bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-structural genes of novel lemur adenoviruses reveal codivergence of virus and host
Authors: Veith Talitha , Bleicker Tobias , Eschbach-Bludau Monika , Brünink Sebastian , Mühlemann Barbara , Schneider Julia , Beheim-Schwarzbach Jörn , Rakotondranary S Jacques , Ratovonamana Yedidya R , Tsagnangara Cedric , Ernest Refaly , Randriantafika Faly , Sommer Simone , Stetter Nadine , Jones Terry C , Drosten Christian , Ganzhorn Jörg U , Corman Victor M
Published: March 2023

Adenoviruses (AdVs) are important human and animal pathogens and are frequently used as vectors for gene therapy and vaccine delivery. Surprisingly, there are only scant data regarding primate AdV origin and evolution, especially in the most basal primate hosts. We detect and sequence AdVs from faeces of two Madagascan lemur species. Complete genome sequence analyses define a new AdV species with a particularly large gene encoding a protein of unknown function in the early gene region 3. Unexpectedly, the new AdV species is not most similar to human or other simian AdVs but to bat adenovirus C. Genome characterisation shows signals of virus–host codivergence in non-structural genes, which show lower diversity than structural genes. Outside a lemur species mixing zone, recombination less frequently separates structural genes, as in human adenovirus C. The evolutionary history of lemur AdVs likely involves both a host switch and codivergence with the lemur hosts.
Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response
Authors: Jennaro Theodore S. , Puskarich Michael A. , Evans Charles R. , Karnovsky Alla , Flott Thomas L. , McLellan Laura A. , Jones Alan E. , Stringer Kathleen A.
Published: March 2023

OBJECTIVES:

Perturbed host metabolism is increasingly recognized as a pillar of sepsis pathogenesis, yet the dynamic alterations in metabolism and its relationship to other components of the host response remain incompletely understood. We sought to identify the early host-metabolic response in patients with septic shock and to explore biophysiological phenotyping and differences in clinical outcomes among metabolic subgroups.

DESIGN:

We measured serum metabolites and proteins reflective of the host-immune and endothelial response in patients with septic shock.

SETTING:

We considered patients from the placebo arm of a completed phase II, randomized controlled trial conducted at 16 U.S. medical centers. Serum was collected at baseline (within 24 hr of the identification of septic shock), 24-hour, and 48-hour postenrollment. Linear mixed models were built to assess the early trajectory of protein analytes and metabolites stratified by 28-day mortality status. Unsupervised clustering of baseline metabolomics data was conducted to identify subgroups of patients.

PATIENTS:

Patients with vasopressor-dependent septic shock and moderate organ dysfunction that were enrolled in the placebo arm of a clinical trial.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Fifty-one metabolites and 10 protein analytes were measured longitudinally in 72 patients with septic shock. In the 30 patients (41.7%) who died prior to 28 days, systemic concentrations of acylcarnitines and interleukin (IL)-8 were elevated at baseline and persisted at T24 and T48 throughout early resuscitation. Concentrations of pyruvate, IL-6, tumor necrosis factor-α, and angiopoietin-2 decreased at a slower rate in patients who died. Two groups emerged from clustering of baseline metabolites. Group 1 was characterized by higher levels of acylcarnitines, greater organ dysfunction at baseline and postresuscitation (p < 0.05), and greater mortality over 1 year (p < 0.001).

CONCLUSIONS:

Among patients with septic shock, nonsurvivors exhibited a more profound and persistent dysregulation in protein analytes attributable to neutrophil activation and disruption of mitochondrial-related metabolism than survivors.
The Effectiveness of the Interventions to Reduce Sound Levels in the ICU: A Systematic Review
Authors: Vreman Jeanette , Lemson Joris , Lanting Cris , van der Hoeven Johannes , van den Boogaard Mark
Published: March 2023

OBJECTIVES:

Excessive noise is ubiquitous in the ICU, and there is growing evidence of the negative impact on work performance of caregivers. This study aims to determine the effectiveness of interventions to reduce noise in the ICU.

DATA SOURCES:

Databases of PubMed, EMBASE, PsychINFO, CINAHL, and Web of Science were systematically searched from inception to September 14, 2022.

STUDY SELECTION:

Two independent reviewers assessed titles and abstracts against study eligibility criteria. Noise mitigating ICU studies were included when having at least one quantitative acoustic outcome measure expressed in A-weighted sound pressure level with an experimental, quasi-experimental, or observational design. Discrepancies were resolved by consensus, and a third independent reviewer adjudicated as necessary.

DATA EXTRACTION:

After title, abstract, and full-text selection, two reviewers independently assessed the quality of each study using the Cochrane’s Risk Of Bias In Nonrandomized Studies of Interventions tool. Data were synthesized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, and interventions were summarized.

DATA SYNTHESIS:

After screening 12,652 articles, 25 articles were included, comprising either a mixed group of healthcare professionals (n = 17) or only nurses (n = 8) from adult or PICU settings. Overall, the methodological quality of the studies was low. Noise reduction interventions were categorized into education (n = 4), warning devices (n = 3), multicomponent programs (n = 15), and architectural redesign (n = 3). Education, a noise warning device, and an architectural redesign significantly decreased the sound pressure levels.

CONCLUSIONS:

Staff education and visual alert systems seem promising interventions to reduce noise with a short-term effect. The evidence of the studied multicomponent intervention studies, which may lead to the best results, is still low. Therefore, high-quality studies with a low risk of bias and a long-term follow-up are warranted. Embedding noise shielding within the ICU-redesign is supportive to reduce sound pressure levels.
Pulse Methylprednisolone Versus Dexamethasone in COVID-19: A Multicenter Cohort Study
Authors: Watanabe Atsuyuki , Inokuchi Ryota , Kuno Toshiki , Uda Kazuaki , Komiyama Jun , Adomi Motohiko , Ishisaka Yoshiko , Abe Toshikazu , Tamiya Nanako , Iwagami Masao
Published: March 2023

IMPORTANCE:

Although pulse (high-dose) methylprednisolone therapy can hypothetically control immune system flare-ups effectively, the clinical benefit of pulse methylprednisolone compared with dexamethasone in COVID-19 remains inconclusive.

OBJECTIVES:

To compare pulse methylprednisolone to dexamethasone as a COVID-19 treatment.

DESIGN, SETTING, AND PARTICIPANTS:

Using a Japanese multicenter database, we identified adult patients admitted for COVID-19 and discharged between January 2020 and December 2021 treated with pulse methylprednisolone (250, 500, or 1,000 mg/d) or IV dexamethasone (≥ 6 mg/d) at admission day 0 or 1.

Main Outcomes and Measures:

The primary outcome was in-hospital mortality. Secondary outcomes were 30-day mortality, new ICU admission, insulin initiation, fungal infection, and readmission. Multivariable logistic regression was conducted to differentiate the dose of pulse methylprednisolone (250, 500, or 1,000 mg/d). Additionally, subgroup analyses by characteristics such as the need for invasive mechanical ventilation (IMV) were also conducted.

RESULTS:

A total of 7,519, 197, 399, and 1,046 patients received dexamethasone, 250, 500, and 1,000 mg/d of methylprednisolone, respectively. The crude in-hospital mortality was 9.3% (702/7,519), 8.6% (17/197), 17.0% (68/399), and 16.2% (169/1,046) for the different doses, respectively. The adjusted odds ratio (95% CI) was 1.26 (0.69–2.29), 1.48 (1.07–2.04), and 1.75 (1.40–2.19) in patients starting 250, 500, and 1,000 mg/d of methylprednisolone, respectively, compared with those starting dexamethasone. In subgroup analyses, the adjusted odds ratio of in-hospital mortality was 0.78 (0.25–2.47), 1.12 (0.55–2.27), and 1.04 (0.68–1.57) in 250, 500, and 1,000 mg/d of methylprednisolone, respectively, among patients with IMV, whereas the adjusted odds ratio was 1.54 (0.77–3.08), 1.62 (1.13–2.34), and 2.14 (1.64–2.80) among patients without IMV.

CONCLUSIONS AND RELEVANCE:

Higher doses of pulse methylprednisolone (500 or 1,000 mg/d) may be associated with worse COVID-19 outcomes when compared with dexamethasone, especially in patients not on IMV.
Intrapulmonary and Intracardiac Shunts in Adult COVID-19 Versus Non-COVID Acute Respiratory Distress Syndrome ICU Patients Using Echocardiography and Contrast Bubble Studies (COVID-Shunt Study): A Prospective, Observational Cohort Study
Authors: Lau Vincent I. , Mah Graham D. , Wang Xiaoming , Byker Leon , Robinson Andrea , Milovanovic Lazar , Alherbish Aws , Odenbach Jeffrey , Vadeanu Cristian , Lu David , Smyth Leo , Rohatensky Mitchell , Whiteside Brian , Gregoire Phillip , Luksun Warren , van Diepen Sean , Anderson Dustin , Verma Sanam , Slemko Jocelyn , Brindley Peter , Kustogiannis Demetrios J. , Jacka Michael , Shaw Andrew , Wheatley Matt , Windram Jonathan , Opgenorth Dawn , Baig Nadia , Rewa Oleksa G. , Bagshaw Sean M. , Buchanan Brian M.
Published: March 2023

OBJECTIVES:

Studies have suggested intrapulmonary shunts may contribute to hypoxemia in COVID-19 acute respiratory distress syndrome (ARDS) with worse associated outcomes. We evaluated the presence of right-to-left (R-L) shunts in COVID-19 and non-COVID ARDS patients using a comprehensive hypoxemia workup for shunt etiology and associations with mortality.

DESIGN:

Prospective, observational cohort study.

SETTING:

Four tertiary hospitals in Edmonton, Alberta, Canada.

PATIENTS:

Adult critically ill, mechanically ventilated, ICU patients admitted with COVID-19 or non-COVID (November 16, 2020, to September 1, 2021).

INTERVENTIONS:

Agitated-saline bubble studies with transthoracic echocardiography/transcranial Doppler ± transesophageal echocardiography assessed for R-L shunts presence.

MEASUREMENTS AND MAIN RESULTS:

Primary outcomes were shunt frequency and association with hospital mortality. Logistic regression analysis was used for adjustment. The study enrolled 226 patients (182 COVID-19 vs 42 non-COVID). Median age was 58 years (interquartile range [IQR], 47–67 yr) and Acute Physiology and Chronic Health Evaluation II scores of 30 (IQR, 21–36). In COVID-19 patients, the frequency of R-L shunt was 31 of 182 COVID patients (17.0%) versus 10 of 44 non-COVID patients (22.7%), with no difference detected in shunt rates (risk difference [RD], –5.7%; 95% CI, –18.4 to 7.0; p = 0.38). In the COVID-19 group, hospital mortality was higher for those with R-L shunt compared with those without (54.8% vs 35.8%; RD, 19.0%; 95% CI, 0.1–37.9; p = 0.05). This did not persist at 90-day mortality nor after adjustment with regression.

CONCLUSIONS:

There was no evidence of increased R-L shunt rates in COVID-19 compared with non-COVID controls. R-L shunt was associated with increased in-hospital mortality for COVID-19 patients, but this did not persist at 90-day mortality or after adjusting using logistic regression.
Orbital Vascular Malformations: Relationship Between Enophthalmos and Clinically Apparent Distensibility with Valsalva
Authors: Cheng Sarah , Roelofs Kelsey A. , Pirakitikulr Nathan , Rootman Daniel B.
Published: March 2023

Purpose:

Determining the hemodynamic characteristics of an orbital vascular malformation is a critical step in management. The purpose of this study is to assess the relationship between enophthalmos and clinically apparent distensibility of orbital vascular malformations, to optimize imaging and treatment.

Methods:

In this cross-sectional cohort study consecutive patients at a single institution were screened for study entry. Data extracted included age, sex, Hertel measurements, presence or absence of distensibility during the Valsalva maneuver, whether lesions were primarily venous or lymphatic based on imaging, and location of the lesion relative to the globe. Enophthalmos was defined as ≥ 2 mm difference from the opposite side. Parametric and nonparametric statistics were used, and linear regression was performed to examine factors predictive of Hertel measurement.

Results:

Twenty-nine patients met the inclusion criteria. Relative enophthalmos ≥2 mm was significantly associated with distensibility (p = 0.03; odds ratio = 5.33). Distensibility and venous dominant morphology were the 2 most important factors associated with enophthalmos on regression analysis. The relative position of the lesion anterior or posterior to the globe did not have a significant bearing on baseline enophthalmos.

Conclusions:

The presence of enophthalmos increases the likelihood that an orbital vascular malformation is distensible. This group of patients was also more likely to be characterized by venous dominant malformations. Baseline clinical enophthalmos may serve as a useful surrogate marker for distensibility and venous dominance, which may be useful in guiding the selection of appropriate imaging.
Surgical Correction of the Deformity After Orbicularis Oculi Muscle Rupture: A Case Report
Authors: Yuan Ye , Wang Lianzhao , Chai Hongli , Yuan Li , Li Qiang , Li Senkai
Published: March 2023

Facial contusion may be accompanied by inconspicuous structural damage of the underlying muscular tissue, leading to unnatural expressions. Surgery can be a choice to correct this dynamic deformity. This case report describes a rare case of orbicularis oculi muscle rupture following blunt injury. Cosmetic improvement was achieved with the surgical restoration of the torn muscle. The etiology of this phenomenon is also discussed.
Necrotizing Granulomatous Papular Reaction Following Multiple Pulsed Dye Laser and Hybrid Fractional Laser Treatments for Rosacea
Authors: Bryar Kate M. , Basti Neha S. , Michels Kristi L. , Thyparampil Preeti J. , Bryar Paul J.
Published: March 2023

This is a case report of a single patient who had pulsed dye laser and hybrid fractional laser treatments for facial rosacea and subsequently developed a prolonged papular reaction in and adjacent to the area of treatment, which was unresponsive to topical therapy. Biopsies of these lesions revealed necrotizing granulomas. This is a previously unreported side effect of these laser treatments and clinicians should be aware of this potential sequela.
Sex differences in pain expressed by patients across diverse disease states: individual patient data meta-analysis of 33,957 participants in 10 randomized controlled trials
Authors: Li Jessica X.L. , Wang Xia , Henry Amanda , Anderson Craig S. , Hammond Naomi , Harris Katie , Liu Hueiming , Loffler Kelly , Myburgh John , Pandian Jeyaraj , Smyth Brendan , Venkatesh Balasubramanian , Carcel Cheryl , Woodward Mark
Published: March 2023

The experience of pain is determined by many factors and has a significant impact on quality of life. This study aimed to determine sex differences in pain prevalence and intensity reported by participants with diverse disease states in several large international clinical trials. Individual participant data meta-analysis was conducted using EuroQol-5 Dimension (EQ-5D) questionnaire pain data from randomised controlled trials published between January 2000 and January 2020 and undertaken by investigators at the George Institute for Global Health. Proportional odds logistic regression models, comparing pain scores between females and males and fitted with adjustments for age and randomized treatment, were pooled in a random-effects meta-analysis. In 10 trials involving 33,957 participants (38% females) with EQ-5D pain score data, the mean age ranged between 50 and 74. Pain was reported more frequently by females than males (47% vs 37%; P < 0.001). Females also reported greater levels of pain than males (adjusted odds ratio 1.41, 95% CI 1.24-1.61; P < 0.001). In stratified analyses, there were differences in pain by disease group (P for heterogeneity <0.001), but not by age group or region of recruitment. Females were more likely to report pain, and at a higher level, compared with males across diverse diseases, all ages, and geographical regions. This study reinforces the importance of reporting sex-disaggregated analysis to identify similarities and differences between females and males that reflect variable biology and may affect disease profiles and have implications for management.
Blood prestin levels in COVID-19 patients
Authors: Turan Mahfuz , Alp Hamit Hakan , Yildiz Hanifi , Baran Ali İrfan , Ekin Selami , Akin Ramazan , Arisoy Ahmet , Çetin Yaser Said , Turan Aydin , Bozan Nazim
Published: March 2023

Background:

Many studies have found that viral infections affect different tissues, including the inner ear. Coronavirus disease 2019 (COVID-19), a viral infection, is a significant health problem worldwide. Prestin is a motor protein with important functions both in the outer hair cells of the inner ear and in cardiac tissue. In addition, prestin is promising as an early biomarker in the detection of ototoxicity. To determine the severity of infection in COVID-19 patients and to determine whether other tissues are affected by the infection, lactate dehydrogenase (LDH), C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase MB (CK-MB), biochemical markers such as ferritin and D-dimer are used. This study aimed to compare prestin levels in patients with COVID-19 and healthy volunteers.

Methods:

In blood samples taken from 45 patients diagnosed with COVID-19 and 40 healthy volunteers, prestin levels were determined with the kit that used an enzyme-linked immunosorbent assay method and was commercially available. At the same time, LDH, CRP, ALT, AST, CK-MB, ferritin, and D-dimer levels were also detected in both patients and healthy control groups and correlations with prestin levels were examined.

Results:

The main result of our study is that serum prestin levels in COVID-19 patients are significantly higher than in healthy controls (p < 0.001). In addition, a statistically significant strong positive correlation was found between prestin-LDL (r = 0.537, p = 0.001), prestin-CRP (r = 0.654, p = 0.001), and prestin-D-dimer (r = 0.659, p = 0.001).

Conclusion:

The levels of prestin, a motor protein in inner ear outer hair cells and cardiac myocytes, were found to be higher in COVID-19 patients than in healthy volunteers. It also showed a positive correlation with CRP and D-dimer. This may be associated with systemic dysfunction.
Canada's Aging Federal Prison Population
Authors: Johansson Jim A. , Holmes Dave , Paradis-Gagné Etienne
Published: March 2023

The Canadian federal prison population is increasingly aging within institutions that were never intended or designed to meet the complex medical and mental health needs of older incarcerated persons. Increasing numbers of incarcerated persons are “aging in place,” and many are dying within federal correctional institutions. Persons convicted of sexual offenses comprise a large—and growing—proportion of this aging population. The Correctional Investigator Canada has recently called for an expansion of access to compassionate release for the aging federal prison population, yet little progress has been made. In this article, we explore the significant challenges faced by the aging population in federal institutions, including insufficient access to appropriate care, challenges in application for compassionate release, and how questions of risk may affect the potential for community transfer. Questions of risk overshadow decisions on early release of incarcerated persons, especially those convicted of sexual offenses. Nurses play a central role in the provision of care to aging incarcerated persons and in advocacy for better access to services when a patient's needs cannot be met within the institution. This article presents a call to action for forensic nurses in Canada (and beyond) to advocate for both improved services within federal correctional institutions and for expedited access to compassionate release of aging incarcerated persons, especially those nearing end of life. The significant disparity in access to health care for aging incarcerated persons compared with their nonincarcerated counterparts represents a significant concern.
An Experiential Approach to Canine-Assisted Learning in Corrections for Prisoners Who Use Substances
Authors: Kosteniuk Brynn , Dell Colleen Anne , Cruz Maria , Chalmers Darlene
Published: March 2023

Canine-assisted interventions are a promising approach to help address substance use and mental health issues in prisons. However, canine-assisted interventions in prisons have not been well explored in relation to experiential learning (EL) theory, despite canine-assisted interventions and EL aligning in many ways. In this article, we discuss a canine-assisted learning and wellness program guided by EL for prisoners with substance use issues in Western Canada. Letters written by participants to the dogs at the conclusion of the program suggest that such programming can help shift relational dynamics and the prison learning environment, benefit prisoners' thinking patterns and perspectives, and help prisoners generalize and apply key learnings to recovery from addiction and mental health challenges. Implications are discussed in relation to clinicians' practices, prisoners' health and wellness, and prison programming.
Prolonged prothrombin time does not correlate with clinical bleeding symptoms in newly diagnosed paediatric leukaemia patients
Authors: Al-Ghafry Maha , Haimed Abraham , Su Julia , Acharya Suchitra S.
Published: March 2023

Prolonged prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) are frequently seen in newly diagnosed paediatric leukaemia patients (NDPLP), which can lead to delayed diagnostic and therapeutic procedures due to concern for bleeding.

A single-centre retrospective chart review of NDPLP between 2015 and 2018 aged 1–21 years.

We analysed 93 NDPLP of whom 33.3% had bleeding symptoms within 30 days of presentation, predominantly mucosal bleeding (80.6%) and petechiae (64.5%). Median laboratory values: white blood cell count 15.7, haemoglobin 8.1, platelets 64, PT 13.2 and a PTT 31. Red blood cells were administered in 41.2%, platelets in 52.9%, fresh frozen plasma in 7.8% and vitamin K in 21.6% of patients. Prolonged PT was found in 54.8% of patients, while aPTT was prolonged in 5.4%. Anaemia and thrombocytopenia did not correlate with prolonged PT (P = 0.73 and P = 0.18, respectively), or prolonged aPTT (P = 0.52 and 0.42). Leukocytosis showed significant correlation with elevated PT (P < 0.001), but not aPTT (P = 0.3). Bleeding symptoms upon presentation did not correlate with prolonged PT (P = 0.83), prolonged aPTT (P = 1) or anaemia (P = 0.06) but had a significant correlation with thrombocytopenia (P ≤ 0.0001).

Therefore, a prolonged PT in NDPLP may not necessitate the reflexive use of blood product replacement, in the absence of significant bleeding, which is likely related to leukocytosis than to a true coagulopathy.
Fibrinogen reflects severity and predicts outcomes in patients with sepsis and septic shock
Authors: Schupp Tobias , Weidner Kathrin , Rusnak Jonas , Jawhar Schanas , Forner Jan , Dulatahu Floriana , Brück Lea Marie , Lübke Johannes , Hoffmann Ursula , Bertsch Thomas , Behnes Michael , Akin Ibrahim
Published: March 2023

The study investigates the diagnostic and prognostic value of fibrinogen and the albumin-to-fibrinogen-ratio (AFR) in patients with sepsis and septic shock. Limited data regarding the prognostic value of fibrinogen and AFR during the course of sepsis or septic shock are available. Consecutive patients with sepsis and septic shock from 2019 to 2021 were included monocentrically. Blood samples were retrieved from the day of disease onset (day 1), as well as on day 2 and 3. Firstly, the diagnostic value of fibrinogen and the AFR for the diagnosis of a septic shock was tested. Secondly, the prognostic value of fibrinogen and AFR was tested with regard to the 30-day all-cause mortality. Statistical analyses included univariable t-tests, Spearman's correlations, C-statistics, Kaplan–Meier and multivariable Cox regression analyses. Ninety-one patients with sepsis and septic shock were included. With an area under the curve (AUC) of 0.653–0.801, fibrinogen discriminated patients with septic shock from those with sepsis. In the septic shock group, fibrinogen levels were shown to decrease from day 1 to 3 (median decrease 41%). In line, fibrinogen was a reliable predictor for 30-day all-cause mortality (AUC 0.661–0.744), whereas fibrinogen levels less than 3.6 g/l were associated with an increased risk of 30-day all-cause mortality (78 vs. 53%; log rank P = 0.004; hazard ratio = 2.073; 95% confidence interval 1.233–3.486; P = 0.006), which was still observed after multivariable adjustment. In contrast, the AFR was no longer associated with the risk of mortality after multivariable adjustment. Fibrinogen was a reliable diagnostic and prognostic tool for the diagnosis of septic shock as well as for 30-day all-cause mortality and superior compared with the AFR in patients admitted with sepsis or septic shock.
Evaluation and management of ileal pouch-anal anastamosis (IPAA) complications in pregnancy, and the impacts of an IPAA on fertility
Authors: Prentice Ralley E. , Wright Emily K. , Flanagan Emma , Kamm Michael A , Goldberg Rimma , Ross Alyson L. , Burns Megan , Bell Sally J.
Published: March 2023

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains the preferred surgical option for medically refractory ulcerative colitis. Management of individuals with an IPAA prior to and during pregnancy presents challenges that can have serious consequences. Infertility, mechanical obstructive and inflammatory pouch complications are frequently encountered in pregnant women with an IPAA. Mechanical obstructions occur due to a variety of underlying aetiologies, including stricturing disease, adhesions and pouch twists. Conservative management of such obstructions often results in resolution of symptoms without a need for endoscopic or surgical intervention, although endoscopic decompression may be attempted in isolation or as a bridge to definitive surgical intervention. Parenteral nutrition, and early delivery, may also be necessary. Faecal calprotectin and intestinal ultrasound, both of which are accurate in pregnancy, are useful in the setting of suspected inflammatory pouch complications, in some circumstances allowing for avoidance of pouchoscopy. Penicillin-based antimicrobials can be considered first line in pregnancy for the management of pouchitis and pre-pouch ileitis, and biologics can be safely instituted in the setting of refractory disease or suspected Crohn’s disease-like inflammation of the pouch or pre-pouch ileum. Pragmatism, clear patient communication and multidisciplinary discussion are essential in approaching pregnant women with complications of an IPAA, particularly given the lack of definitive evidence to guide therapeutic decisions.
The Impact of Language Discordance on Patients’ Perception of a Clinical Encounter and Trust in Provider
Authors: Caldwell Lauren , Halder Gabriela E. , White Amanda B. , High Rachel A. , Wright Michelle L. , Rogers Rebecca G.
Published: March 2023

Importance

The impact of language discordance on care for Spanish-speaking patients with pelvic floor disorders is unknown.

Objective

The aim of this study was to compare the impact of language concordance with the impact of language discordance on the patient experience and trust in their provider.

Methods

This cross-sectional cohort study enrolled English- and Spanish-speaking patients during initial evaluation in a urogynecology clinic. English- and Spanish-speaking patients seen by native English- or Spanish-speaking providers were recruited to the language-concordant group. The language-discordant group included Spanish-speaking patients seen with a translator or by nonnative Spanish-speaking providers. Patients completed the Trust in Physician Scale and the Consumer Assessment of Healthcare Providers and Systems Clinician and Group Survey (CG-CAHPS). Patients and providers rated the provider's Spanish proficiency on a 10-point scale from 0 (low) to 10 (high). Symptom bother questionnaires were completed 4–6 months after enrollment.

Results

Eighty women were recruited, with 40 in each group. Mean age was 55.4 ± 12.9 years. The majority identified as White (75%) and Hispanic (77.5%). Trust in Physician Scale scores were similar between groups (46.2 ± 8.5 vs 44.4 ± 7.5, P > 0.05). The provider communication, provider rating, and recommendation domains of the CG-CAHPS did not differ between groups (all P > 0.05). Provider self-rating of Spanish proficiency was lower than patient ratings (7.5 ± 1.8 vs 9.8 ± 0.5, P < 0.001). There was no difference between groups in symptom bother at 4–6 months (all P > 0.05).

Conclusions

Patient-provider language discordance does not affect patient trust in the provider or perception of the encounter as measured by the Trust in Physician Scale and CG-CAHPS questionnaires.
Bayesian clustering of multiple zero-inflated outcomes
Authors: Franzolini Beatrice , Cremaschi Andrea , van den Boom Willem , De Iorio Maria
Published: March 2023

Several applications involving counts present a large proportion of zeros (excess-of-zeros data). A popular model for such data is the hurdle model, which explicitly models the probability of a zero count, while assuming a sampling distribution on the positive integers. We consider data from multiple count processes. In this context, it is of interest to study the patterns of counts and cluster the subjects accordingly. We introduce a novel Bayesian approach to cluster multiple, possibly related, zero-inflated processes. We propose a joint model for zero-inflated counts, specifying a hurdle model for each process with a shifted Negative Binomial sampling distribution. Conditionally on the model parameters, the different processes are assumed independent, leading to a substantial reduction in the number of parameters as compared with traditional multivariate approaches. The subject-specific probabilities of zero-inflation and the parameters of the sampling distribution are flexibly modelled via an
enriched
finite mixture with random number of components. This induces a two-level clustering of the subjects based on the zero/non-zero patterns (outer clustering) and on the sampling distribution (inner clustering). Posterior inference is performed through tailored Markov chain Monte Carlo schemes. We demonstrate the proposed approach on an application involving the use of the messaging service WhatsApp.

This article is part of the theme issue ‘Bayesian inference: challenges, perspectives, and prospects’.
Being Bayesian in the 2020s: opportunities and challenges in the practice of modern applied Bayesian statistics
Authors: Bon Joshua J. , Bretherton Adam , Buchhorn Katie , Cramb Susanna , Drovandi Christopher , Hassan Conor , Jenner Adrianne L. , Mayfield Helen J. , McGree James M. , Mengersen Kerrie , Price Aiden , Salomone Robert , Santos-Fernandez Edgar , Vercelloni Julie , Wang Xiaoyu
Published: March 2023

Building on a strong foundation of philosophy, theory, methods and computation over the past three decades, Bayesian approaches are now an integral part of the toolkit for most statisticians and data scientists. Whether they are dedicated Bayesians or opportunistic users, applied professionals can now reap many of the benefits afforded by the Bayesian paradigm. In this paper, we touch on six modern opportunities and challenges in applied Bayesian statistics: intelligent data collection, new data sources, federated analysis, inference for implicit models, model transfer and purposeful software products.

This article is part of the theme issue ‘Bayesian inference: challenges, perspectives, and prospects’.
Hierarchical Bayesian non-response models for error rates in forensic black-box studies
Authors: Khan Kori , Carriquiry Alicia
Published: March 2023

Forensic science plays a critical role in the United States criminal legal system. Historically, however, most feature-based fields of forensic science, including firearms examination and latent print analysis, have not been shown to be scientifically valid. Recently, black-box studies have been proposed as a means of assessing whether these feature-based disciplines are valid, at least in terms of accuracy, reproducibility and repeatability. In these studies, forensic examiners frequently either do not respond to every test item or select an answer equivalent to ‘don’t know’. Current black-box studies do not account for these high levels of missingness in statistical analyses. Unfortunately, the authors of black-box studies typically do not share the data necessary to meaningfully adjust estimates for the high proportion of missing responses. Borrowing from work in the context of small area estimation, we propose the use of hierarchical Bayesian models that do not require auxiliary data to adjust for non-response. Using these models, we offer the first formal exploration of the impact that missingness is playing in error rate estimations reported in black-box studies. We show that error rates currently reported as low as 0.4% could actually be at least 8.4% in models accounting for non-response where inconclusive decisions are counted as correct, and over 28% when inconclusives are counted as missing responses. These proposed models are not the answer to the missingness problem in black-box studies. But with the release of auxiliary information, they can be the foundation for new methodologies to adjust for missingness in error rate estimations.

This article is part of the theme issue ‘Bayesian inference: challenges, perspectives, and prospects’.
Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?
Authors: Athar Mohd , Gervasoni Silvia , Catte Andrea , Basciu Andrea , Malloci Giuliano , Ruggerone Paolo , Vargiu Attilio Vittorio
Published: March 2023

Bacterial resistance to antibiotics has been long recognized as a priority to address for human health. Among all micro-organisms, the so-called multi-drug resistant (MDR) bacteria, which are resistant to most, if not all drugs in our current arsenal, are particularly worrisome. The World Health Organization has prioritized the ESKAPE (

Enterococcus faecium

,

Staphylococcus aureus

,

Klebsiella pneumoniae

,

Acinetobacter baumannii

,

Pseudomonas aeruginosa

and

Enterobacter

species) pathogens, which include four Gram-negative bacterial species. In these bacteria, active extrusion of antimicrobial compounds out of the cell by means of ‘molecular guns’ known as efflux pumps is a main determinant of MDR phenotypes. The resistance-nodulation-cell division (RND) superfamily of efflux pumps connecting the inner and outer membrane in Gram-negative bacteria is crucial to the onset of MDR and virulence, as well as biofilm formation. Thus, understanding the molecular basis of the interaction of antibiotics and inhibitors with these pumps is key to the design of more effective therapeutics. With the aim to contribute to this challenge, and complement and inspire experimental research, in silico studies on RND efflux pumps have flourished in recent decades. Here, we review a selection of such investigations addressing the main determinants behind the polyspecificity of these pumps, the mechanisms of substrate recognition, transport and inhibition, as well as the relevance of their assembly for proper functioning, and the role of protein–lipid interactions. The journey will end with a perspective on the role of computer simulations in addressing the challenges posed by these beautifully complex machineries and in supporting the fight against the spread of MDR bacteria.
A gene pathogenicity tool ‘GenePy’ identifies missed biallelic diagnoses in the 100,000 Genomes Project
Authors: Seaby Eleanor G. , Leggatt Gary , Cheng Guo , Thomas N. Simon , Ashton James J , Stafford Imogen ,   Genomics England Consortium, Baralle Diana , Rehm Heidi L. , O’Donnell-Luria Anne , Ennis Sarah
Published: March 2023

The 100,000 Genomes Project (100KGP) diagnosed a quarter of recruited affected participants, but 26% of diagnoses were in genes not on the chosen gene panel(s); with many beingde novovariants of high impact. However, assessing biallelic variants without a gene panel is challenging, due to the number of variants requiring scrutiny. We sought to identify potential missed biallelic diagnoses independent of the gene panel applied using GenePy - a whole gene pathogenicity metric.

GenePy scores all variants called in a given individual, incorporating allele frequency, zygosity, and a user-defined deleterious metric (CADD v1.6 applied herein). GenePy then combines all variant scores for individual genes, generating an aggregate score per gene, per participant. We calculated GenePy scores for 2862 recessive disease genes in 78,216 individuals in 100KGP. For each gene, we ranked participant GenePy scores for that gene, and scrutinised affected individuals without a diagnosis whose scores ranked amongst the top-5 for each gene. We assessed these participants’ phenotypes for overlap with the disease gene associated phenotype for which they were highly ranked. Where phenotypes overlapped, we extracted rare variants in the gene of interest and applied phase, ClinVar and ACMG classification looking for putative causal biallelic variants.

3184 affected individuals without a molecular diagnosis had a top-5 ranked GenePy gene score and 682/3184 (21%) had phenotypes overlapping with one of the top-ranking genes. After removing 13 withdrawn participants, in 122/669 (18%) of the phenotype-matched cases, we identified a putative missed diagnosis in a top-ranked gene supported by phasing, ClinVar and ACMG classification. A further 334/669 (50%) of cases have a possible missed diagnosis but require functional validation. Applying GenePy at scale has identified potential diagnoses for 456/3183 (14%) of undiagnosed participants who had a top-5 ranked GenePy score in a recessive disease gene, whilst adding only 1.2 additional variants (per individual) for assessment.
Unexplained infertility is frequently caused by defective CatSper function preventing sperm from penetrating the egg coat
Authors: Young Samuel , Schiffer Christian , Wagner Alice , Patz Jannika , Potapenko Anton , Herrmann Leonie , Nordhoff Verena , Pock Tim , Krallmann Claudia , Stallmeyer Birgit , Röpke Albrecht , Kierzek Michelina , Biagioni Cristina , Wang Tao , Haalck Lars , Deuster Dirk , Hansen Jan N , Wachten Dagmar , Risse Benjamin , Behre Hermann M , Schlatt Stefan , Kliesch Sabine , Tüttelmann Frank , Brenker Christoph , Strünker Timo
Published: March 2023

The infertility of many couples seems to rest on an enigmatic dysfunction of the men’s sperm, rendering early diagnosis and evidence-based treatment by medically assisted reproduction impossible. Using a novel laboratory test, we assessed the function of the flagellar Ca2+channel CatSper in sperm of almost 2,300 men undergoing a fertility workup. Thereby, we identified a group of men with mutations inCATSPERgenes affecting the function of the channel. Although standard semen and computer-assisted sperm analysis were unremarkable, the couples required intracytoplasmic sperm injection (ICSI) to conceive a child. We show that their seemingly unexplained infertility and need for ICSI is, in fact, due to the failure of CatSper-deficient human sperm to hyperactivate and penetrate the egg coat. In summary, our study reveals that defective CatSper function represents the most common cause of unexplained male-factor infertility known thus far and that CatSper-related infertility can readily be diagnosed, enabling evidence-based treatment.
A dynamical computational model of theta generation in hippocampal circuits to study theta-gamma oscillations during neurostimulation
Authors: Vardalakis Nikolaos , Aussel Amélie , Rougier Nicolas P. , Wagner Fabien B.
Published: March 2023

Neurostimulation of the hippocampal formation has shown promising results for modulating memory but the underlying mechanisms remain unclear. In particular, the effects on hippocampal theta-nested gamma oscillations and theta phase reset, which are both crucial for memory processes, are unknown. Moreover, these effects cannot be investigated using current computational models, which consider theta oscillations with a fixed amplitude and phase velocity. Here, we developed a novel computational model that includes the medial septum, represented as a set of abstract Kuramoto oscillators producing a dynamical theta rhythm with phase reset, and the hippocampal formation, composed of biophysically-realistic neurons and able to generate theta-nested gamma oscillations under theta drive. We showed that, for theta inputs just below the threshold to induce self-sustained theta-nested gamma oscillations, a single stimulation pulse could switch the network behavior from non-oscillatory to a state producing sustained oscillations. Next, we demonstrated that, for a weaker theta input, pulse train stimulation at the theta frequency could transiently restore seemingly physiological oscillations. Importantly, the presence of phase reset influenced whether these two effects depended on the phase at which stimulation onset was delivered, which has practical implications for designing neurostimulation protocols that are triggered by the phase of ongoing theta oscillations. This novel model opens new avenues for studying the effects of neurostimulation on the hippocampal formation. Furthermore, our hybrid approach that combines different levels of abstraction could be extended in future work to other neural circuits that produce dynamical brain rhythms.
AI-Designed, Mutation-Resistant Broad Neutralizing Antibodies Against Multiple SARS-CoV-2 Strains
Authors: Kang Yue , Jiao Yang , Jin Kevin , Pan Lurong
Published: March 2023

In this study, we generated a Digital Twin for SARS-CoV-2 by integrating data and meta-data with multiple data types and processing strategies, including machine learning, natural language processing, protein structural modeling, and protein sequence language modeling. This approach enabled the computational design of broadly neutralizing antibodies against over 1300 different historical strains of SARS-COV-2 containing 64 mutations in the receptor binding domain (RBD) region. The AI-designed antibodies were experimentally validated in real-virus neutralization assays against multiple strains including the newer Omicron strains that were not included in the initial design base. Many of these antibodies demonstrate strong binding capability in ELISA assays against the RBD of multiple strains. These results could help shape future therapeutic design for existing strains, as well as predicting hidden patterns in viral evolution that can be learned by AI for developing future antiviral treatments.
Novel Herpesvirus Transcripts with Putative Regulatory Roles in DNA Replication and Global Transcription
Authors: Torma Gábor , Tombácz Dóra , Almsarrhad Islam A.A. , Csabai Zsolt , Nagy Gergely Ármin , Kakuk Balázs , Gulyás Gábor , Spires Lauren McKenzie , Gupta Ishaan , Fülöp Ádám , Dörmő Ákos , Prazsák István , Mizik Máté , Dani Virág Éva , Csányi Viktor , Zádori Zoltán , Toth Zsolt , Boldogkői Zsolt
Published: March 2023

In the last couple of years, the rapid advances and decreasing costs of sequencing technologies have revolutionized transcriptomic research. Long-read sequencing (LRS) techniques are able to detect full-length RNA molecules in a single run without the need for additional assembly steps. LRS studies have revealed an unexpected transcriptomic complexity in a variety of organisms, including viruses. A number of transcripts with proven or putative regulatory role, mapping close to or overlapping the replication origins (Oris) and the nearby transcription activator genes, have been described in herpesviruses. In this study, we applied both newly generated and previously published LRS and short-read sequencing datasets to discover additional Ori-proximal transcripts in nine herpesviruses belonging to all of the three subfamilies (alpha, beta and gamma). We identified novel long non-coding RNAs (lncRNAs), as well as splice and length isoforms of mRNAs and lncRNAs. Furthermore, our analysis disclosed an intricate meshwork of transcriptional overlaps at the examined genomic regions. Our results suggest the existence of a ‘super regulatory center’, which controls both the replication and the global transcription through multilevel interactions between the molecular machineries.
Genomic dissection of endemic carbapenem resistance: metallo-beta-lactamase gene dissemination through clonal, plasmid and integron transfer pathways
Authors: Macesic Nenad , Hawkey Jane , Vezina Ben , Wisniewski Jessica A. , Cottingham Hugh , Blakeway Luke V. , Harshegyi Taylor , Pragastis Katherine , Badoordeen Gnei Zweena , Dennison Amanda , Spelman Denis W. , Jenney Adam W.J. , Peleg Anton Y.
Published: March 2023

Infections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades ofblaIMP-4evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified extreme gene promiscuity across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types. An initial multi-species outbreak of conserved IncC plasmids (95 genomes across 37 strains) allowed endemicity to be established through the ability ofblaIMP-4to disseminate in successful strain-genetic setting pairs we termed ‘propagators’, in particularSerratia marcescensandEnterobacter hormaechei. From this reservoir,blaIMP-4persisted through diversification of genetic settings that resulted from transfer ofblaIMP-4plasmids between bacterial hosts and of the integron carryingblaIMP-4between plasmids. Our findings provide a framework for understanding endemicity and spread of MBLs and may have broader applicability to other carbapenemase-producing organisms.