bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital insensitivity to pain: a novel mutation affecting a U12-type intron causes multiple aberrant splicing of SCN9A
Authors: Marchi Margherita , D'Amato Ilaria , Andelic Mirna , Cartelli Daniele , Salvi Erika , Lombardi Raffaella , Gumus Evren , Lauria Giuseppe
Published: November 2021

Mutations in the alpha subunit of voltage-gated sodium channel 1.7 (NaV1.7), encoded by SCN9A gene, play an important role in the regulation of nociception and can lead to a wide range of clinical outcomes, ranging from extreme pain syndromes to congenital inability to experience pain. To expand the phenotypic and genotypic spectrum of SCN9A-related channelopathies, we describe the proband, a daughter born from consanguineous parents, who had pain insensitivity, diminished temperature sensation, foot burns, and severe loss of nociceptive nerve fibers in the epidermis. Next-generation sequencing of SCN9A (NM_002977.3) revealed a novel homozygous substitution (c.377+7T>G) in the donor splice site of intron 3. As the RNA functional testing is challenging, the in silico analysis is the first approach to predict possible alterations. In this case, the computational analysis was unable to identify the splicing consensus and could not provide any prediction for splicing defects. The affected intron indeed belongs to the U12 type, a family of introns characterised by noncanonical consensus at the splice sites, accounting only for 0.35% of all human introns, and is not included in most of the training sets for splicing prediction. A functional study on proband RNA showed different aberrant transcripts, where exon 3 was missing and an intron fragment was included. A quantification study using real-time polymerase chain reaction showed a significant reduction of the NaV1.7 canonical transcript. Collectively, these data widen the spectrum of SCN9A-related insensitivity to pain by describing a mutation causing NaV1.7 deficiency, underlying the nociceptor dysfunction, and highlight the importance of molecular investigation of U12 introns' mutations despite the silent prediction.
Patterns of opioid dispensing and associated wage replacement duration in workers with accepted claims for low back pain: a retrospective cohort study
Authors: Di Donato Michael , Xia Ting , Iles Ross , Buchbinder Rachelle , Collie Alex
Published: November 2021

This study aimed to identify patterns of opioid dispensing in Australian workers with low back pain (LBP) and determine the association of dispensing patterns with wage replacement duration. Australian workers' compensation claimants with LBP and at least 1 day of wage replacement were included. We used group-based trajectory modelling to identify opioid dispensing patterns over a two-and-a-half-year period from reported LBP onset and quantile regression to compare wage replacement duration between each dispensing pattern group. Opioids were dispensed to one-third of workers with LBP (N = 3205, 33.3%) at least once during their claim. Three dispensing patterns were identified. Most had a short-term low-volume opioid dispensing pattern (N = 2166, 67.6%), whereas 798 (24.9%) had a long-term moderate-volume pattern and 241 (7.5%) had a long-term high-volume pattern. Workers with dispensed opioids had significantly longer wage replacement duration than those without dispensed opioids (median [weeks]: 63.6 vs 7.1, respectively). In addition, moderate-volume and high-volume long-term dispensing groups had significantly longer wage replacement duration compared with the short-term dispensing group (median [weeks]: 126.9, 126.0, and 30.7, respectively). Without controlling for pain severity, these results offer limited evidence that opioids lead to longer wage replacement duration. Further research controlling for pain severity, psychosocial factors, and recovery expectations is required to confirm whether the relationship between opioid dispensing pattern and wage replacement duration is causal in nature.
Unique considerations for exercise programs to prevent future low back pain: the patient perspective
Authors: Ayre Julie , Jenkins Hazel , McCaffery Kirsten J. , Maher Christopher G. , Hancock Mark J.
Published: November 2021

There is moderate quality evidence that exercise can help to prevent future low back pain (LBP). This study aimed to explore patient needs and preferences for exercise programs to prevent LBP and the outcomes of these programs that would be most important to a patient. Researchers conducted 26 semistructured interviews with people with LBP. Interviews were audio-recorded, transcribed, and analysed using framework thematic analysis. Three themes were developed. Theme 1 emphasised that everyone's LBP was different, translating to preferences for tailored prevention programs with a high level of initial supervision and individualised biomedical explanations for the program. Theme 2 highlighted important outcomes. Pain was considered not only for intensity but also for the duration, frequency, and severity of flare-ups or episodes. Other important outcomes were general fitness and capacity to engage in everyday activities, social interactions, and work. Theme 3 outlined aspects of exercise programs that were considered important for people with fluctuating pain, including how to foster a sense of “progress,” set realistic expectations, and support patients to establish exercise routines that can adapt to fluctuating pain. Theme 4 discussed participants' desire for social connection. Patients want exercise programs for LBP prevention, which are highly individualised, provide meaningful explanations of exercises, and help them maintain exercise in the long-term. Clinicians should discuss with patients the transition from a focus on treatment to the prevention of LBP. This provides greater opportunity to adjust goals and expectations and provide relevant education. Balancing the need for individualised care against affordability presents an ongoing challenge.
Use of Monospot Testing in the Diagnosis of Infectious Mononucleosis in the Collegiate Student–Athlete Population
Authors: Wang Eric X. , Kussman Andrea , Hwang Calvin E.
Published: November 2021

Objective:

To determine the utility of monospot testing in the diagnosis of mononucleosis in the collegiate student–athlete clinical setting.

Design:

Retrospective cohort study.

Setting:

National Collegiate Athletic Association Division I sports medicine clinic.

Patients:

All varsity student athletes who had a monospot test and Epstein–Barr virus (EBV) titers obtained from January 1, 2016, through March 31, 2020, (n = 199) were included.

Independent Variables:

Monospot, EBV antibody titers, and liver transaminase results.

Main Outcome Measures:

Using EBV titers indicating acute or recent infection as the gold standard for diagnosing infectious mononucleosis (IM), the reliability of a positive monospot test and elevated liver transaminases for the diagnosis of IM were examined.

Results:

The monospot test had a sensitivity and specificity of 80.0% and 90.6%, respectively, with a positive predictive value of 36.4% and a negative predictive value of 98.5% in this cohort. All athletes diagnosed with IM also had elevated liver transaminases.

Conclusions:

The specificity of the monospot test is lower than previously reported in the literature, and a positive test is not sufficient to diagnose mononucleosis in this clinical setting. Positive monospot results should be confirmed with EBV antibody testing. Elevated transaminase levels are highly correlated with acute IM and could play a supporting role in the diagnosis.
Remdesivir and GS-441524 Extraction by Ex Vivo Extracorporeal Life Support Circuits
Authors: Imburgia Carina E. , Rower Joseph E. , Green Danielle J. , Mcknite Autumn M. , Kelley Walter E. , Reilly Christopher A. , Watt Kevin M.
Published: November 2021

Patients with severe, COVID-related multi-organ failure often require extracorporeal life support (ECLS) such as extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT). An ECLS can alter drug exposure via multiple mechanisms. Remdesivir (RDV) and its active metabolite GS-441524 are likely to interact with ECLS circuits, resulting in lower than expected exposures. We evaluated circuit-drug interactions in closed loop, ex vivo ECMO and CRRT circuits. We found that mean (standard deviation) recovery of RDV at 6 hours after dosing was low in both the ECMO (33.3% [2.0]) and CRRT (3.5% [0.4]) circuits. This drug loss appears to be due primarily to drug adsorption by the circuit materials and potentially due to metabolism in the blood. GS-441524 recovery at 6 hours was high in the ECMO circuit 75.8% (16.5); however, was not detectable at 6 hours in the CRRT circuit. Loss in the CRRT circuit appears to be due primarily to efficient hemodiafiltration. The extent of loss for both molecules, especially in CRRT, suggests that in patients supported with ECMO and CRRT, RDV dosing adjustments are needed.
Acquired Bernard–Soulier syndrome and hypodysfibrinogenaemia because of multiple myeloma
Authors: Sehgal Tushar , Altohami Mohammed , Lafferty Nicholas , Desborough Michael , Boyce Sara , Kazmi Rashid , Jenner Matthew
Published: November 2021

We describe a case of a patient with multiple myeloma with initial presentation simulating a bleeding disorder. Detailed coagulation work-up showed hypodysfibrinogenaemia along with a platelet function defect consistent with acquired Bernard–Soulier syndrome (BSS). Multiple plasma exchanges led to significant improvement in his bleeding symptoms. To the best of our knowledge, this is the first described case of simultaneous presentation of hypodysfibrinogenaemia and BSS secondary to multiple myeloma.
Robot-assisted radical cystectomy: surgical technique, perioperative and oncologic outcomes
Authors: Hussein Ahmed A. , Li Qiang , Guru Khurshid A.
Published: November 2021

Purpose of review

Radical cystectomy is a complex procedure that encompasses surgery involving the urinary, gastrointestinal tracts and the retroperitoneum, with significant morbidity. Robot-assisted radical cystectomy (RARC) has been introduced to improve perioperative outcomes.

Recent findings

It has been shown to provide equivalent oncologic outcomes to open radical cystectomy while providing some benefits in terms of perioperative outcomes. A complete intracorporeal approach utilizing intracorporeal urinary diversion may potentially offer additional benefits.

Herein, we describe our technique for RARC and intracorporeal urinary diversion, as well as a review of oncologic and perioperative outcomes.
Functional Changes in Cortical Activity of Patients Submitted to Knee Osteoarthritis Treatment
Authors: Iuamoto Leandro Ryuchi , Imamura Marta , Sameshima Koichi , Meyer Alberto , Simis Marcel , Battistella Linamara Rizzo , Fregni Felipe
Published: November 2021

Introduction

There is evidence that brain plasticity is the central mechanism involved in the functional recovery process of patients with knee osteoarthritis. Studies involving the analysis of central nervous system mechanisms of pain control and recovery could provide more data on future therapeutic approaches.

Objective

The aim of the study was to explore possible functional changes in cortical activity of patients submitted to knee osteoarthritis standardized pain treatment using electroencephalography.

Methodology

Ten patients with clinical and radiological diagnosis of painful knee unilateral or bilateral osteoarthritis were recruited to participate in clinical (Pain’s Visual Analog Scale), radiological (Kellgren-Lawrence Scale), and neurophysiological (electroencephalography) assessments to evaluate cortical activity during cortical pain modulation activity. The clinical and neurophysiological analyses were performed before and after standardized pain treatment.

Results

Eight patients participated in this study. A significant improvement in pain perception and relative increase in interhemispheric connectivity after therapies was observed. In electroencephalography analysis, tests with real movement showed a relative increase in density directed at Graph’s analysis.

Conclusions

Relative increase density directed measures at connectivity analysis in electroencephalography after pain treatment can be possible parameters to be explored in future research with a larger number of patients.
System-Level Determinants of Access to Flap Reconstruction after Abdominoperineal Resection
Authors: Dayani Fara , Sheckter Clifford C. , Rochlin Danielle H. , Nazerali Rahim S.
Published: November 2021

Background:

Reconstruction following abdominoperineal resection improves outcomes by reducing wound-related complications, particularly in irradiated patients. Little is known regarding system-level factors that impact patients’ access to reconstructive surgery following abdominoperineal resection. This study aimed to identify barriers to undergoing reconstruction following abdominoperineal resection.

Methods:

Using the National Inpatient Sample database from 2012 to 2014, all encounters with colorectal or anorectal carcinoma patients who underwent abdominoperineal resection were extracted based on International Classification of Disease, Ninth Revision, diagnosis and procedure codes. Multivariable logistic regression analyzed the outcome of undergoing reconstruction.

Results:

The weighted sample included encounters with 19,205 abdominoperineal resection patients, of whom 1243 (6.5 percent) received a flap. Notable patient-level predictors of receiving a flap included age younger than 55 years (OR, 1.82; 95 percent CI, 1.23 to 2.74; p = 0.003) and neoadjuvant chemoradiation therapy (OR, 1.37; 95 percent CI, 1.01 to 1.88; p = 0.041). Race, sex, income level, insurance type, and Elixhauser Comorbidity Index were not associated with increased odds of receiving a flap. For facility-level factors, urban teaching hospitals (OR, 23.6; 95 percent CI, 3.29 to 169.4; p = 0.002) and larger hospital bedsize (OR, 2.64; 95 percent CI, 1.53 to 4.56; p = 0.000) were associated with higher odds of reconstruction. Plastic surgery facility volume was not found to be a significant predictor of undergoing flap reconstruction (p > 0.05).

Conclusions:

Patients undergoing abdominoperineal resection at academic centers were over 23 times more likely to undergo reconstruction, after adjusting for available confounders. Patients undergoing abdominoperineal resection at smaller, nonacademic centers may not have equitable access to reconstruction despite being appropriate candidates. Given the morbidity of abdominoperineal resection, patients should be referred to large, academic centers to have access to flap reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Intraflap Vascular Catheterization Method for Monitoring, Prevention, and Intervention of Thrombogenesis in Free-Flap Surgery
Authors: Saiga Atsuomi , Kubota Yoshitaka , Yamaji Yoshihisa , Mitsukawa Nobuyuki
Published: November 2021

Background

Thrombosis at the anastomotic site is a significant problem in free tissue transfer with microvascular anastomosis. We report a newly developed intraflap vascular catheterization (IFVC) technique for monitoring hemodynamics, prevention of thrombogenesis, and transcatheter intervention of free-flap thrombosis.

Methods

We performed a hospital-based, prospective study. Ninety-three patients underwent free tissue transfer by a single surgeon in a single hospital. In the IFVC group (n = 40), catheters were inserted into the arterial and venous branches of the flap main pedicle vessels near the anastomoses. The catheters were connected to the pressure monitor. A bolus injection of urokinase was administered every hour to the artery, and a continuous infusion of saline was initiated to the vein. The bolus injection of urokinase solution reached the arterial anastomosis by the retrograde flow. During the postoperative period, rapid injection of urokinase or saline was performed according to the pressure monitor. Intraflap vascular catheterization monitoring was performed postoperatively for 72 hours.

Results

The overall flap survival rate in the IFVC group was 100% (40 of 40), whereas the overall flap survival rate in the non-IFVC group was 96% (51 of 53). In a subgroup analysis of lower extremity reconstruction, the flap survival rate was 100% (22 of 22) with no cases of reanastomosis requiring a return to the operation room in the IFVC group. By contrast, the flap survival rate was 92% (22 of 24), with 6 cases of reanastomosis requiring a return to the operation room in the non-IFVC group (P = 0.04).

Conclusions

The IFVC method enables monitoring, prevention, and intervention of thrombi at anastomotic sites of the free flap. Intraflap vascular catheterization may increase free tissue transfer success rate, especially in high-risk cases, such as free-flap reconstruction after the lower extremity trauma or venous leg ulcer.
Shifting acute stroke management to the prehospital setting
Authors: Ebinger Martin , Audebert Heinrich J.
Published: November 2021

Purpose of review

The earlier the treatment, the better the outcomes after acute ischemic stroke. Optimizing prehospital care bears potential to shorten treatment times. We here review the recent literature on mothership vs. drip-and-ship as well as mobile stroke unit concepts.

Recent findings

Mobile stroke units result in the shortest onset-to-treatment times in mostly urban settings.

Future research should focus on further streamlining processes around mobile stroke units, especially improving dispatch algorithms and improve referral for endovascular therapy.
Conceptualization and management of personality disorders in Russian psychiatry
Authors: Kulygina Maya A. , Chetkina Anastasiya S. , Berezantsev Andrei Yu.
Published: November 2021

Purpose of review

This article aims to present the current picture on conceptualization, diagnosis and care provision of personality disorders (PD) in modern Russia. These issues are highly relevant to Russian psychiatry, which has a rich historical tradition of analysing psychopathic constitution, personality types and dynamics.

Recent findings

This narrative review covers the main tendencies in the recent Russian academic literature devoted to PD. PD are most frequently investigated in the frames of forensic psychiatry, in which expert conclusions and assessment of the risk factors for socially dangerous behaviour are particularly important. Another area of research concerns comorbidity, since PD often affect other health conditions or are co-occurrent with other mental or behavioural problems. Specialists have also focused on the challenges of therapy in PD.

Reviewed manuscripts show a pathogenic and pathoplastic role of personality factors in manifestation of other mental, behavioural or somatic disorders. Analysis of pathocharacterological profile and self-regulation processes is a major component in assessing and diagnosing PD. The principal perspectives in this particular area focus on evidence-based research of mechanisms of personality pathology and validation of targeted personalized combined therapeutic approaches.
The unmitigated profile of COVID-19 infectiousness
Authors: Sender Ron , Bar-On Yinon M. , Park Sang Woo , Noor Elad , Dushoff Jonathan , Milo Ron
Published: November 2021

Quantifying the temporal dynamics of infectiousness of individuals infected with SARS-CoV-2 is crucial for understanding the spread of the COVID-19 pandemic and for analyzing the effectiveness of different mitigation strategies. Many studies have tried to use data from the onset of symptoms of infector-infectee pairs to estimate the infectiousness profile of SARS-CoV-2. However, both statistical and epidemiological biases in the data could lead to an underestimation of the duration of infectiousness. We correct for these biases by curating data from the initial outbreak of the pandemic in China (when mitigation steps were still minimal), and find that the infectiousness profile is wider than previously thought. For example, our estimate for the proportion of transmissions occurring 14 days or more after infection is an order of magnitude higher - namely 19% (95% CI 10%-25%). The inferred generation interval distribution is sensitive to the definition of the period of unmitigated transmission, but estimates that rely on later periods are less reliable due to intervention effects. Nonetheless, the results are robust to other factors such as the model, the assumed growth rate and possible bias of the dataset. Knowing the unmitigated infectiousness profile of infected individuals affects estimates of the effectiveness of self-isolation and quarantine of contacts. The framework presented here can help design better quarantine policies in early stages of future epidemics using data from the initial stages of transmission.
Encounters after Appointments Cancelled Due to COVID-19 in the Veterans Affairs Health Care System
Authors: Tran Linda Diem , Rose Liam , Urech Tracy , Vashi Anita
Published: November 2021

This statistical brief examines subsequent encounters after a cancellation due to COVID-19 in the Veterans Affairs System. We find that he vast majority of VA patients that had appointments cancelled in mid-March to mid-April of 2020 had another encounter within 180 days. The most common next encounter was a virtual visit with a VA provider on the same day of the original appointment. We also find that patients that saw a provider through VA community care had a lower median time to next encounter.
COVID-19 management in social care in England: a systematic review of changing policies and newspaper reported staff perspectives
Authors: Bertini Lavinia , Bogen-Johnston Leanne , Middleton Jo , Wood Wendy , Sadhwani Shanu , Forder Julien , Roland Daniel , Sharp Rebecca , Drury John , Cassell Jackie A
Published: November 2021

Adult social care has been a major focus of public attention and infection control guidance during the COVID-19 pandemic, with a high mortality both for carers and those receiving care. To protect themselves and others from infection, staff in residential and domiciliary care settings had to quickly adapt to infection control measures that heavily impacted on their working and every-day life, whilst navigating new responsibilities, uncertainties and anxieties. We sought to explore the production and reception of guidance and look at ways these can be adapted to improve the working life of care staff in domiciliary and residential care whilst reducing the risk of SARS-CoV-2 transmission amid this pandemic and of future emerging infections.

We conducted two complementary and integrated systematic reviews of published documents in the pre-vaccination era: (1) National guidance for social care (conducted between 29 July to 28 October 2020), and (2) Newspaper coverage of infection control issues in social care (conducted between 27th July to 10th September 2020).

Three higher order common themes emerged in the integrated systematic review of guidance documents and newspaper articles: a) Testing, b) Personal Protective Equipment, c) Employment. The reviews revealed a sharp disjunction between the content of infection control guidance and its usability and applicability in social care settings. We suggest that infection control guidance needs to be better adapted to social care settings and informed by the sector. The practicalities of care work and care settings need to be at the core of the process for guidance to be relevant and effective. Modes and timings of communications also need to be optimised.
Durability of anti-Spike antibodies in the infant after maternal COVID-19 vaccination
Authors: Shook Lydia L. , Atyeo Caroline G. , Yonker Lael M. , Fasano Alessio , Gray Kathryn J. , Alter Galit , Edlow Andrea G.
Published: November 2021

COVID-19 vaccination in pregnancy generates functional anti-Spike IgG antibodies that are known to cross the placenta. However, the durability of vaccine-induced maternal anti-S IgG in infant circulation, and how it compares to durability of antibody from maternal natural infection, is unknown. We quantified anti-S IgG in 92 2-month and 6-month-old infants whose mothers were vaccinated in pregnancy, and in 12 6-month-old infants after maternal natural infection with SARS-CoV-2. In the vaccinated group, 94% (58/62) of infants had detectable anti-S IgG at 2 months, and 60% (18/30) had detectable antibody at 6 months. In contrast, 8% (1/12) of infants born to women infected with SARS-CoV-2 in pregnancy had detectable anti-S IgG at the 6-month timepoint. Vaccination resulted in significantly higher maternal and cord titers at delivery and significantly greater antibody persistence in infants at 6 months, compared to natural infection.
Economic evaluation of a cluster randomized, non-inferiority trial of differentiated service delivery models of HIV treatment in Zimbabwe
Authors: Benade Mariet , Nichols Brooke , Fatti Geoffrey , Kuchukhidze Salome , Takarinda Kudakwashe , Mabhena-Ngorima Nicoletta , Grimwood Ashraf , Rosen Sydney
Published: November 2021

Background

About 85% of Zimbabwe’s >1.4 million people living with HIV are on antiretroviral treatment (ART). Further expansion of its treatment program will require more efficient use of existing resources. Two promising strategies for reducing resource utilization per patient are multi-month medication dispensing and community-based service delivery. We evaluated the costs to providers and patients of community-based, multi-month ART delivery models in Zimbabwe.

Methods

We used resource and outcome data from a cluster-randomized non-inferiority trial of three differentiated service delivery (DSD) models targeted to patients stable on ART: 3-month facility-based care (3MF), community ART refill groups (CAGs) with 3-month dispensing (3MC), and CAGs with 6-month dispensing (6MC). Using local unit costs, we estimated the annual cost in 2020 USD of providing HIV treatment per patient from the provider and patient perspectives.

Results

In the trial, retention at 12 months was 93.0% in the 3MF, 94.8% in the 3MC, and 95.5% in the 6MC arms. The total average annual cost of HIV treatment per patient was $187 (standard deviation $39), $178 ($30), and $167 ($39) in each of the three arms, respectively. The annual cost/patient was dominated by ART medications (79% in 3MF, 87% in 3MC; 92% in 6MC), followed by facility visits (12%, 5%, 5%, respectively) and viral load (8%, 8%, 2%, respectively). When costs were stratified by district, DSD models cost slightly less, with 6MC the least expensive in all districts. Savings were driven by differences in the number of facility visits made/year, as expected, and low uptake of annual viral load tests in the 6-month arm. The total annual cost to patients to obtain HIV care was $10.03 ($2) in the 3MF arm, $5.12 ($0.41) in the 3MC arm, and $4.40 ($0.39) in the 6MF arm.

Conclusions

For stable ART patients in Zimbabwe, 3- and 6-month community-based multi-month dispensing models cost less for both providers and patients than 3-month facility-based care and had non-inferior outcomes.
Set1-mediated histone H3K4 methylation is required for azole induction of the ergosterol biosynthesis genes and antifungal drug resistance inCandida glabrata
Authors: Baker Kortany M. , Hoda Smriti , Saha Debasmita , Georgescu Livia , Serratore Nina D. , Zhang Yueping , Lanman Nadia A. , Briggs Scott D.
Published: November 2021

Candida glabratais an opportunistic pathogen that has developed the ability to adapt and thrive under azole treated conditions. The common mechanisms that can result inCandidadrug resistance are due to mutations or overexpression of the drug efflux pump or the target of azole drugs, Cdr1 and Erg11, respectively. However, the role of epigenetic histone modifications in azole-induced gene expression and drug resistance are poorly understood inC. glabrata. In this study, we show for the first time that Set1 mediates histone H3K4 mono-, di-, and trimethylation inC. glabrata. In addition, loss ofSET1and histone H3K4 methylation results in increased susceptibility to azole drugs in bothC. glabrataandS. cerevisiae. Intriguingly, this increase in susceptibility to azole drugs in strains lacking Set1-mediated histone H3K4 methylation is not due to altered transcript levels ofCDR1,PDR1or Cdr1’s ability to efflux drugs. Genome-wide transcript analysis revealed that Set1 is necessary for azole-induced expression of 12 genes involved in the late biosynthesis of ergosterol includingERG11andERG3. Importantly, chromatin immunoprecipitation analysis showed that histone H3K4 trimethylation was detected on chromatin of actively transcribedERGgenes. Furthermore, H3K4 trimethylation increased upon azole-induced gene expression which was also found to be dependent on the catalytic activity of Set1. Altogether, our findings show that Set1-mediated histone H3K4 methylation governs the intrinsic drug resistant status inC. glabratavia epigenetic control of azole-inducedERGgene expression.

IMPORTANCE

C. glabratais the second most commonly isolated species fromCandidainfections, coming in second toC. albicans. Treatment ofC. glabratainfections are difficult due to their natural resistance to antifungal azole drugs and their ability to adapt and become multidrug resistant. In this study, we investigated the contributing cellular factors for controlling drug resistance. We have determined that an epigenetic mechanism governs the expression of genes involved in the late ergosterol biosynthesis pathway, an essential pathway that antifungal drugs target. This epigenetic mechanism involves histone H3K4 methylation catalyzed by the Set1 methyltransferase complex (COMPASS). We also show that Set1-mediated histone H3K4 methylation is needed for expression of specific azole induced genes and azole drug resistance inC. glabrata. Identifying epigenetic mechanisms contributing to drug resistance and pathogenesis could provide alternative targets for treating patients with fungal infections.
Hidden temporal structure of the ongoing task impacts detection strategy and is reflected in pupillary dynamics
Authors: Lawlor Jennifer , Zagala Agnès , Jamali Sara , Boubenec Yves
Published: November 2021

Estimating temporal regularities in incoming sensory inputs supports optimal decisions in noisy environments. In particular, inferred temporal structure can ease the detection of likely target events. Here we postulated that timely urgency signals can adapt subjects’ decision-making to the ongoing task temporal structure, possibly through neuromodulatory tone. To test this hypothesis, we used an auditory change detection task in which targets followed a block-based temporal contingency, unbeknownst to participants. False alarm occurrences were driven by the distribution of target timings, indicating that participants adapted their behavior to the ongoing temporal structure. Task-evoked pupillary responses were larger for blocks with earliest target timings, and correlated with individual subjects’ behavioral adaptation. Individual pupil responses matched an urgency signal extracted from a decision model fitted to behavior. This work demonstrates that internal temporal expectation can be tracked through pupillary dynamics, suggesting a role of neuromodulatory systems in context-dependent modulation of decision variable dynamics.
Anatomical connectivity along the anterior-posterior axis of the human hippocampus: new insights using quantitative fibre-tracking
Authors: Dalton Marshall A. , D’Souza Arkiev , Lv Jinglei , Calamante Fernando
Published: November 2021

The hippocampus supports multiple cognitive functions including episodic memory. Recent work has highlighted functional differences along the anterior-posterior axis of the human hippocampus but the neuroanatomical underpinnings of these differences remain unclear. We leveraged track-density imaging to systematically examine anatomical connectivity between the cortical mantle and the anterior-posterior axis of the in-vivo human hippocampus. We first identified the most highly connected cortical areas and detailed the degree to which they preferentially connect along the anterior-posterior axis of the hippocampus. Then, using a tractography pipeline specifically tailored to measure the location and density of streamline endpoints within the hippocampus, we characterised where, within the hippocampus, these cortical areas preferentially connect. Our results were striking in showing that different parts of the hippocampus preferentially connect with distinct cortical areas. Furthermore, we provide evidence that both gradients and circumscribed areas of dense extrinsic anatomical connectivity exist within the human hippocampus. These findings inform conceptual debates in the field by unveiling how specific regions along the anterior-posterior axis of the hippocampus are associated with different cortical inputs/outputs. Overall, our results represent a major advance in our ability to map the anatomical connectivity of the human hippocampus in-vivo and inform our understanding of the neural architecture of hippocampal dependent memory systems in the human brain. This detailed characterization of how specific portions of the hippocampus anatomically connect with cortical brain regions may promote a better understanding of its role in cognition and we emphasize the importance of considering the hippocampus as a heterogeneous structure.
A pilot randomised prospective comparison of two approaches for tibial nailing using clinical and novel imaging outcome measures – study protocol
Authors: Davies Benjamin M , Ali Erden , Chou Daud , Hull Peter , Rawal Jaikirty , McKay James , McCaskie Andrew , Carrothers Andrew
Published: November 2021

Fractures of the tibia are frequently treated with an intra-medullary nail. This can be inserted through either a supra-patella or infra-patella surgical incision. Concerns over potential damage to the cartilage of the knee with supra-patella insertion has impacted upon its adoption despite benefits in terms of easier nail placement and potentially reduced blood loss and pain.

This randomised pilot study will use patient reported outcome measures (PROMS) and novel MRI sequences designed to assess damage to the structure of cartilage to compare these two methods of tibial intra-medullary nailing.

Twenty individuals with tibial shaft fractures will be randomised to either method of nail insertion (ten individuals in each arm). MRI scans and PROMS will be used to assess cartilage damage and general function up to 6 months post operatively.

The results of the study will be used to inform a potential multi-centre study.
Proteolysis Targeting Chimeras With Reduced Off-targets
Authors: Nguyen Tuan M. , Sreekanth Vedagopuram , Deb Arghya , Kokkonda Praveen , Tiwari Praveen K. , Donovan Katherine A. , Shoba Veronika , Chaudhary Santosh K. , Mercer Jaron A. M. , Lai Sophia , Sadagopan Ananthan , Jan Max , Fischer Eric S. , Liu David R. , Ebert Benjamin L. , Choudhary Amit
Published: November 2021

Proteolysis Targeting Chimeras (PROTACs), a class of heterobifunctional molecules that recruit target proteins to E3 ligases, have gained traction for targeted protein degradation. However, pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other targets, such as zinc-finger (ZF) proteins, that hold key functions in normal development and disease progression. This off-target degradation of pomalidomide-based PROTACs raises concerns about their therapeutic applicability and long-term side effects. Therefore, there is a crucial need to develop rules for PROTAC design that minimize off-target degradation. In this study, we developed a high-throughput platform that interrogates the off-target degradation of ZF domains and discovered, using this platform, that PROTACs with the current design paradigm induce degradation of several ZF proteins. To identify new rules for PROTAC design, we generated a library of pomalidomide analogs that allowed systematic exploration of the impact of positional isomerism (e.g., C4 and C5 positions of the phthalimide ring), hydrogen bonding, steric and hydrophobic effects on propensities for ZF protein degradation. We found that modifications of appropriate size on the C5 position reduced off-target ZF degradation. We validated these results using immunoblotting, target engagement, and global mass spectrometric studies. We applied our newfound design principles on a previously developed ALK oncoprotein-targeting PROTAC and generated PROTACs with enhanced potency and minimal off-target degradation. We envision the reported off-target profiling platform and pomalidomide analogs will find utility in design of specific PROTACs.
PURC v2.0: A Program for Improved Sequence Inference for Polyploid Phylogenetics and Other Manifestations of the Multiple-Copy Problem
Authors: Schafran Peter , Li Fay-Wei , Rothfels Carl J.
Published: November 2021

Inferring the true biological sequences from amplicon mixtures remains a difficult bioinformatic problem. The traditional approach is to cluster sequencing reads by similarity thresholds and treat the consensus sequence of each cluster as an “operational taxonomic unit” (OTU). Recently, this approach has been improved upon by model-based methods that correct PCR and sequencing errors in order to infer “amplicon sequence variants” (ASVs). To date, ASV approaches have been used primarily in metagenomics, but they are also useful for identifying allelic or paralogous variants and for determining homeologs in polyploid organisms. To facilitate the usage of ASV methods among polyploidy researchers, we incorporated ASV inference alongside OTU clustering inPURC v2.0, a major update to PURC (Pipeline for Untangling Reticulate Complexes). In addition to preserving original PURC functions,PURC v2.0allows users to process PacBio CCS/HiFi reads through DADA2 to generate and annotate ASVs for multiplexed data, with outputs including separate alignments for each locus ready for phylogenetic inference. In addition,PURC v2.0features faster demultiplexing than the original version and has been updated to be compatible with Python 3. In this chapter we present results indicating thatPURC v2.0(using the ASV approach) is more likely to infer the correct biological sequences in comparison to the earlier OTU-based PURC, and describe how to prepare sequencing data, runPURC v2.0under several different modes, and interpret the output. We expect thatPURC v2.0will provide biologists with a method for generating multi-locus “moderate data” datasets that are large enough to be phylogenetically informative and small enough for manual curation.
Sharing individualised template MRI data for MEG source reconstruction: a solution for open data while keeping subject confidentiality
Authors: Vinding Mikkel C. , Oostenveld Robert
Published: November 2021

The increasing requirements for adoption of FAIR data management and sharing original research data from neuroimaging studies can be at odds with protecting the anonymity of the research participants due to the person-identifiable anatomical features in the data. We propose a solution to this dilemma for anatomical MRIs used in MEG source analysis. In MEG analysis, the channel-level data is reconstructed to the source-level using models derived from anatomical MRIs. Sharing data, therefore, requires sharing the anatomical MRI to replicate the analysis. The suggested solution is to replace the individual anatomical MRIs with individualised warped templates that can be used to carry out the MEG source analysis and that provide sufficient geometrical similarity to the original participants’ MRIs.

First, we demonstrate how the individualised template warping can be implemented with one of the leading open-source neuroimaging analysis toolboxes. Second, we compare results from four different MEG source reconstruction methods performed with an individualised warped template to those using the participant’s original MRI. While the source reconstruction results are not numerically identical, there is a high similarity between the results for single dipole fits, dynamic imaging of coherent sources beamforming, and atlas-based virtual channel beamforming. There is a moderate similarity between minimum-norm estimates, as anticipated due to this method being anatomically constrained and dependent on the exact morphological features of the cortical sheet.

We also compared the morphological features of the warped template to those of the original MRI. These showed a high similarity in grey matter volume and surface area, but a low similarity in the average cortical thickness and the mean folding index within cortical parcels.

Taken together, this demonstrates that the results obtained by MEG source reconstruction can be preserved with the warped templates, whereas the anatomical and morphological fingerprint is sufficiently altered to protect the anonymity of research participants. In cases where participants consent to sharing anatomical MRI data, it remains preferable to share the original defaced data with an appropriate data use agreement. In cases where participants did not consent to share their MRIs, the individualised warped MRI template offers a good compromise in sharing data for reuse while retaining anonymity for those research participants.
Adhesion strength between cells regulate non-monotonic growth by a biomechanical feedback mechanism
Authors: Malmi-Kakkada Abdul N , Sinha Sumit , Li Xin , Thirumalai D.
Published: November 2021

We probe the interplay between intercellular interactions and pressure fluctuations associated with single cells in regulating cell proliferation using simulations of a minimal model for three-dimensional multicellular spheroid (MCS) growth. The emergent spatial variations in the cell division rate, that depends on the location of the cells within the MCS, is regulated by intercellular adhesion strength (fad). This in turn results in non-monotonic proliferation of cells in the MCS with varying adhesion strength, which accords well with experimental results. A biomechanical feedback mechanism coupling the fad and cell-dependent pressure fluctuations relative to a threshold value (pc) determines the onset of a dormant phase, and explains the non-monotonic proliferation response. Increasing fad from low values enhances cell proliferation because pressure on individual cells is smaller compared to pc. In contrast, at high fad, cells readily become dormant and cannot rearrange effectively, leading to arrested cell proliferation. Our work, which shows that proliferation is regulated by pressure-adhesion feedback loop, may be a general feature of tumor growth.
Ecological changes have driven biotic exchanges across the Indian Ocean
Authors: Bernardes Samuel C. , von Rintelen Kristina , von Rintelen Thomas , Pepato Almir R. , Page Timothy J. , de Bruyn Mark
Published: November 2021

The Indian Ocean has a complex geological history that has drawn the attention of naturalists for almost a century now. Due to its tectonic history, many geological elements and processes have been evoked to explain the exchange of species between landmasses. Here, we revisited previous studies on twenty-three taxa to investigate trends across time since the Gondwana breakup. We investigated these datasets by applying a time-calibrated Bayesian framework to them and reconstructing their ancestral ranges. We conclude that ecological transformations have presented opportunities for the establishment of migrants. The role of donating and receiving migrants has shifted several times according to these transformations. Time-specific trends show weak evidence for the stepping-stones commonly suggested as physical routes between landmasses. However, before its collision with Asia, India may have served as an intermediary for such exchanges.
Metformin Suppresses SARS-CoV-2 in Cell Culture
Authors: Parthasarathy Haripriya , Tandel Dixit , Siddiqui Abdul Hamid , Harshan Krishnan H.
Published: November 2021

Comorbidities such as diabetes worsen COVID-19 severity and recovery. Metformin, a first-line medication for type 2 diabetes, has antiviral properties and certain studies have also indicated its prognostic potential in COVID-19. Here, we report that metformin significantly inhibits SARS-CoV-2 growth in cell culture models. First, a steady increase in AMPK phosphorylation was detected as infection progressed, suggesting its important role during viral infection. Activation of AMPK in Calu3 and Caco2 cell lines using metformin revealed that metformin suppresses SARS-CoV-2 infectious titers up to 99%, in both naïve as well as infected cells. TCID50 values from dose-variation studies in infected cells were found to be 0.8 and 3.5 mM in Calu3 and Caco2 cells, respectively. Role of AMPK in metformin’s antiviral suppression was further confirmed using other pharmacological compounds, AICAR and Compound C. Collectively, our study demonstrates that metformin is effective in limiting the replication of SARS-CoV-2 in cell culture and thus possibly could offer double benefits s diabetic COVID-19 patients by lowering both blood glucose levels and viral load.
A tripartite structure, the complex nuclear receptor element (cNRE), is a cis-regulatory module of viral origin required for atrial chamber preferential gene expression
Authors: Santos Luana Nunes , da Souza Costa Ângela Maria , Nikolov Martin , Sampaio Allysson Coelho , Stockdale Frank E. , Wangø Gang F , Castillo Hozana Andrade , Grizante Mariana Bortoletto , Dudczig Stefanie , Vasconcelos Michelle , Rosenthal Nadia , Jusuf Patricia Regina , de Oliveira Paulo , de Freitas Matos Tatiana Guimarães , Nikovits William , Schubert Michael , Ramialison Mirana , Xavier-Neto José
Published: November 2021

Optimal cardiac function requires appropriate contractile proteins in each heart chamber. Atria require slow myosins to act as variable reservoirs, while ventricles demand fast myosin for swift pumping functions. Hence, myosin is under chamber-biased cis-regulatory control to achieve this functional distribution. Failure in proper regulation of myosin genes can lead to severe congenital heart dysfunction. The precise regulatory input leading to cardiac chamber-biased expression remains uncharted. To address this, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III (SMyHC III) promoter that drives specific gene expression to the atria to uncover the regulatory information leading to chamber expression and understand their evolutionary origins. We show that SMyHC III gene states are autonomously orchestrated by a complex nuclear receptor cis-regulatory element (cNRE), a 32- bp sequence with hexanucleotide binding repeats. Using in vivo transgenic assays in zebrafish and mouse models, we demonstrate that preferential atrial expression is achieved by the combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Through comparative genomics, we provide evidence that the cNRE emerged from an endogenous viral element, most likely through infection of an ancestral host germline. Our study reveals an evolutionary pathway to cardiac chamber-specific expression.