bluuebunny/crossref_metadata_2025 huggingface dataset:
Oliguria on the Day of Intubation Is Associated With Mortality in Patients With Acute Respiratory Distress Syndrome
Authors: Fadel Raef A. , Murskyj Ivanna , Abou Asala Elian , Nasiri Nour , Alsaadi Ayman , Scott Ashley , Ouellette Daniel
Published: June 2022

OBJECTIVES:

To investigate the relationship between oliguric acute kidney injury (AKI) and mortality in patients with acute respiratory distress syndrome (ARDS).

DESIGN:

Retrospective cohort study.

SETTING:

This investigation took place at a single-center, tertiary referral multidisciplinary comprehensive healthcare hospital in metropolitan Detroit, Michigan.

PATIENTS:

Adult patients 18 years old or older hospitalized in the ICU and diagnosed with ARDS on mechanical ventilation.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Three hundred eight patients were included in the final analysis. Risk factors associated with mortality included advanced age (p < 0.001), increased body mass index (p = 0.008), and a history of chronic kidney disease (p = 0.023). Presence of AKI by day 1 of intubation, with elevated creatinine (p = 0.003) and oliguria (p < 0.001), was significantly associated with mortality. On multivariate analysis, advanced age (relative risk [RR], 1.02), urine output on the day of intubation (RR, 0.388), bicarbonate level (RR, 0.948), and Sequential Organ Failure Assessment severity score (RR, 1.09) were independently associated with mortality. A receiver operating characteristic curve identified a threshold urine output on the day of intubation of 0.7 mL/kg/hr (area under the curve, 0.75; p < 0.001) as most closely associated with inpatient mortality (i.e., urine output < 0.7 mL/kg/hr is associated with mortality).

CONCLUSIONS:

For patients with ARDS, oliguria on the day of intubation was independently associated with increased mortality. Urine output of less than 0.7 mL/kg/hr predicted 80% of inpatient deaths. These findings herald an augmented understanding of the role of urine output in medical decision-making and prognostication.
Cell therapy in corneal endothelial disease
Authors: Wong Evan N. , Mehta Jodhbir S.
Published: June 2022

Purpose of review

Endothelial keratoplasty is the current gold standard for treating corneal endothelial diseases, achieving excellent visual outcomes and rapid rehabilitation. There are, however, severe limitations to donor tissue supply and uneven access to surgical teams and facilities across the globe. Cell therapy is an exciting approach that has shown promising early results. Herein, we review the latest developments in cell therapy for corneal endothelial disease.

Recent findings

We highlight the work of several groups that have reported successful functional outcomes of cell therapy in animal models, with the utilization of human embryonic stem cells, human-induced pluripotent stem cells and cadaveric human corneal endothelial cells (CECs) to generate populations of CECs for intracameral injection. The use of corneal endothelial progenitors, viability of cryopreserved cells and efficacy of simple noncultured cells, in treating corneal decompensation is of particular interest. Further additions to the collective understanding of CEC physiology, and the process of cultivating and administering effective cell therapy are reviewed as well.

The latest developments in cell therapy for corneal endothelial disease are presented. The continuous growth in this field gives rise to the hope that a viable solution to the large numbers of corneal blind around the world will one day be reality.
A Learning Health System Approach to Hospital Quality Performance Benchmarking: The Composite Hospital Quality Index
Authors: Pollock Benjamin D. , Franco Pablo Moreno , Noe Katherine H. , Poe John D. , Limper Andrew H. , Farrugia Gianrico , Ting Henry H. , Dowdy Sean C.
Published: June 2022

US hospital quality rankings and ratings use disparate methodologies and are weakly correlated. This causes confusion for patients and hospital quality staff. At the authors’ institution, a Composite Hospital Quality Index (CHQI) was developed to combine hospital quality ratings. This approach is described and a calculator is shared here for other health systems to explore their performance. Among the US News and World Report Top 50 Hospitals, hospital-specific numeric summary scores were aggregated from the 2021 Centers for Medicare and Medicaid Services (CMS) Hospital Overall Star Rating, the Spring 2021 Leapfrog Safety Grade, and the April 2021 Hospital Consumer Assessment of Healthcare Providers and Systems Star Rating. The CHQI is the hospital-specific sum of the national percentile-rankings across these 3 ratings. In this example, mean (SD) percentiles were as follows: CMS Stars 74 (19), Hospital Consumer Assessment of Healthcare Providers and Systems 63 (19), Leapfrog 65 (24), with mean (SD) CHQI of 202 (49). The CHQI is used at the authors’ institution to identify improvement opportunities and ensure that high-quality care is delivered across the health system.
Factors related to preparedness for emergency hemodialysis in the event of a natural disaster
Authors: Nihonyanagi Reiko , Tsukasaki Keiko , Itatani Tomoya , Nakai Hisao , Toda Daisuke
Published: June 2022

This study aimed to explore patients’ preparedness for emergency hemodialysis in the event of a natural disaster and to determine the factors affecting such preparedness.

A cross-sectional study was conducted in undergoing hemodialysis at dialysis facilities in Sapporo, Hokkaido. The participants were a cohort of 256 outpatients aged 20 years or older, 186 (72.7%) were male, and the average age was 61.9 ± 10.9 years. The participants were divided into those who had prepared for emergency dialysis treatment and those who had not. Cross tabulations were performed on the 2 groups using the following participant attributes: preparedness for dialysis during a disaster, knowledge of how to protect themselves during a disaster, and intention to dialyze and evacuate during a disaster, followed by binomial logistic regression analysis.

Of the 256 study patients, 184 (71.9%) were not prepared for dialysis treatment. In logistic regression models, patients who were not prepared for dialysis treatment were found to have higher odds of being employed (odds ratio (OR): 2.469; 95% confidence interval (CI): 1.205-5.058), not being aware of disaster information acquisition methods in the event of a disaster (OR: 4.580, 95%; CI: 2.048-10.241), did not receive explanations on proper disaster response from dialysis facility staff (OR: 2.557, 95%; CI: 1.319-4.954), and believing that their family away from home would not be concerned about them (OR: 2.021; 95% CI: 1.062-3.847).

Disaster preparedness in patients undergoing dialysis remain inadequate. Dialysis facilities need to strengthen their explanations of disaster response, particularly with regard to working, middle-aged people.
External validation of Villalta score in high-middle income country patients with deep vein thrombosis
Authors: de Ávila Rafael Bernardes , Marcondes Giulianna Barreira , Dias Silfayner Victor Mathias , da Silveira Beatriz Périco , de Amorim Jorge Eduardo , Neto Henrique Jorge Guedes , Nakano Luis Carlos Uta , Flumignan Ronald Luiz Gomes
Published: June 2022

Post-thrombotic syndrome (PTS) is a late complication that does not have a cure yet, with a prevalence estimated between 20 to 75%, associated with previous deep vein thrombosis event. Although the Villalta score (VS) is the gold-standard clinical tool for diagnostic and prognostic evaluation of PTS, there are currently no VS intra-rater agreement established and no validation studies for VS’ application into Brazilian Portuguese. We sought to translate and validate VS reliability systematically; and, secondarily, to compare the ultrasound findings with the severity of PTS.

We systematically translated the original VS into Brazilian Portuguese (BP). Fifty participants who underwent two outpatient visits were evaluated using the translated VS. We assessed its intra-rater and inter-rater agreement and compared BP VS versus CEAP clinical component (CEAP C), and the clinical PTS severity versus the duplex ultrasound (DUS) findings. The study and its report followed the Guidelines for Reporting Reliability and Agreement Studies.

The intra-rater evaluation of VS grades had a simple Kappa coefficient of 0.73, and the simple Kappa coefficient inter-rater for VS grades was 0.67. When VS was compared to CEAP C, it established a remarkably high correlation over 0.9. There was difference among VS values compared to DUS initial deep vein thrombosis territory, with femoropopliteal showing higher values than distal veins. Higher VS values were correlated to DUS venous recanalization and reflux.

There was a substantial inter-rater and intra-rater agreement when the BP VS was applied; and when compared to CEAP C, VS showed a high correlation. When VS grading was compared to DUS characteristics, there were significant statistical and clinical correlation, with presence of reflux and recanalization showing higher VS values. This external VS validation also changes the clinical practice allowing the VS use in a different population and establishes the VS intra-rater agreement.
Superb microvascular imaging for distinguishing thyroid nodules
Authors: Jin Hui , Wang Cong , Jin Xin
Published: June 2022

Background:

Earlier studies have shown that the superb microvascular imaging (SMI) can detect tumor angiogenesis to distinguish thyroid nodules, but there is no systematic review. This meta-analysis aimed to identify the accuracy of ultrasound SMI for the diagnosis of thyroid nodules.

Methods:

We searched PubMed, Cochrane Library, and CBM databases. A meta-analysis was conducted using STATA version 14.0 and Meta-Disc version 1.4 software. We calculated the summary statistics for sensitivity, specificity, positive and negative likelihood ratio (LR+/LR−), diagnostic odds ratio, and the synthetic receiver operating characteristic curve. Data will be pooled by either a fixed-effects model or a random-effects model according to the results of heterogeneity identification.

Results:

11 studies that met the inclusion criteria were included in this meta-analysis. The quality assessment of the study of diagnostic accuracy studies scores of all included studies were ≥22. A total of 1003 thyroid malignant nodules and 957 thyroid benign nodules were assessed. The main outcome included: the pooled sensitivity was 0.81 (95% confidence intervals (CI) = 0.79–0.84), and the pooled specificity was 0.86 (95% CI = 0.84–0.88); the pooled LR+ was 5.79 (95% CI = 4.44–7.54), and the pooled negative LR− was 0.23 (95% CI = 0.20–0.26); the pooled diagnostic odds ratio of SMI in the diagnosis of thyroid nodules was 26.84 (95% CI = 19.13–37.60). The area under the synthetic receiver operating characteristic curve was 0.89 (95% CI = 0.86–0.91). We found no evidence for publication bias (t = 0.72, P = .49).

Conclusion:

Our meta-analysis indicates that SMI may have high diagnostic accuracy in distinguishing benign and malignant thyroid nodules.

Systematic review registration:

INPLASY202080084.
Hypocomplementemia during tocilizumab treatment
Authors: Bieber Amir , Markovits Doron , Toledano Kohava , Tavor Yonit , Mader Reuven , Balbir-Gurman Alexandra , Braun-Moscovici Yolanda
Published: June 2022

Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the long-term outcome of patients treated with TCZ who developed hypocomplementemia regarding serious bacterial infections or autoimmune diseases (AID).

The charts of patients treated with TCZ at two rheumatology centers were reviewed retrospectively. Data regarding patients’ age, gender, disease duration, autoantibodies status, previous or concomitant treatments, blood counts, liver enzymes, C3 and C4 levels at baseline and during TCZ treatment, episodes of infections, allergic reactions, and AID were analyzed. Univariate analysis was used to compare patients with low C3, C4 levels versus patients with normal C3, C4 levels. Variables that were statistically significant associated or tended to be associated with low C3 or C4 were included in multiple variable logistic regression.

Of 132 patients treated with TCZ, 108 had serial measurements of serum complement concentration. Thirty-three (30%) patients developed low C4 levels and 23 (21%) had also low C3. Mean TCZ treatment period was 4.9 years (range, 1–14 years). All patients had normal complement levels at baseline. Leukopenia occurred in 18 (16.7%) patients, 14 of whom (77%) had low complement. Persistent leukopenia was observed in 8% and 5.3% of patients with normal C3 and C4 levels, respectively, as opposed to 47% and 42% of patients with low C3 or low C4, respectively. Low C3, C4 levels correlated with prolonged TCZ treatment retention time and effectiveness. There were no serious bacterial infections or new onset AID.

Hypocomplementemia during TCZ treatment was accompanied by leukopenia that correlated with treatment duration. Hypocomplementemia was not associated with serious bacterial infections or new onset AID. Decreased complement levels were associated with treatment longevity. The role of monitoring complement level in predicting treatment response or assessing disease activity deserves further investigation.
Comparison of the Neer classification to the 2018 update of the Orthopedic Trauma Association/AO fracture classification for classifying proximal humerus fractures
Authors: Marmor Meir T. , Agel Julie , Dumpe Jarrod , Kellam James F. , Marecek Geoffrey S. , Meinberg Eric , Nguyen Mai P. , Sims Stephen , Soles Gillian L. , Karam Matthew D.
Published: June 2022

Background:

The classification of fractures is necessary to ensure a reliable means of communication for clinical interaction, education and research. The Neer classification is the most commonly used classification for proximal humerus fractures. In 2018 the Orthopedic Trauma Association (OTA) and the AO Foundation provided an update to the OTA/AO Fracture Classification Scheme addressing many of the concerns about the previous versions of the classification. The objective of the present study was to evaluate the rater reliability of the 2 classifications and if the classifications subjectively better characterized the fracture patterns.

Methods:

X-rays and CT scans of 24 proximal humerus fractures were given to 7 independent raters for classification according to the Neer and 2018 OTA/AO classification. Both full-forms and short-forms of the classifications were tested. The Fleiss Kappa statistic was used to assess inter-rater agreement and intra-rater consistency for the 2 classifications. For each case the raters subjectively commented on how well each classification was able to characterize the fracture pattern.

Results:

All raters graded the 2018 OTA/AO classification as good as or better than the Neer classification for an adequate description of the fracture patterns. The short-form 2018 OTA/AO classification had the most 4 rater and 5 rater agreement cases and the second most 6 rater agreement cases. The short-form Neer classification had the second most 4 rater and 5 rater agreement cases and the most 6 rater agreement cases. The full 2018 OTA/AO had the least 4, 5, or 6 rater agreement cases of all the classification systems. Inter-rater agreement was fair for the full and short form of both the Neer and 2018 OTA/AO classification. The full and short Neer classifications together with the short 2018 OTA/AO classification had moderate intra-rater consistency, while the full 2018 OTA/AO classification only had slight intra-rater consistency.

Conclusions:

The 2018 OTA/AO classification is equivalent in its short-form to the Neer classification in inter-rater reliability and intra-rater consistency; and is superior in its full form for characterizing specific fracture types. The low inter-rater reliability of the full 2018 OTA/AO classification is a concern that may need to be addressed in the future.
Enhanced Recovery After Surgery Pathway in Kidney Transplantation: The Road Less Traveled
Authors: Elsabbagh Ahmed M. , Ghoneim Islam , Moiz Abdul , Welch Kristen , Brown J. Sidni
Published: June 2022

Background.

Enhanced recovery after surgery (ERAS) pathway is a multimodal perioperative care pathway designed to achieve early recovery after surgery. ERAS protocols have not yet been well recognized in kidney transplantation. The aim of this study was to investigate the impact of ERAS pathway on early recovery and short-term clinical outcomes of kidney transplant.

Methods.

This is a single-center retrospective analysis comparing the outcomes of 20 adult kidney transplant recipients subjected to ERAS pathway with 20 adult recipients operated before ERAS with traditional standard of care.

Results.

There were no significant differences between both groups regarding age, gender, race, dialysis status, living donor percentage, cold ischemia time, and warm ischemia time. Median hospital stay for ERAS patients was 2 d. Overall median pain scores were significantly lower in the ERAS group versus non-ERAS group (morning after surgery pain score 2 versus 5; peak pain score 4.5 versus 10; lowest pain score 0 versus 2; P = 0.0001). ERAS patients had earlier ambulation (walking) and oral nutrition (regular diet) (first versus second day postoperatively in traditional group). Earlier bowel movement was observed in ERAS patients. There were no significant differences in graft function or 30-d readmission rates between both groups.

Conclusions.

Implementation of ERAS pathway in kidney transplantation is feasible. Using ERAS is associated with less pain, earlier ambulation and advancement of oral nutrition, and short hospital stay.
Lipoprotein profile and metabolic fine-mapping of genetic lipid risk loci
Authors: Suhre Karsten , Al-Ishaq Raghad , Belkadi Aziz , Habib Tanwir , Halama Anna , Stephan Nisha , Thareja Gaurav , Zaghlool Shaza , Fauman Eric B. , Najafi-Shoushtari S. Hani
Published: June 2022

Dysregulated blood lipid levels sit at the nexus of cardiometabolic disorders and are major predictors of human cardiovascular health. Using five major lipid traits (HDL-C, LDL-C, non- HDL-C, TC, and TG), a recent genome-wide association study (GWAS) in 1.65 million individuals identified and fine-mapped over 1,000 genetic loci that may be implicated in the etiology of dyslipidemia and related cardiovascular disease. However, a deeper functional understanding of these associations is needed to assess their therapeutic potential as druggable targets. Here we leveraged data from over 98,000 participants of UK Biobank for deep molecular phenotypic refinement and identified 225 lipid risk variants that associated with 168 distinct NMR-derived lipoprotein and metabolic traits, doubling the number of loci that are discoverable when using the five “classical” lipid traits alone. Hypothesis-free testing of >14,000 ratios between metabolite pairs significantly increased statistical power (p-gain) at 72% of the loci, revealing distinct groups of variants with functionally matching NMR-ratios that affect lipoprotein metabolism, transport, and remodeling (LPmtr). We demonstrate how these NMR- trait and -ratio associations can be used in the functional interpretation of the respective lipid risk loci and their evaluation as potential drug targets. Our study reveals a comprehensive picture of the biological roles that the different genetic variants play in LPmtr and supports the emerging view that lipoprotein size and core composition are essential for the understanding, prevention and treatment of lipid-related disorders, beyond the “classical” five major lipid traits currently used in clinical practice.
Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1
Authors: Schwarzer Adrian , Oliveira Matheus , Kleppa Marc-Jens , Slattery Scott D. , Anantha Andy , Cooper Alan , Hannink Mark , Schambach Axel , Dörrie Anneke , Kotlyarov Alexey , Gaestel Matthias , Hembrough Todd , Levine Jedd , Luther Michael , Stocum Michael , Stiles Linsey , Weinstock David , Liesa Marc , Kostura Matthew J.
Published: June 2022

Constitutive activation of the ATF4-mediated integrated stress response (ATF4-ISR) is common in cancer and buffers the metabolic challenges imposed by rapid proliferation. However, hyperactivation of the ISR can induce apoptosis. Here we demonstrate that novel pyrazolo-thiazole derivates activate the mitochondrial protease OMA1 which subsequently induces apoptosis in diffuse large B-cell lymphoma (DLBCL) cells. Apoptosis is dependent on the OMA1 mediated cleavage of DELE1 which leads to activation of HRI and induction of the ATF4 ISR. Screening in 406 cancer cell lines identified an inverse correlation between sensitivity to OMA1 activators and expression of the mitochondrial protein FAM210B. Ectopic overexpression of FAM210B specifically blocks OMA1 activation and apoptosis induction by pyrazolo-thiazole activators in DLBCL. OMA1 activators, including the preclinical candidate BTM-3566, selectively killed ABC, GCB, and double-hit DLBCL lines and induced complete tumor regression across a panel of DLBCL patient-derived xenografts.

Significance

Here we describe a novel class of small molecules that activate the mitochondrial protease OMA1 and induce therapeutic responses in DLBCL preclinical models in vitro and in vivo. OMA1 activation drives apoptosis through ATF4-ISR, an orthogonal mechanism to current therapies.
Development and Effectiveness Testing of a Mobile Health Education Package for Stroke Prevention Among Stroke Survivors
Authors: Odetunde Marufat Oluyemisi , Ibrahim Sekinat Omowumi , Oluwagbade Gideon Tolu , Odole Adesola Christiana , Mbada Chidozie Emmanuel , Komolafe Morenikeji A.
Published: June 2022

Background

Interventions based on social cognitive theory are more patient-centered and focused on principles that can enlighten and encourage adoption of healthy habits. Addressing limited stroke literacy among stroke survivors based on social cognitive theory is an effective means to reduce secondary stroke risk. The use of trending Mobile Health (m-health) devices can be a valuable interventional approach to achieve this through improved stroke literacy.

Objectives

The objectives of this study were to develop and test effectiveness of m-health based educational package for stroke prevention among stroke survivors.

Method

This was a multimodal methodology involving content development and effectiveness testing using Delphi protocol and pretest-posttest design respectively. Development involved items selection, rating and retention; script writing, translation and recording into an audio and video educational packages. Effectiveness testing involved 30 consenting, consecutively assigned SSVs in each of audio (AIG) and video (VIG) intervention group. Stroke literacy was assessed at baseline, 2nd and 4th week post-intervention. Participants’ socio-demographic data were also collected. Data was summarized using descriptive and inferential statistics. Alpha value was set at p<0.05.

Results

Majority of the participants were male (63.3%), over 60 years old (51.7%), hypertensive (83.3%) and had tertiary education (31.7%). Knowledge of stroke risk factors improved between AIG and VIG from baseline (11 23±4 01 and 10.07±3.24) to 2nd week (17 73±0.78 and 15.30±1.78) and 4th week (17.97±0.18 and 16.77±1.01) post-intervention respectively. There were significant differences between the two groups (p<0.01).

Conclusion

Mobile-health education based on social cognitive theory effectively improves stroke literacy among SSVs and should be tested among larger samples in the community.
CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration following radiation-induced injury
Authors: McKendrick John G. , Jones Gareth-Rhys , Elder Sonia S. , Mercer Ella , Magalhaes Marlene S. , Rocchi Cecilia , Hegarty Lizi M. , Johnson Amanda L. , Schneider Christoph , Becher Burkhard , Pridans Clare , Mabbott Neil , Liu Zhaoyuan , Ginhoux Florent , Bajenoff Marc , Gentek Rebecca , Bain Calum C. , Emmerson Elaine
Published: June 2022

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in xerostomia, or chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant cell type in the salivary glands and are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. Yet, the nature and role of macrophages in salivary gland homeostasis and whether or not they contribute to tissue repair/regeneration following injury is not well understood. Here, we have used single cell RNA-seq, multi-parameter flow cytometry and fluorescence microscopy to map the heterogeneity of the salivary gland macrophage compartment throughout development and following radiation-induced injury. We show that there are highly dynamic changes in the composition of the salivary gland macrophage compartment with age, in part due to changes in the ontogeny of these cells, determined using a suite of complementary fate mapping systems. A combination of mutant mice and antibody blockade demonstrates that salivary gland macrophages are dependent on CSF1, but not IL-34 or GM-CSF, for their development and maintenance. Finally, using an in vivo model of radiation-induced salivary gland injury combined with a novel Mafb-specific depletion system, we demonstrate an essential role for macrophages. Without macrophages the clearance of cells with DNA damage, and effective tissue repair following such injury, is severely comprised. Our data, therefore, indicate a strong case for exploring the therapeutic potential of manipulating macrophages in order to promote tissue repair and thus minimise salivary gland dysfunction after radiotherapy.
Conserved reward-mediated, reinforcement-learning mechanisms in Pavlovian and instrumental tasks
Authors: Afshar Neema Moin , Cinotti François , Martin David , Khamassi Mehdi , Calu Donna J. , Taylor Jane R. , Groman Stephanie M.
Published: June 2022

Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based, instrumental tasks parallel those engaged by Pavlovian based behavioral procedures. Recently, computational work has suggested that individual differences in the attribution of incentive salience to reward predictive cues, i.e., sign- and goal-tracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior. Moreover, it is not appreciated if these systems that are characterized computationally using model-free and model-based algorithms are conserved across tasks for individual animals. In the current study, we used a within- subject design to assess sign-tracking and goal-tracking behaviors using a Pavlovian conditioned approach task, and, then characterized behavior using an instrumental multi-stage decision-making (MSDM) task in rats. We hypothesized that both Pavlovian and instrumental learning processes may be driven by common reinforcement-learning mechanisms. Our data confirm that sign-tracking behavior was associated with greater reward-mediated, model-free reinforcement learning and that it was also linked to model-free reinforcement learning in the MSDM task. Computational analyses revealed that Pavlovian model-free updating was correlated with model-free reinforcement learning in the MSDM task. These data provide key insights into the computational mechanisms mediating associative learning that could have important implications for normal and abnormal states.

Significance Statement

Model-free and model-based computations that guide instrumental, decision-making processes may also be recruited in Pavlovian based behavioral procedures. Here, we used a within-subject design to test the hypothesis that both Pavlovian and instrumental learning processes were driven by common reinforcement-learning mechanisms. Sign- tracking and goal-tracking behaviors were assessed in rats using a Pavlovian conditioned approach task, and, then instrumental behavior characterized using a multi- stage decision-making (MSDM) task. We report that sign-tracking behavior was associated with greater model-free, but not model-based, learning in the MSDM task. These data suggest that Pavlovian and instrumental behaviors are driven by conserved reinforcement-learning mechanisms.
Transit-amplifying progenitor with maturation-dependent behavior contributes to epidermal renewal
Authors: Ghuwalewala Sangeeta , Jiang Kevin , Ragi Sara , Shalloway David , Tumbar Tudorita
Published: June 2022

Transit-amplifying progenitor populations with phased behavior have long been postulated as essential to epidermal renewal, but not experimentally observed in vivo. Here we identify a population with bi-phasic behavior using CreER genetic cell-marking in mice for long-term lineage tracing and clonal analysis. Nascent, highly expressing Aspm cells undergo an amplification-phase followed by a timed transition into an extinction-phase, with near complete loss of descending cells from skin. Generalized birth-death modeling of Aspm-CreER and a Dlx1-CreER population that behaves like a stem cell demonstrates neutral competition for both populations, but neutral drift only for the stem cells. This work identifies a long-missing class of non-self-renewing epidermal progenitors with bi-phasic behavior that appears time-dependent as the lineage matures, indicative of a transit-amplifying cell. This has broad implications for understanding cell fate decisions and tissue renewal mechanisms.

One-sentence summary

We identify a long-missing class of non-self-renewing epidermal progenitors with bi-phasic and maturation-dependent behavior in vivo.
A neuron model with unbalanced synaptic weights explains asymmetric effects of ketamine in auditory cortex
Authors: López-Jury Luciana , García-Rosales Francisco , González-Palomares Eugenia , Wetekam Johannes , Hechavarria Julio C.
Published: June 2022

Although new advances in neuroscience allow the study of vocal communication in awake animals, substantial progress in the processing of vocalizations has been made from brains of anaesthetized preparations. Thus, understanding how anaesthetics affect neuronal responses is of paramount importance. Here, we used electrophysiological recordings and computational modelling to study how the auditory cortex of bats responds to vocalizations under anaesthesia and in wakefulness. We found that multifunctional neurons that process echolocation and communication sounds were affected by ketamine anaesthesia in a manner that could not be predicted by known anaesthetic effects. In wakefulness, acoustic contexts (preceding echolocation or communication sequences) led to stimulus-specific suppression of lagging sounds, accentuating neuronal responses to sound transitions. However, under anaesthesia, communication contexts (but not echolocation) led to a global suppression of responses to lagging sounds. Such asymmetric effect was dependent on the frequency composition of the contexts and not on their temporal patterns. We constructed a neuron model that could replicate the data obtainedin vivo. In the model, anaesthesia modulates spiking activity in a channel-specific manner, decreasing responses of cortical inputs tuned to high-frequency sounds and increasing adaptation in the respective cortical synapses. Combined, our findings obtainedin vivoandin silicoreveal that ketamine anaesthesia does not reduce uniformly the neurons’ responsiveness to low and high frequency sounds. This effect depends on combined mechanisms that unbalance cortical inputs and ultimately affect how auditory cortex neurons respond to natural sounds in anaesthetized preparations.
Hotspot ofde novotelomere addition stabilizes linear amplicons in yeast grown in sulfate-limiting conditions
Authors: Hoerr Remington E. , Eng Alex , Payen Celia , Di Rienzi Sara C. , Raghuraman M. K. , Dunham Maitreya J. , Brewer Bonita J. , Friedman Katherine L.
Published: June 2022

Evolution is driven by the accumulation of competing mutations that influence survival. A broad form of genetic variation is the amplification or deletion of DNA (≥50 bp) referred to as copy number variation. In humans, copy number variation may be inconsequential, contribute to minor phenotypic differences, or cause conditions such as birth defects, neurodevelopmental disorders, and cancers. To identify mechanisms that drive copy number variation, we monitored the experimental evolution ofSaccharomyces cerevisiaepopulations grown under sulfate-limiting conditions. Cells with increased copy number of the geneSUL1, which encodes a primary sulfate transporter, exhibit a fitness advantage. Previously, we reported interstitial inverted triplications ofSUL1as the dominant rearrangement in a haploid population. Here, in a diploid population, we find instead that small linear fragments containingSUL1form and are sustained over several generations. Many of the linear fragments are stabilized byde novotelomere addition within a telomere-like sequence nearSUL1(within theSNF5gene). Using an assay that monitors telomerase action following an induced chromosome break, we show that this region acts as a hotspot ofde novotelomere addition and that required sequences map to a region of <250 base pairs. Consistent with previous work showing that association of the telomere-binding protein Cdc13 with internal sequences stimulates telomerase recruitment, mutation of a four-nucleotide motif predicted to associate with Cdc13 abolishesde novotelomere addition. Our study suggests that internal telomere-like sequences that stimulatede novotelomere addition can contribute to adaptation by promoting genomic plasticity.
Targeted gene expression profiling for accurate endometrial receptivity testing
Authors: Meltsov Alvin , Saare Merli , Teder Hindrek , Paluoja Priit , Arffman Riikka , Piltonen Terhi , Laudanski Piotr , Wielgoś Mirosław , Gianaroli Luca , Koel Mariann , Peters Maire , Salumets Andres , Palta Priit , Krjutškov Kaarel
Published: June 2022

STUDY QUESTION

How accurately can a targeted gene expression sequencing assay estimate endometrial receptivity corresponding to the window of implantation?

DESIGN

Endometrial biopsies (n=175) from healthy fertile volunteers (n=66), polycystic ovarian syndrome (PCOS) patients (n=39), and recurrent implantation failure (RIF) patients (n=44) were collected and sequenced with TAC-seq (Targeted Allele Counting by sequencing) method targeting 68 biomarker genes for endometrial receptivity. The expressional profiles were clustered, and differential expression analysis was performed on the model development group, using 63 endometrial biopsies spanning over proliferative (PE, n=18), early-secretory (ESE, n=18), mid-secretory (MSE, n=17) and late-secretory (LSE, n=10) endometrial phases. A quantitative predictor model was trained on the development group and validated on sequenced samples from healthy women, consisting of 52 paired samples taken from ESE and MSE phases and five LSE phase samples from 31 individuals. Finally, the developed test was applied to 44 MSE phase samples gathered from a study group of patients diagnosed with RIF.

RESULTS

The developed assay successfully captures the unique receptivity profile of the endometrium using 68 biomarker genes. When compared to healthy women of the same cycle phase, we did not detect any significant gene expression bias caused by PCOS in PE, ESE, MSE, and LSE samples. In validation samples (n=57), we detected displaced WOI in 1.8% of the samples from fertile women. In the RIF study group, we detected a significantly higher proportion of the samples with shifted WOI than in the validation set of samples from fertile women, 15.9% and 1.8%, respectively.

CONCLUSIONS

The developed beREADY screening test enables highly sensitive and dynamic detection of selected transcriptome biomarkers, providing a quantitative and accurate prediction of endometrial receptivity status for personalised embryo transfer.
Effects of hydrometeorological and other factors on SARS-CoV-2 reproduction number in three contiguous countries of Tropical Andean South America: a spatiotemporally disaggregated time series analysis
Authors: Colston Josh M. , Hinson Patrick , Nguyen Nhat-Lan H. , Chen Yen Ting , Badr Hamada S. , Kerr Gaige H. , Gardner Lauren M. , Martin David N. , Quispe Antonio M. , Schiaffino Francesca , Kosek Margaret N. , Zaitchik Benjamin F.
Published: June 2022

Background

The COVID-19 pandemic has caused societal disruption globally and South America has been hit harder than other lower-income regions. This study modeled effects of 6 weather variables on district-level SARS-CoV-2 reproduction numbers (Rt) in three contiguous countries of Tropical Andean South America (Colombia, Ecuador, and Peru), adjusting for environmental, policy, healthcare infrastructural and other factors.

Methods

Daily time-series data on SARS-CoV-2 infections were sourced from health authorities of the three countries at the smallest available administrative level. Rtvalues were calculated and merged by date and unit ID with variables from a Unified COVID-19 dataset and other publicly available sources for May – December 2020. Generalized additive mixed effects models were fitted.

Findings

Relative humidity and solar radiation were inversely associated with SARS-CoV-2 Rt. Days with radiation above 1,000 KJ/m2saw a 1.3%, and those with humidity above 50%, a 1.0% reduction in Rt. Transmission was highest in densely populated districts, and lowest in districts with poor healthcare access and on days with least population mobility. Temperature, region, aggregate government policy response and population age structure had little impact. The fully adjusted model explained 3.9% of Rtvariance.

Interpretation

Dry atmospheric conditions of low humidity increase, and higher solar radiation decrease district-level SARS-CoV-2 reproduction numbers, effects that are comparable in magnitude to population factors like lockdown compliance. Weather monitoring could be incorporated into disease surveillance and early warning systems in conjunction with more established risk indicators and surveillance measures.

Funding

NASA’s Group on Earth Observations Work Programme (16-GEO16-0047).
GOntact: using chromatin contacts to infer Gene Ontology enrichments for cis-regulatory elements
Authors: Laverré Alexandre , Tannier Eric , Veber Philippe , Necsulea Anamaria
Published: June 2022

While the genomic positions and the patterns of activity of enhancer elements can now be efficiently determined, predicting their target genes remains a difficult task. Although chromatin conformation capture data has revealed numerous long-range regulatory interactions between genes and enhancers, enhancer target genes are still traditionally inferred based on genomic proximity. This approach is at the basis of GREAT, a widely used tool for analyzing the functional significance of sets of cis-regulatory elements. Here, we propose a new tool, named GOntact, which infers regulatory relationships using promoter-capture Hi-C (PCHi-C) data and uses these predictions to derive Gene Ontology enrichments for sets of cis-regulatory elements. We apply GOntact on enhancer and PCHi-C data from human and mouse and show that it generates functional annotations that are coherent with the patterns of activity of enhancers. We find that there is substantial overlap between functional predictions obtained with GREAT and GOntact but that each method can yield unique testable hypotheses, reflecting the underlying differences in target gene assignment. With the increasing availability of high-resolution chromatin contact data, we believe that GOntact can provide better-informed functional predictions for cis-regulatory elements.
Characterizing the diversity of L2/3 human neocortical neurons in epilepsy
Authors: Kushner J. Keenan , Hoffman Paige B. , Brzezinski Christine , Huntsman Molly M. , Alexander Allyson L.
Published: June 2022

In the current study, we performed whole-cell current clamp recordings from human cortical neurons in layer 2/3 of the human neocortex in order to characterize the diversity of L2/3 human neocortical neurons in epileptic foci with various etiologies in order to begin to elucidate the underlying mechanisms of hyperexcitability which are still mostly unknown. We differentiated neuronal subtypes based on their firing patterns and AHP kinetics or epilepsy subtype (malformation of cortical development (MCD) vs. other (non-MCD)). We found that L2/3 pyramidal neurons have diverse firing properties and action potential kinetics, with some neurons looking remarkably similar to LTS interneurons. We also saw that L2/3 pyramidal neurons could be split into those with fast AHPs and those without, medium AHPs (mAHPs). Based on these parameters, we were unable to significantly differentiate neurons based on firing properties indicating that AHP component kinetics alone do not dictate L2/3 pyramidal neuron firing in human epileptic cortical slices. We also report significant differences in intrinsic properties between MCD and non-MCD and control L2/3 pyramidal neurons and are the first to characterize that wash on of the proconvulsant drug, 4-aminopyridine (4-AP), leads to increased AP duration, less firing rate (FR) accommodation, and slowed down AHPs. Overall, the present study is the first to characterize the large variability of L2/3 human neocortical pyramidal neurons, to compare between L2/3 pyramidal neurons within the epileptic foci between MCD and non-MCD cases, to use control tissue from tumor patients without incidence of seizure, and to determine the influence of 4-AP on L2/3 pyramidal neuron intrinsic properties.
Estimating Speed-Accuracy Trade-offs to Evaluate and Understand Closed-Loop Prosthesis Interfaces
Authors: Mamidanna Pranav , Dideriksen Jakob L , Dosen Strahinja
Published: June 2022

Objective

Closed-loop prosthesis interfaces, combining electromyography (EMG)-based control with non-invasive supplementary feedback, represent a promising direction to develop the next generation of user prosthesis interfaces. However, we still lack an understanding of how users make use of these interfaces, and how to evaluate competing interfaces. In this study we use the framework of speed accuracy trade-off functions (SAF) to understand, evaluate and compare the performance afforded by two closed-loop user-prosthesis interfaces.

Approach

Ten able-bodied participants and one amputee performed a force matching task in a functional box-and-blocks setup at 3 different speeds. All participants were subject to both interfaces in a crossover fashion with a one-week washout period. Importantly, both interfaces used (identical) direct proportional control but differed in the feedback provided to the participant – EMG feedback vs force feedback. We thereby estimated the SAFs afforded by the two interfaces, and additionally sought to understand how participants planned and executed the task in the various conditions.

Main results

We found that execution speed significantly influenced the performance, and that EMG feedback afforded better performance overall. Notably, we found that there was a difference in SAF between the two interfaces, with EMG feedback enabling participants to attain higher accuracies faster than Force feedback. Further, both interfaces enabled participants to develop flexible control policies, while EMG feedback also afforded participants to generate smoother more repeatable EMG commands.

Significance

Overall, the results indicate that closed-loop prosthesis interfaces afford subjects to exhibit a wide range of performance, which is affected both by the interface and the execution speed. Thereby, we argue that it is important to consider the speed accuracy trade-offs to rigorously evaluate and compare (closed-loop) user-prosthesis interfaces.
Antigenic escape accelerated by the presence of immunocompromised hosts
Authors: Kumata Ryuichi , Sasaki Akira
Published: June 2022

The repeated emergence of SARS-CoV-2 escape mutants from host immunity has obstructed the containment of the current pandemic and poses a serious threat to humanity. Prolonged infection in immunocompromised patients has received increasing attention as a driver of immune escape, and accumulating evidence suggests that viral genomic diversity and emergence of immune-escape mutants are promoted in immunocompromised patients. However, because immunocompromised patients comprise a small proportion of the host population, whether they have a significant impact on antigenic evolution at the population level is unknown. We used an evolutionary epidemiological model combining antigenic evolution and epidemiological dynamics in host populations with heterogeneity in immune competency to determine the impact of immunocompromised patients on the pathogen evolutionary dynamics of antigenic escape from host immunity. We derived analytical formulae of the speed of antigenic evolution in heterogeneous host populations and found that even a small number of immunocompromised hosts in the population significantly accelerates antigenic evolution. Our results demonstrate that immunocompromised hosts play a key role in viral adaptation at the population level and emphasize the importance of critical care and surveillance of immunocompromised hosts.
The association of catechol-O-methyltransferase genetic polymorphism rs4680 in physical activity among adult women
Authors: Gotlieb Lilach , Ben-Zaken Sigal
Published: June 2022

Background

The aim of the study was to explore associations between COMT A/G rs4680 polymorphisms and physical activity (PA) among healthy middle-aged women. PA is a multifactorial trait in which dopamine plays a pivotal role. The enzyme catecholamine O-methyl transferase (COMT) degrades dopamine in the synaptic area. The COMT rs4680 genetic polymorphism results in either COMT Met allele or COMT Val allele. This functional polymorphism causes differences in enzyme activity with low enzymatic activity (and higher dopamine levels), associated with the Met allele; high enzymatic activity is associated with the Val allele.

Method

Ninety healthy women, aged 47+5.5 years from similar demographic backgrounds, participated in the study. PA engagement was assessed by the BAECKA questionnaire of habitual physical activity PA. Genomic DNA was extracted from buccal epithelial cells for COMT rs4680 analysis.

Results

Despite a similar demographic background of the participants, a large variance was found in all PA indexes. A-allele carriers’ prevalence was the significantly higher (83%) among highly active women compared to its prevalence among moderate (64%) and low (47%) active women.

Conclusions

It seems that COMT A/G rs4680 A-allele carriers might be associated with a relatively high rate of PA practitioners in general and running in particular