels of compression and bending. We then estimated shear modulus in orthogonal image planes and compared these values to relaxation times and strains within regions of the disc. Intratissue strain depended on the loading mode, and shear modulus in the nucleus pulposus was typically an order of magnitude lower than the annulus fibrosis, except in bending, where the apparent stiffness depended on the loading. Relative shear moduli estimated from strain data derived under compression generally did not correspond with those from bending experiments, with no correlations in the sagittal plane and only 4 of 15 regions correlated in the coronal plane, suggesting that future inverse models should incorporate multiple loading conditions. Strain imaging and strain-based estimation of material properties may serve as imaging biomarkers to distinguish healthy and diseased discs. Additionally, image-based elastography and relaxometry may be viewed as complementary measures of disc structure and function to assess degeneration in longitudinal studies.
Exploration of the main active metabolites fromTinospora crispa(L.) Hook. f. & Thomson stem as insulin sensitizer in L6.C11 skeletal muscle cell by integratingin vitro, metabolomics, and molecular docking
Authors: Zuhri Ummu Mastna , Yuliana Nancy Dewi , Fadilah Fadilah , Erlina Linda , Purwaningsih Erni Hernawati , Khatib Alfi
Published: September 2023

Ethnopharmacological relevance

Tinospora crispa(L.) Hook. f. & Thomson stem (TCS) has long been used as folk medicine for the treatment of diabetes mellitus. Previous study revealed that TCS possesses multi-ingredients and multi-targets characteristic potential as insulin sensitizer activity. However, its mechanisms of action and molecular targets are still obscure.

Aim of the study

In the present study, we investigated the effects of TCS against insulin resistance in muscle cells through integratingin vitroexperiment and identifying its active biomarker using metabolomics and in molecular docking validation.

Materials and methods

We used centrifugal partition chromatography (CPC) to isolate 33 fractions from methanolic extract of TCS, and then used UHPLC-Orbitrap-HRMS to identify the detectable metabolites in each fraction. We assessed the insulin sensitization activity of each fraction using enzyme-linked immunosorbent assay (ELISA), and then used confocal immunocytochemistry microscopy to measure the translocation of glucose transporter 4 (GLUT4) to the cell membrane. The identified active metabolites were further simulated for its molecular docking interaction using Autodock Tools.

Results

The polar fractions of TCS significantly increased insulin sensitivity, as measured by the inhibition of phosphorylated insulin receptor substrate-1 (pIRS1) at serine-312 residue (ser312) also the increasing number of translocated GLUT4 and glycogen content. We identified 58 metabolites of TCS, including glycosides, flavonoids, alkaloids, coumarins, and nucleotides groups. The metabolomics and molecular docking simulations showed the presence of minor metabolites consisting of tinoscorside D, higenamine, and tinoscorside A as the active compounds.

Conclusions

Our findings suggest that TCS is a promising new treatment for insulin resistance and the identification of the active metabolites in TCS could lead to the development of new drugs therapies for diabetes that target these pathways.

Highlights

TCS attenuated insulin resistance in skeletal muscle through lowering IRS ser312 phosphorylation, increasing translocation of GLUT4 and glycogen content.

Tinoscorside D, tinoscorside A, and higenamine were identified as the primary bioactive compounds of TCS.
GLP-1 Receptor Agonist Improves Metabolic Disease in a Pre-clinical Model of Lipodystrophy
Authors: Roumane Ahlima , Mcilroy George D. , Sommer Nadine , Han Weiping , Heisler Lora K. , Rochford Justin J.
Published: September 2023

Individuals with lipodystrophies typically suffer from significant metabolic disease linked to adipose tissue dysfunction including severe insulin resistance and lipoatrophic diabetes, hepatic steatosis and hyperphagia. Current treatment options are limited and beter therapies for affected individuals are urgently needed. No systematic, detailed analyses exist of the effects of glucagon like peptide-1 receptor (GLP-1R) agonists in the treatment of lipoatrophic diabetes. Here we examined the effects of the GLP-1R agonist liraglutide in seipin knockout mice, a pre-clinical model of generalised lipodystrophy. Acute liraglutide treatment of seipin knockout mice significantly improved insulin, glucose and pyruvate tolerance. Once-daily injection of seipin knockout mice with liraglutide for 14 days led to a modest reduction in food intake but significant improvements in hepatomegaly associated with steatosis and significantly reduced markers of liver fibrosis. Detailed examination of the pancreas revealed that liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Thus, GLP-1R agonist liraglutide significantly improved multiple aspects of lipoatrophic diabetes and hepatic steatosis in mice with congenital generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.
Determination of hydrogen bonds in Gromacs: new implementation to overcome the limitation
Authors: Gorelov S.V. , Titov A. I. , Tolicheva O.A. , Konevega A. L. , Shvetsov A. V.
Published: September 2023

This work describes a new software algorithm associated with determination of hydrogen bonds in biomacromolecules and their environment. The already existing algorithm for determining hydrogen bond networks in Gromacs has a number of impenetrable limitations in the analysis of structures and trajectories. The new implementation of the algorithm for determining hydrogen bond networks in the form of a native Gromacs trajectory analysis module allows to quickly analyze molecular dynamics trajectories without restrictions, thereby overcoming the limitation of original algorithm.

The application of the developed algorithm made it possible to obtain and analyze the networks of hydrogen bonds of the studied defensin-like protein Pentadiplandra brazzeana, as well as to study the lifetime of hydrogen bonds between the residues of this protein and water molecules. The data obtained using the new implementation coincided with the experimental one.

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MIGRENE: The toolbox for microbial and individualized GEMs, reactobiome and community network modelling
Authors: Bidkhori Gholamreza , Shoaie Saeed
Published: September 2023

Motivation

Understanding microbial metabolism is crucial for evaluating shifts in human host-microbiome interactions during health and disease. However, the primary hurdle in the realm of constraint-based modeling and genome-scale metabolic models (GEMs) pertaining to host-microbiome interactions lies in the efficient utilization of metagenomic data for constructing GEMs that encompass unexplored and uncharacterized genomes. Challenges persist in effectively employing metagenomic data to address individualized microbial metabolism to investigate host-microbiome interactions.

Result

To tackle this issue, we have created a computational framework designed for personalized microbiome metabolism. This framework takes into account factors such as microbiome composition, metagenomic species profiles and microbial gene catalogues. Subsequently, it generates GEMs at microbial level and individualized microbiome metabolism, including reaction richness, reaction abundance, reactobiome, individualized reaction set enrichment (iRSE), and community models.

Availability and implementation

The MIGRENE toolbox is freely available at our GitHub repositoryhttps://github.com/sysbiomelab/MIGRENE. Comprehensive tutorials on the GitHub were provided for each step of the workflow.