bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective Study on the Effect of the Timing of Exposure on Confidence Level in Applying to Physical Medicine and Rehabilitation Residency Programs
Authors: Kim Soojin , Fry Alexandra , Kim Dae Hyun , Kezar Laura B.
Published: May 2021

Residency specialty choice, a complex decision-making process, is often influenced by confidence level built upon knowledge, experience, and fit with the specialty. Despite the need for physiatrists with population growth, especially people with disability and older patients, limited growth in the number of residency positions and delayed exposure to the field of physical medicine and rehabilitation potentially contribute to a lack of confidence in pursuing physical medicine and rehabilitation. Early introduction to a specialty has been shown to impact specialty selection. Thus, this study aims to explore the impact of timing of exposure to physiatry on the confidence level of physical medicine and rehabilitation residents in their specialty choice. A survey for current physical medicine and rehabilitation residents was developed and distributed to residency program directors with a request to forward it to all residents. The response rate was low at 13%; however, the results provide a window into the experience of today’s medical and premedical students. Interestingly, of the 175 respondents, a similar number reported first exposure to physiatry during third year and before medical school. In addition, earlier exposure was associated with higher confidence levels in specialty choice, the most powerful factor being the exposure to the specialty before starting medical school or during the preclinical years in medical school. These findings highlight opportunities to improve the physiatry workforce by providing earlier exposure to the specialty, even before medical school. Based on the results of the survey and ongoing discussions among medical students, residents, and faculty leaders, the authors review current recruitment efforts and new ideas.
Proposed Decannulation Criteria for COVID-19 Patients
Authors: Giménez Gloria C. , Müller-Thies Marlene , Prado Francisco J. , Bach John R.
Published: May 2021

A 66-yr-old man had been intubated for 21 days for severe COVID-19 infection. He then underwent tracheotomy, retained the tube for 2 mos, and then was discharged home on 10 liters of O2/min breathing via a tracheostomy collar. We were consulted for tracheostomy tube decannulation. Mechanical insufflation-exsufflation was used via the tracheostomy tube to clear secretions, increase vital capacity, and normalize O2 saturation. He practiced nasal and mouthpiece noninvasive ventilatory support once a capped fenestrated cuffless tracheostomy tube was placed, although he did not need noninvasive ventilatory support after decannulation. He was decannulated despite O2 dependence. Although he required antibiotics for almost 3 mos before decannulation and after it, he had no further episodes of lung infection for at least the next 4 mos from the point of decannulation.
Assessment of Myofascial Trigger Points via Imaging
Authors: Mazza Dario F. , Boutin Robert D. , Chaudhari Abhijit J.
Published: May 2021

This study systematically reviewed the published literature on the objective characterization of myofascial pain syndrome and myofascial trigger points using imaging methods. PubMed, Embase, Ovid, and the Cochrane Library databases were used, whereas citation searching was conducted in Scopus. Citations were restricted to those published in English and in peer-reviewed journals between 2000 and 2021. Of 1762 abstracts screened, 69 articles underwent full-text review, and 33 were included. Imaging data assessing myofascial trigger points or myofascial pain syndrome were extracted, and important qualitative and quantitative information on general study methodologies, study populations, sample sizes, and myofascial trigger point/myofascial pain syndrome evaluation were tabulated. Methodological quality of eligible studies was assessed based on the Quality Assessment of Diagnostic Accuracy Studies criteria. Biomechanical properties and blood flow of active and latent myofascial trigger points assessed via imaging were found to be quantifiably distinct from those of healthy tissue. Although these studies show promise, more studies are needed. Future studies should focus on assessing diagnostic test accuracy and testing the reproducibility of results to establish the best performing methods. Increasing methodological consistency would further motivate implementing imaging methods in larger clinical studies. Considering the evidence on efficacy, cost, ease of use and time constraints, ultrasound-based methods are currently the imaging modalities of choice for myofascial pain syndrome/myofascial trigger point assessment.
Creating a Resident Research Track in Synergy With the Rehabilitation Medicine Scientist Training Program
Authors: Sherrier Matthew , Schroeder Allison , Davis W. Austin , Boninger Michael , Helkowski Wendy M.
Published: May 2021

Physician scientists play an important role in the translation of research findings to patient care; however, their training faces numerous challenges. Residency research track programs represent an opportunity to facilitate the training of future physician scientists in physical medicine and rehabilitation, although optimal program organization and long-term outcomes remain unknown. The Rehabilitation Medicine Scientist Training Program is a National Institutes of Health–funded program aimed at addressing the shortage of physician researchers in the field of physical medicine and rehabilitation by providing instruction, mentorship, and networking opportunities for a successful research career. While the opportunities provided through the Rehabilitation Medicine Scientist Training Program provide critical education and guidance at a national level, trainees are most successful with availability of strong local support and mentorship. The purpose of this article was to present a realistic and easily applicable structure for a physical medicine and rehabilitation residency research track that can be used in concert with the Rehabilitation Medicine Scientist Training Program.
Associations of Hepatosteatosis With Cardiovascular Disease in HIV-Positive and HIV-Negative Patients: The Liverpool HIV–Heart Project
Authors: Heseltine Thomas , Murray Scott , Ortega-Martorell Sandra , Olier Ivan , Lip Gregory Y.H. , Khoo Saye
Published: May 2021

Background:

Hepatosteatosis (HS) has been associated with cardiovascular disorders in the general population. We sought to investigate whether HS is a marker of cardiovascular disease (CVD) risk in HIV-positive individuals, given that metabolic syndrome is implicated in the increasing CVD burden in this population.

Aims:

To investigate the association of HS with CVD in HIV-positive and HIV-negative individuals.

Methods and results:

We analyzed computed tomography (CT) images of 1306 subjects of whom 209 (16%) were HIV-positive and 1097 (84%) HIV-negative. CVD was quantified by the presence of coronary calcification from both dedicated cardiac CT and nondedicated thorax CT. HS was diagnosed from CT data sets in those with noncontrast dedicated cardiac CT and those with venous phase liver CT using previously validated techniques. Previous liver ultrasound was also assessed for the presence of HS. The HIV-positive group had lower mean age (P < 0.005), higher proportions of male sex (P < 0.005), and more current smokers (P < 0.005). The HIV-negative group had higher proportions of hypertension (P < 0.005), type II diabetes (P = 0.032), dyslipidemia (P < 0.005), statin use (P = 0.008), and HS (P = 0.018). The prevalence of coronary calcification was not significantly different between the groups. Logistic regression (LR) demonstrated that in the HIV-positive group, increasing age [odds ratio (OR): 1.15, P < 0.005], male sex (OR 3.37, P = 0.022), and HS (OR 3.13, P = 0.005) were independently associated with CVD. In the HIV-negative group, increasing age (OR: 1.11, P < 0.005), male sex (OR 2.97, P < 0.005), current smoking (OR 1.96, P < 0.005), and dyslipidemia (OR 1.66, P = 0.03) were independently associated with CVD. Using a machine learning random forest algorithm to assess the variables of importance, the top 3 variables of importance in the HIV-positive group were age, HS, and male sex. In the HIV-negative group, the top 3 variables were age, hypertension and male sex. The LR models predicted CVD well, with the mean area under the receiver operator curve (AUC) for the HIV-positive and HIV-negative cohorts being 0.831 [95% confidence interval (CI): 0.713 to 0.928] and 0.786 (95% CI: 0.735 to 0.836), respectively. The random forest models outperformed LR models, with a mean AUC in HIV-positive and HIV-negative populations of 0.877 (95% CI: 0.775 to 0.959) and 0.828 (95% CI: 0.780 to 0.873) respectively, with differences between both methods being statistically significant.

Conclusion:

In contrast to the general population, HS is a strong and independent predictor of CVD in HIV-positive individuals. This suggests that metabolic dysfunction may be attributable to the excess CVD risk seen with these patient groups. Assessment of HS may help accurate quantification of CVD risk in HIV-positive patients.
Longitudinal Changes in Sex Hormone–Binding Globulin in Men With HIV
Authors: Pena Dias Jenny , Haberlen Sabina A. , Dobs Adrian S. , Lake Jordan E. , Palella Frank J. , Kingsley Lawrence A. , Price Jennifer C. , Basaria Shehzad , Varadhan Ravi , Margolick Joseph B. , Thio Chloe L. , Brown Todd T.
Published: May 2021

Background:

Sex hormone–binding globulin (SHBG) is a glycoprotein that regulates sex hormone bioavailability and increases with age in the general population. SHBG concentrations are higher in people with HIV, a population in whom accelerated aging has been hypothesized. It is unclear whether longitudinal changes in SHBG increase over time and differ by HIV serostatus.

Methods:

In a longitudinal study, SHBG was measured in 182 men with HIV (MWH) and 267 men without HIV (seronegative) from the Multicenter AIDS Cohort Study and matched for age, race, site, and time, with ≥2 SHBG serum samples over the 10 years after HAART initiation. Multivariable linear mixed-effects regression models were used to evaluate whether log-transformed SHBG [ln(SHBG)] and its rate of change differed by HIV serostatus.

Results:

At baseline, the mean age in MWH was similar to that in HIV-seronegative men (51 ± 5 vs 49 ± 6 years). However, SHBG mean values were higher in MWH compared with those in HIV-seronegative men (65.6 ± 48.8 vs. 45.4 ± 22 nmol/L, P < 0.001). In a fully adjusted model, SHBG increased over time and at a faster rate in MWH compared with that in HIV-seronegative men: [2.0%/year (95% CI: 1.4 to 2.7) vs 1.3%/year (95% CI: 0.8 to 1.8), respectively, P = 0.038]. Among MWH, higher SHBG concentrations were significantly associated with lower CD4+ T-cell count [β= −0.02 (95% CI: −0.03 to −0.0002), P < 0.05], fewer cumulative years on zidovudine [β = −0.027 (95% CI: −0.045 to −0.009), P < 0.001], and greater cumulative years on nonnucleoside reverse transcriptase inhibitors drugs [β = 0.022 (95% CI: 0.0006 to 0.04), P < 0.05].

Conclusions:

Aging-related increases in SHBG were faster in MWH compared with those in HIV-seronegative men and were related to poorer immunologic status and antiretroviral medication exposure. The mechanisms and consequences of these findings require further investigation.
Trends in Follow-Up Visits Among People Living With HIV: Results From the TREAT Asia and Australian HIV Observational Databases
Authors: Jiamsakul Awachana , Boyd Mark , Choi Jun Yong , Edmiston Natalie , Kumarasamy Nagalingeswaran , Hutchinson Jolie , Law Matthew , Ditangco Rossana ,   on behalf of the TREAT Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD) of IeDEA Asia-Pacific
Published: May 2021

Background:

Less frequent follow-up visits may reduce the burden on people living with HIV (PLHIV) and health care facilities. We aimed to assess trends in follow-up visits and survival outcomes among PLHIV in Asia and Australasia.

Settings:

PLHIV enrolled in TREAT Asia HIV Observational Database (TAHOD) or Australian HIV Observational Database (AHOD) from 2008 to 2017 were included.

Methods:

Follow-up visits included laboratory testing and clinic visit dates. Visit rates and survival were analyzed using repeated measure Poisson regression and competing risk regression, respectively. Additional analyses were limited to stable PLHIV with viral load <1000 copies/mL and self-reported adherence ≥95%.

Results:

We included 7707 PLHIV from TAHOD and 3289 PLHIV from AHOD. Visit rates were 4.33 per person-years (/PYS) in TAHOD and 3.68/PYS in AHOD. Both TAHOD and AHOD showed decreasing visit rates in later calendar years compared with that in years 2008–2009 (P < 0.001 for both cohorts). Compared with PLHIV with 2 visits, those with ≥4 visits had poorer survival: TAHOD ≥4 visits, subhazard ratio (SHR) = 1.88, 95% confidence interval (CI): 1.16 to 3.03, P = 0.010; AHOD ≥4 visits, SHR = 1.80, 95% CI: 1.10 to 2.97, P = 0.020; whereas those with ≤1 visit showed no differences in mortality. The association remained evident among stable PLHIV: TAHOD ≥4 visits, SHR = 5.79, 95% CI: 1.84 to 18.24, P = 0.003; AHOD ≥4 visits, SHR = 2.15, 95% CI: 1.20 to 3.85, P = 0.010, compared with 2 visits.

Conclusions:

Both TAHOD and AHOD visit rates have declined. Less frequent visits did not affect survival outcomes; however, poorer health possibly leads to increased follow-up and higher mortality. Reducing visit frequency may be achievable among PLHIV with no other medical complications.
Brief Report: No Difference in Urine Tenofovir Levels in Patients Living With HIV on Unboosted Versus Dose-Adjusted Boosted Tenofovir Alafenamide
Authors: Johnson Kelly A. , Okochi Hideaki , Glidden David V. , Gandhi Monica , Spinelli Matthew
Published: May 2021

Background:

Tenofovir alafenamide (TAF) is increasingly used in HIV treatment, with or without agents that require pharmacologic boosters such as ritonavir/cobicistat. Boosters increase TAF levels, so the TAF dose is lowered in single-pill combinations. We hypothesized that individuals on dose-adjusted boosted TAF would have similar urine tenofovir (TFV) concentrations to those on unboosted TAF.

Setting/Methods:

We collected urine samples from patients with HIV on TAF, with evidence of virologic suppression and high self-reported adherence at 2 San Francisco clinics from June 2019 to January 2020. We measured urine TFV levels by liquid chromatography/tandem mass spectrometry and used linear regression to compare natural log-transformed urine TFV levels for patients on boosted versus unboosted TAF.

Results:

Our analysis included 30 patients on unboosted TAF (25 mg daily TAF) and 15 on boosted TAF (12 on 10 mg daily TAF and 3 on 25 mg daily TAF). Patients on unboosted vs. boosted TAF had similar baseline age, weight, sex, and creatinine. In unadjusted univariate linear regression, there were no significant differences in urine TFV levels based on presence/absence of boosting after TAF dose reduction to 10 mg (geometric mean ratio 1.07; 95% confidence interval: 0.53 to 2.16). This finding was unchanged in adjusted analysis.

Conclusions:

No significant differences in urine TFV levels were seen for patients on unboosted vs. boosted dose-reduced TAF. These results have important implications for our forthcoming point-of-care urine immunoassay for TAF, implying that separate adherence cutoffs will not be necessary for patients on boosters and dose-reduced TAF. A single POC TAF immunoassay will, thus, support monitoring on most TAF-based antiretroviral therapy.
A Systematic Review and Meta-analysis of Randomized Controlled Trials Comparing Intraoperative Red Blood Cell Transfusion Strategies
Authors: Lenet Tori , Baker Laura , Park Lily , Vered Michael , Zahrai Amin , Shorr Risa , Davis Alexandra , McIsaac Daniel I. , Tinmouth Alan , Fergusson Dean A. , Martel Guillaume
Published: May 2021

Objective:

The objective of this work was to carry out a meta-analysis of RCTs comparing intraoperative RBC transfusion strategies to determine their impact on postoperative morbidity, mortality, and blood product use.

Summary of Background Data:

RBC transfusions are common in surgery and associated with widespread variability despite adjustment for casemix. Evidence-based recommendations guiding RBC transfusion in the operative setting are limited.

Methods:

The search strategy was adapted from a previous Cochrane Review. Electronic databases were searched from January 2016 to February 2021. Included studies from the previous Cochrane Review were considered for eligibility from before 2016. RCTs comparing intraoperative transfusion strategies were considered for inclusion. Co-primary outcomes were 30-day mortality and morbidity. Secondary outcomes included intraoperative and perioperative RBC transfusion. Meta-analysis was carried out using random-effects models.

Results:

Fourteen trials (8641 patients) were included. One cardiac surgery trial accounted for 56% of patients. There was no difference in 30-day mortality [relative risk (RR) 0.96, 95% confidence interval (CI) 0.71–1.29] and pooled postoperative morbidity among the studied outcomes when comparing restrictive and liberal protocols. Two trials reported worse composite outcomes with restrictive triggers. Intraoperative (RR 0.53, 95% CI 0.43–0.64) and perioperative (RR 0.70, 95% CI 0.62–0.79) blood transfusions were significantly lower in the restrictive group compared to the liberal group.

Conclusions:

Intraoperative restrictive transfusion strategies decreased perioperative transfusions without added postoperative morbidity and mortality in 12/14 trials. Two trials reported worse outcomes. Given trial design and generalizability limitations, uncertainty remains regarding the safety of broad application of restrictive transfusion triggers in the operating room. Trials specifically designed to address intraoperative transfusions are urgently needed.
Prehospital shock index and systolic blood pressure are highly specific for pediatric massive transfusion
Authors: Zhu Caroline S. , Braverman Maxwell , Goddard Sabrina , McGinity Ashley C. , Pokorny Douglas , Cotner-Pouncy Tracy , Eastridge Brian J. , Epley Sondra , Greebon Leslie J. , Jonas Rachelle B. , Liao Lillian , Nicholson Susannah E. , Schaefer Randall , Stewart Ronald M. , Winckler Christopher J. , Jenkins Donald H.
Published: May 2021

BACKGROUND

While massive transfusion protocols (MTPs) are associated with decreased mortality in adult trauma patients, there is limited research on the impact of MTP on pediatric trauma patients. The purpose of this study was to compare pediatric trauma patients requiring massive transfusion with all other pediatric trauma patients to identify triggers for MTP activation in injured children.

METHODS

Using our level I trauma center’s registry, we retrospectively identified all pediatric trauma patients from January 2015 to January 2018. Massive transfusion (MT) was defined as infusion of 40 mL/kg of blood products in the first 24 hours of admission. Patients missing prehospital vital sign data were excluded from the study. We retrospectively collected data including demographics, blood utilization, variable outcome data, prehospital vital signs, prehospital transport times, and Injury Severity Scores. Statistical significance was determined using Mann-Whitney U test and χ2 test. p Values of less than 0.05 were considered significant.

RESULTS

Thirty-nine (1.9%) of the 2,035 pediatric patients met the criteria for MT. All-cause mortality in MT patients was 49% (19 of 39 patients) versus 0.01% (20 of 1996 patients) in non-MT patients. The two groups significantly differed in Injury Severity Score, prehospital vital signs, and outcome data.

Both systolic blood pressure (SBP) of <100 mm Hg and shock index (SI) of >1.4 were found to be highly specific for MT with specificities of 86% and 92%, respectively. The combination of SBP of <100 mm Hg and SI of >1.4 had a specificity of 94%. The positive and negative predictive values of SBP of <100 mm Hg and SI of >1.4 in predicting MT were 18% and 98%, respectively. Based on positive likelihood ratios, patients with both SBP of <100 mm Hg and SI of >1.4 were 7.2 times more likely to require MT than patients who did not meet both of these vital sign criteria.

CONCLUSION

Pediatric trauma patients requiring early blood transfusion present with lower blood pressures and higher heart rates, as well as higher SIs and lower pulse pressures. We found that SI and SBP are highly specific tools with promising likelihood ratios that could be used to identify patients requiring early transfusion.

LEVEL OF EVIDENCE

Therapeutic/care management, level V.
Advanced prehospital resuscitative care: Can we identify trauma patients who might benefit?
Authors: Irfan Ahmer , Juneja Kavina , Abraham Peter , Smedley W. Andrew , Stephens Shannon W. , Griffin Russell L. , Ward William , Hallmark Robert , Qasim Zaffer , Carroll Shannon L. , Reiff Donald , Holcomb John B. , Jansen Jan O.
Published: May 2021

BACKGROUND

Uncontrolled truncal hemorrhage remains the most common cause of potentially preventable death after injury. The notion of earlier hemorrhage control and blood product resuscitation is therefore attractive. Some systems have successfully implemented prehospital advanced resuscitative care (ARC) teams. Early identification of patients is key and is reliant on rapid decision making and communication. The purpose of this simulation study was to explore the feasibility of early identification of patients who might benefit from ARC in a typical US setting.

METHODS

We conducted a prospective observational/simulation study at a level I trauma center and two associated emergency medical service (EMS) agencies over a 9-month period. The participating EMS agencies were asked to identify actual patients who might benefit from the activation of a hypothetical trauma center-based ARC team. This decision was then communicated in real time to the study team.

RESULTS

Sixty-three patients were determined to require activation. The number of activations per month ranged from 2 to 15. The highest incidence of calls occurred between 4 pm to midnight. Of the 63 patients, 33 were transported to the trauma center. The most common presentation was with penetrating trauma. The median age was 27 years (interquartile range, 24–45 years), 75% were male, and the median Injury Severity Score was 11 (interquartile range, 7–20). Based on injury patterns, treatment received, and outcomes, it was determined that 6 (18%) of 33 patients might have benefited from ARC. Three of the patients died en-route to or soon after arrival at the trauma center.

CONCLUSION

The prehospital identification of patients who might benefit from ARC is possible but faces challenges. Identifying strategies to adapt existing processes may allow better utilization of the existing infrastructure and should be a focus of future efforts.

LEVEL OF EVIDENCE

Prognostic/Epidemiologic, level III.
SARS-CoV-2 Beta Variant Substitutions Alter Spike Glycoprotein Receptor Binding Domain Structure and Stability
Authors: Moss Daniel L. , Rappaport Jay
Published: May 2021

The emergence of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and the subsequent COVID-19 pandemic has visited a terrible cost on the world in the forms of disease, death, and economic turmoil. The rapid development and deployment of extremely effective vaccines against SARS-CoV-2 have seemingly brought within reach the end of the pandemic. However, the virus has acquired mutations; and emerging variants of concern (VOC) are more infectious and reduce the efficacy of existing vaccines. While promising efforts to combat these variants are underway, the evolutionary pressures leading to these variants are poorly understood. To that end, here we have studied the effects on the structure and function of the SARS-CoV-2 spike glycoprotein receptor-binding domain of three amino-acid substitutions found in several variants of concern, including alpha (B.1.1.7), beta (B.1.351), and gamma (P.1). We found that these substitutions alter the RBD structure, stability, and ability to bind to ACE2, in such a way as to possibly have opposing and compensatory effects. These findings provide new insights into how these VOC may have been selected for infectivity while maintaining the structure and stability of the receptor binding domain.
Regulatory interplay between RNase III and asRNAs in E. coli; the case of AsflhD and the master regulator of motility, flhDC
Authors: Lejars Maxence , Caillet Joël , Guillier Maude , Plumbridge Jacqueline , Hajnsdorf Eliane
Published: May 2021

In order to respond to ever-changing environmental cues, bacteria have evolved resilient regulatory mechanisms controlling gene expression. At the post-transcriptional level, this is achieved by a combination of RNA-binding proteins, such as ribonucleases (RNases) and RNA chaperones, and regulatory RNAs including antisense RNAs (asRNAs). AsRNAs bound to their complementary mRNA are primary targets for the double-strand-specific endoribonuclease, RNase III. By comparing primary and processed transcripts in an rnc strain, mutated for RNase III, and its isogenic wild type strain, we detected several asRNAs. We confirmed the existence of RNase III-sensitive asRNA for crp, ompR, phoP and flhD genes, encoding master regulators of gene expression. AsflhD, the asRNA to the master regulator of motility flhDC, is slightly induced under heat-shock conditions in a sigma24 (RpoE)-dependent manner. We demonstrate that expression of AsflhD asRNA is involved in the transcriptional attenuation of flhD and thus participates in the control of the whole motility cascade. This study demonstrates that AsflhD and RNase III are additional players in the complex regulation ensuring a tight control of flagella synthesis and motility.

Importance

The importance of asRNAs in the regulation of gene expression has long been underestimated. Here, we confirm that asRNAs can be part of layered regulatory networks since some are found opposite to genes encoding global regulators. In particular, we show how an antisense RNA (AsflhD) to the gene expressing a transcription factor serving as the primary regulator of bacterial swimming motility (FlhD4C2) is involved in the transcriptional attenuation of flhD, which in turn impacts the expression of other genes of the motility cascade. The role of AsflhD highlights the importance of discrete fine-tuning mechanisms in the control of complex regulatory networks.
Computational modelling of COVID-19: A study of compliance and superspreaders
Authors: Lee Faith , Ortiz Maria Perez , Shawe-Taylor John
Published: May 2021

Background

The success of social distancing implementations of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) depends heavily on population compliance. Mathematical modelling has been used extensively to assess the rate of viral transmission from behavioural responses. Previous epidemics of SARS-Cov-2 have been characterised by superspreaders, a small number of individuals who transmit a disease to a large group of individuals, who contribute to the stochasticity (or randomness) of transmission compared to other pathogens such as Influenza. This growing evidence proves an urgent matter to understand transmission routes in order to target and combat outbreaks.

Objective

To investigate the role of superspreaders in the rate of viral transmission with various levels of compliance.

Method

A SEIRS inspired social network model is adapted and calibrated to observe the infected links of a general population with and without superspreaders on four compliance levels. Local and global connection parameters are adjusted to simulate close contact networks and travel restrictions respectively and each performance assessed. The mean and standard deviation of infections with superspreaders and non-superspreaders were calculated for each compliance level.

Results

Increased levels of compliance of superspreaders proves a significant reduction in infections. Assuming long-lasting immunity, superspreaders could potentially slow down the spread due to their high connectivity.

Discussion

The main advantage of applying the network model is to capture the heterogeneity and locality of social networks, including the role of superspreaders in epidemic dynamics. The main challenge is the immediate attention on social settings with targeted interventions to tackle superspreaders in future empirical work.

Conclusion

Superspreaders play a central role in slowing down infection spread following compliance guidelines. It is crucial to adjust social distancing measures to prevent future outbreaks accompanied by population-wide testing and effective tracing.
Distinct immune responses in patients infected with influenza or SARS-CoV-2, and in COVID-19 survivors, characterised by transcriptomic and cellular abundance differences in blood
Authors: Legebeke Jelmer , Lord Jenny , Penrice-Randal Rebekah , Vallejo Andres F. , Poole Stephen , Brendish Nathan J. , Dong Xiaofeng , Hartley Catherine , Holloway John W. , Lucas Jane S. , Williams Anthony P. , Wheway Gabrielle , Strazzeri Fabio , Gardner Aaron , Schofield James P.R. , Skipp Paul J. , Hiscox Julian A. , Polak Marta E. , Clark Tristan W. , Baralle Diana
Published: May 2021

Background

The worldwide pandemic caused by SARS-CoV-2 has claimed millions of lives and has had a profound effect on global life. Understanding the pathogenicity of the virus and the body’s response to infection is crucial in improving patient management, prognosis, and therapeutic strategies. To address this, we performed functional transcriptomic profiling to better understand the generic and specific effects of SARS-CoV-2 infection.

Methods

Whole blood RNA sequencing was used to profile a well characterised cohort of patients hospitalised with COVID-19, during the first wave of the pandemic prior to the availability of approved COVID-19 treatments and who went on to survive or die of COVID-19, and patients hospitalised with influenza virus infection between 2017 and 2019. Clinical parameters between patient groups were compared, and several bioinformatic tools were used to assess differences in transcript abundances and cellular composition.

Results

The analyses revealed contrasting innate and adaptive immune programmes, with transcripts and cell subsets associated with the innate immune response elevated in patients with influenza, and those involved in the adaptive immune response elevated in patients with COVID-19. Topological analysis identified additional gene signatures that differentiated patients with COVID-19 from patients with influenza, including insulin resistance, mitochondrial oxidative stress and interferon signalling. An efficient adaptive immune response was furthermore associated with patient survival, while an inflammatory response predicted death in patients with COVID-19. A potential prognostic signature was found based on a selection of transcript abundances, associated with circulating immunoglobulins, nucleosome assembly, cytokine production and T cell activation, in the blood transcriptome of COVID-19 patients, upon admission to hospital, which can be used to stratify patients likely to survive or die.

Conclusions

The results identified distinct immunological signatures between SARS-CoV-2 and influenza, prognostic of disease progression and indicative of different targeted therapies. The altered transcript abundances associated with COVID-19 survivors can be used to predict more severe outcomes in patients with COVID-19.
Seven-day COVID-19 quarantine may be too short: assessing post-quarantine transmission risk in four university cohorts
Authors: Liu Andrew Bo , Davidi Dan , Landsberg Hannah Emily , Francesconi Maria , Platt Judy T. , Nguyen Giang T. , Yune Sehyo , Deckard Anastasia , Puglin Jamie , Haase Steven B. , Hamer Davidson H. , Springer Michael
Published: May 2021

Background

Despite rising rates of vaccination, quarantine remains critical to control SARS-CoV-2 transmission. COVID-19 quarantine length around the world varies in part due to the limited amount of empirical data.

Objective

To assess post-quarantine transmission risk for various quarantine lengths.

Design

Cohort study.

Setting

Four US universities, September 2020 to February 2021.

Participants

3,641 students and staff were identified as close contacts to SARS-CoV-2-positive individuals. They entered strict or non-strict quarantine and were tested on average twice per week for SARS-CoV-2. Strict quarantine included designated housing with a private room, private bathroom and meal delivery. Non-strict quarantine potentially included interactions with household members.

Measurements

Dates of exposure and last negative and first positive tests during quarantine.

Results

Of the 418 quarantined individuals who eventually converted to positive, 11%, 4.2%, and 1.2% were negative and asymptomatic on days 7, 10 and 14, respectively. The US CDC recently shortened its quarantine guidance from 14 to 7 days based on estimates of 2.3-8.6% post-quarantine transmission risk at day 7, significantly below the 11% risk we report here. Notably, 6% of individuals tested positive after day 7 in strict quarantine, versus 14% in non-strict quarantine. Ongoing exposure during quarantine likely explains the higher rate of COVID-19 in non-strict quarantine.

Limitations

Quarantine should be longer for individuals using antigen testing, given antigen testing’s lower sensitivity than qPCR. Results apply in settings in which SAR-CoV-2 variants do not affect latent period.

Conclusions

To maintain the 5% transmission risk that the CDC used in its guidance, our data suggest that quarantine with qPCR testing 1 day before intended release should extend to 10 days for non-strict quarantine.

Funding Source

None.
Calorie Restriction in combination with GABA: improved glycaemic control in type 2 diabetes mouse model
Authors: Rathwa Nirali , Parmar Nishant , Palit Sayantani Pramanik , Patel Roma , Bhaskaran Ravi Shankar , Ramachandran A. V. , Begum Rasheedunnisa
Published: May 2021

Aim

Dysfunctional adipocytes and β-cells are crucial in the advancement of obesity-induced type 2 diabetes (T2D). Calorie restriction (CR) improves insulin sensitivity and fasting blood glucose (FBG) levels, while γ-aminobutyric acid (GABA), a neurotransmitter secreted by β-cells, exerts regenerative effects.

Methods

High-fat diet (HFD) and streptozotocin (STZ) induced T2D mouse model was used to assess the effect of CR and GABA combination therapy. The mice were fed with CR diet (30% reduction of HFD) and treated with GABA (2.5 mg/kg i.p) daily for 5 weeks. Assessment of FBG, body weight (BW), insulin sensitivity, glucose tolerance, and estimation of plasma insulin and lipid profile were carried out by standard methods. The mRNA expression of target genes [liver (glucoregulatory enzymes), adipose tissue (lipid metabolism markers) and skeletal muscle (mitochondrial biogenesis markers)] was assessed by SYBR Green-qPCR. Oxygen consumption rate for mitochondrial complex I, II and III was measured in skeletal muscle using Oxytherm Clark-type oxygen electrode. The effect of monotherapies and combination treatment on pancreatic β-cell regeneration and apoptosis was analysed by IHC.

Results

CR+GABA group showed significant reduction in FBG levels, improved lipid profile and whole-body insulin responsiveness as indicated by increased insulin levels, insulin sensitivity and glucose tolerance compared to the monotherapies. The transcript expression profile of glucoregulatory enzymes in the liver showed significant reduction in G6Pase, PEPCK, Glycogen Phosphorylase and increased GCK expression in CR+GABA group as compared to the monotherapies The ACC and ATG expression was up-regulated in adipose tissue; and significant increase in SIRT-1, PGC-1α and TFAM expression with up-regulated mitochondrial complex I and III activities was observed in CR+GABA group as compared to the monotherapies. Percentage of BrdU/Insulin and PDX1/Ngn3/Insulin co-positive cells was significantly higher in CR+GABA treated group than the monotherapy and HFD+STZ groups. Finally, there was a significant reduction in TUNEL/Insulin co-positive cells suggesting reduced apoptosis in CR+GABA treated group.

Conclusion

Our results suggest that CR in combination with GABA ameliorates T2D in HFD+STZ treated mice, by GABA induced β-cell regeneration and CR mediated insulin sensitivity.
Functional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols
Authors: Bean Björn D.M. , Mulvihill Colleen J. , Garge Riddhiman K. , Boutz Daniel R. , Rousseau Olivier , Floyd Brendan M. , Cheney William , Gardner Elizabeth C. , Ellington Andrew D. , Marcotte Edward M. , Gollihar Jimmy D. , Whiteway Malcolm , Martin Vincent J.J.
Published: May 2021

The yeast Saccharomyces cerevisiae is a powerful tool for studying G protein-coupled receptors (GPCRs) as they can be functionally coupled to its pheromone response pathway. However, some exogenous GPCRs, including the mu opioid receptor, are non-functional in yeast, which may be due to the presence of the fungal sterol ergosterol instead of the animal sterol cholesterol. We engineered yeast to produce cholesterol and introduced the human mu opioid receptor, creating an opioid biosensor capable of detecting the peptide DAMGO at an EC50 of 62 nM and the opiate morphine at an EC50 of 882 nM. Furthermore, introducing mu, delta, and kappa opioid receptors from diverse vertebrates consistently yielded active opioid biosensors that both recapitulated expected agonist binding profiles with EC50s as low as 2.5 nM and were inhibited by the antagonist naltrexone. Additionally, clinically relevant human mu opioid receptor alleles, or variants with terminal mutations, resulted in biosensors that largely displayed the expected changes in activity. We also tested mu opioid receptor-based biosensors with systematically adjusted biosynthetic intermediates of cholesterol, enabling us to relate sterol profiles with biosensor sensitivity. Finally, cholesterol-producing and sterol intermediate biosensor backgrounds were applied to other human GPCRs, resulting in SSTR5, 5-HTR4, FPR1 and NPY1R signaling with varying degrees of cholesterol dependence. Our sterol-optimized platform will be a valuable tool in generating human GPCR-based biosensors, aiding in ongoing receptor deorphanization efforts, and providing a framework for high-throughput screening of receptors and effectors.
Reprogramming adult tendon healing using regenerative neonatal regulatory T cells
Authors: Arvind Varun , Howell Kristen , Huang Alice H.
Published: May 2021

Tendinopathy is a common clinical problem leading to significant musculoskeletal disability. Using a neonatal mouse model of tendon regeneration compared to adult tendon fibrosis, we identified a unique immune profile in regeneration that is associated with type 2 macrophage polarization and regulatory T cell (Treg) infiltration. Neonatal Treg ablation resulted in a dysregulated immune response leading to failed tenocyte recruitment and loss of functional regeneration. Transcriptional profiling of adult and neonatal tendon Tregs revealed distinct type 1 and type 2 immune signatures that facilitate macrophage polarization following injury. Finally, adoptive transfer of mouse and human neonatal Tregs was sufficient to improve functional regeneration, in contrast to adult Treg transfer. Collectively, these studies uncover a critical role for neonatal Tregs in controlling immune polarization to promote an environment permissive for tendon regeneration. Our findings provide a basis for immune modulating therapies to facilitate regenerative adult tendon healing.
Diurnal variation in neuronal chloride levels and seizure susceptibility, in neocortex, reflecting changes in activity of chloride-cation-cotransporters
Authors: Pracucci Enrico , Graham Robert , Alberio Laura , Nardi Gabriele , Cozzolino Olga , Pillai Vinoshene , Saieva Luciano , Walsh Darren , Landi Silvia , Zhang Jinwei , Trevelyan Andrew J. , Ratto Gian-Michele
Published: May 2021

The main inhibitory synaptic currents, gated by gamma-aminobutyric acid (GABA), are mediated by Cl--conducting channels1–3, and are therefore sensitive to changes in the chloride electrochemical gradient. GABAergic activity dictates the neuronal firing range4,5 and timing6–9, which in turn influences the rhythms of the brain, synaptic plasticity, and flow of information in neuronal networks7,10–12. The intracellular chloride concentration [Cl-]i is, therefore, ideally placed to be a regulator of neuronal activity. Chloride levels have been thought to be stable in adult cortical networks, except when associated with pathological activation13–16. Here, we used 2-photon LSSmClopHensor imaging, in anaesthetized young adult mice13, to show that [Cl-] inside pyramidal cells shows a physiological diurnal rhythm, with an approximately 1.8-fold range, equating to an ~15mV positive shift in ECl at times when mice are typically awake (midnight), relative to when they are usually asleep (midday). This change of [Cl-]i alters the stability of cortical networks, as demonstrated by a greater than 3-fold longer latency to seizures induced by 4-aminopyridine at midday, compared to midnight. Importantly, both [Cl-]i and latency to seizure, in night-time experiments, were shifted in line with day-time measures, by inhibition of NKCC1. The redistribution of [Cl-]i reflects diurnal changes in surface expression and phosphorylation states of the cation-chloride-co-transporters, KCC2 and NKCC1, leading to a greatly reduced chloride-extrusion capacity at night (awake period). Our data demonstrate a means by which changes in the biochemical state of neurons are transduced into altered brain states.
Mapping Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells
Authors: Shetty Ankitha , Bhosale Santosh D. , Tripathi Subhash Kumar , Buchacher Tanja , Biradar Rahul , Rasool Omid , Moulder Robert , Galande Sanjeev , Lahesmaa Riitta
Published: May 2021

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell-differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among these, FOSL1 and FOSL2 influence the effector responses of Th17 cells. However, the molecular mechanisms underlying these functions are unclear, owing to the poorly characterized protein interaction networks of these factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification–mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a major fraction of these interactors to be associated with RNA binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17-fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass-spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL factors that potentially govern Th17 cell-differentiation and associated pathologies.
Flexibility of a mammalian lipidome — insights from mouse lipidomics
Authors: Surma Michał A. , Gerl Mathias J. , Herzog Ronny , Helppi Jussi , Simons Kai , Klose Christian
Published: May 2021

Lipidomics has become an indispensable method for the quantitative assessment of lipid metabolism in basic, clinical, and pharmaceutical research. It allows for the generation of information-dense datasets in a large variety of experimental setups and model organisms. Previous studies, mostly conducted in mice (Mus musculus), have shown a remarkable specificity of the lipid compositions of different cell types, tissues, and organs. However, a systematic analysis of the overall variation of the mouse lipidome is lacking. To fill this gap, in the present study, the effect of diet, sex, and genotype on the lipidomes of mouse tissues, organs, and bodily fluids has been investigated. Baseline quantitative lipidomes consisting of 796 individual lipid molecules belonging to 24 lipid classes are provided for 10 different sample types. Furthermore, the susceptibility of lipidomes to the tested parameters is assessed, providing insights into the organ-specific lipidomic plasticity and flexibility. This dataset provides a valuable resource for basic and pharmaceutical researchers working with murine models and complements existing proteomic and transcriptomic datasets. It will inform experimental design and facilitate interpretation of lipidomic datasets.
Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as the primary mechanism of vaccine-induced protection against HIV-1
Authors: Shangguan Shida , Ehrenberg Philip K. , Geretz Aviva , Yum Lauren , Kundu Gautam , May Kelly , Fourati Slim , Nganou-Makamdop Krystelle , Williams LaTonya D. , Sawant Sheetal , Lewitus Eric , Pitisuttithum Punnee , Nitayaphan Sorachai , Chariyalertsak Suwat , Rerks-Ngarm Supachai , Rolland Morgane , Douek Daniel , Gilbert Peter , Tomaras Georgia D. , Michael Nelson , Vasan Sandhya , Thomas Rasmi
Published: May 2021

A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanism for protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial, showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.