bluuebunny/crossref_metadata_2025 huggingface dataset:
Vedolizumab-induced acute interstitial lung injury in a 39-year-old male with ulcerative colitis
Authors: Rizos Evripidis D. , Antonogiannaki Elvira-Markela , Chatzidakis Alexandros , Kallieri Maria , Tsilogianni Zoi , Manali Effrosyni D. , Economopoulos Nikolaos , Triantafyllou Konstantinos , Papiris Spyros A. , Polymeros Dimitrios
Published: June 2021

Vedolizumab, an anti-integrin antibody, is effective for moderate to severe ulcerative colitis and Crohn’s disease treatment with a good safety profile due to its gut selective mechanism of action. Upper respiratory tract vedolizumab adverse events are common; however, they are mild and do not require treatment withdrawal. Herein, we present a 39-year-old patient under vedolizumab treatment for ulcerative colitis who presented acute severe interstitial lung injury that necessitated vedolizumab withdrawal and systemic steroids administration.
Hypoglycemia is an early, independent predictor of bacteremia and in-hospital death in patients with cirrhosis
Authors: Saiman Yedidya , Mahmud Nadim
Published: June 2021

Background and aims

Bacteremia is a common cause of death in patients with cirrhosis and early antimicrobial therapy can be life-saving. Severe liver disease impairs glucose metabolism such that hypoglycemia may be a presenting sign of infection in patients with cirrhosis. We explored this association using granular retrospective data.

Methods

We conducted a case-control analysis from 1 January 2008 to 31 December 17 in the University of Pennsylvania Health System. We identified the first blood culture results from all cirrhosis hospitalizations and obtained detailed vital sign and laboratory data in the 24–72 h prior to culture results. We used multivariable logistic regression to develop models predicting blood culture positivity and in-hospital mortality. We repeated these analyses restricted to normothermic individuals. Restricted cubic splines were used to model nonlinearity in the glucose variable.

Results

We identified 1274 cirrhosis admissions with blood culture results (52.7% positive). In adjusted models, minimum glucose 24–72 h prior to blood culture result date was a significant predictor of blood culture positivity. In particular, glucose levels below 100 mg/dL significantly increased the probability of subsequent positive blood culture (e.g. odds ratio 1.89 for 50 mg/dL vs. 100 mg/dL, P = 0.004). This relationship persisted when restricting the cohort to normothermic individuals. Glucose levels <100 mg/dL in patients with bacteremia were also positively associated with in-hospital mortality.

Conclusions

Early hypoglycemia is predictive of subsequently documented bacteremia and in-hospital mortality in patients with cirrhosis, even among normothermic individuals. In patients without other overt signs of infection, low glucose values may serve as an additional data point to justify early antibiosis.
Hepatitis C Treatment by Nonspecialist Providers in the Direct-acting Antiviral Era
Authors: Kapadia Shashi N. , Johnson Phyllis , Marks Kristen M. , Schackman Bruce R. , Bao Yuhua
Published: June 2021

Background:

Hepatitis C virus (HCV) remains under-treated in the United States and treatment by nonspecialist providers can expand access. We compare HCV treatment provision and treatment completion between nonspecialist and specialist providers.

Methods:

This retrospective study used claims data from the Healthcare Cost Institute from 2013 to 2017. We identified providers who prescribed HCV therapy between 2013 and 2017, and patients enrolled in private insurance or Medicare Advantage who had pharmacy claims for HCV treatment. We measured HCV treatment completion, determined based on prescription fills for the minimum expected duration of the antiviral regimen. Using propensity score–weighted regression, we compared the likelihood of early treatment discontinuation by the type of treating provider.

Results:

The number of providers prescribing HCV treatment peaked in 2015 and then declined. The majority were gastroenterologists, although the proportion of general medicine providers increased to 17% by 2017. Among the 23,463 patients analyzed, 1008 (4%) discontinued before the expected minimum duration. In the propensity score–weighted analysis, patients treated by general medicine physicians had similar odds of treatment discontinuation compared with those treated by gastroenterologists [odds ratio (OR)=1.00, 95% confidence interval (CI): 0.99–1.01, P=0.45]. Results were similar when comparing gastroenterologists to nonphysician providers (OR=1.00, 95% CI: 0.99–1.01, P=0.53) and infectious diseases specialists (OR=1.00, 95% CI: 0.99–1.01, P=0.71).

Conclusions:

HCV treatment providers remain primarily gastroenterologists, even in the current simplified treatment era. Patients receiving treatment from general medicine or nonphysician providers had a similar likelihood of treatment completion, suggesting that removing barriers to the scale-up of treatment by nonspecialists may help close treatment gaps for hepatitis C.
Primary Care Providers in Federally Qualified Health Centers Can Treat Hepatitis C Effectively Without Ongoing Consultative Support From Specialists
Authors: Moore Richard A. , Fried Michael W. , Wright Brad
Published: June 2021

Background:

Hepatitis C virus (HCV) infection remains underdiagnosed and undertreated, but treatment advances may allow primary care providers to address gaps in care by delivering HCV treatment themselves.

Objective:

The objective of this study was to evaluate results of an HCV treatment program at a federally qualified health center (FQHC) in rural North Carolina and assess the extent to which program success depends upon ongoing consultative support from specialists.

Methods:

In this retrospective cohort study, we used data on 381 FQHC patients internally referred for HCV care from January 2015 to December 2018, with follow-up through December 2019. Using modified Poisson regression analyses we compared outcomes during periods with (2015–2016) and without (2017–2018) consultative support. Outcomes included treatment initiation, completion, and cure. We also modeled the likelihood of keeping the first appointment, but because multiple referral attempts were made among nonresponsive patients throughout the study period, we could not compare this outcome in periods with and without consultative support.

Results:

Of all patients referred for evaluation, 91.3% kept at least 1 appointment, 74.1% initiated treatment, 72% completed treatment, and 68.1% were cured. When comparing periods with and without consultative support, there were no significant differences in treatment initiation ([relative risk (RR): 0.975, 95% confidence interval (CI): 0.871, 1.092], treatment completion (RR: 0.989, 95% CI: 0.953, 1.027), or cure (RR: 0.977, 95% CI: 0.926, 1.031).

Conclusions:

After 2 years of consultative support from specialists, primary care providers at FQHCs can deliver HCV treatment effectively without ongoing support. However, more research is needed to determine whether our findings are generalizable across primary care settings.
Diabetes in chronic pancreatitis: risk factors and natural history
Authors: Goodarzi Mark O. , Petrov Maxim S. , Andersen Dana K. , Hart Phil A.
Published: June 2021

Purpose of review

The purpose of this review is to delineate risk factors for the development of diabetes in patients with chronic pancreatitis. The natural history including progression to diabetes and complications that develop once diabetes occurs in chronic pancreatitis is also reviewed.

Recent findings

Studies have found that predictors of diabetes in chronic pancreatitis include both risk factors for type 2 diabetes (e.g., obesity, genetic variants) as well as pancreas-specific factors (e.g., pancreatic calcification, exocrine insufficiency). Rates of diabetes in chronic pancreatitis are strongly related to the duration of chronic pancreatitis, reflecting progressive dysfunction and damage to the insulin-secreting beta cells. Patients with diabetes and chronic pancreatitis experience an excess burden of complications, including higher all-cause and cancer-related mortality.

The high incidence and significant impact of diabetes on the morbidity and mortality of patients with chronic pancreatitis highlights the urgent need for clinically applicable models to predict diabetes in those with chronic pancreatitis, allowing efforts for targeted interventions to prevent diabetes. Research being carried out in the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer holds promise to fulfill these goals.
Equity of access to renal transplantation: a European perspective
Authors: Wu Diana A. , Oniscu Gabriel C.
Published: June 2021

Purpose of review

Renal transplantation offers the chance for patients with end-stage renal disease (ESRD) to have a significantly longer, healthier and better quality life compared with remaining on dialysis. Inequities have been demonstrated at multiple points in the transplantation pathway. In this review, the factors contributing to inequity in access to renal transplantation will be explored from a European perspective.

Recent findings

Despite improvements in patient assessment and revision of organ-offering schemes, there remain persistent inequities in access to the waiting list, allocation of a deceased donor transplant, receiving a living donor transplant and achieving preemptive transplantation. Older age, lower socioeconomic status and health literacy are key factors that continue to impact equity of access to transplantation.

A number of modifiable factors have been identified affecting access to transplantation, Increased patient education together with a better access to and promotion of living donation may help address some of these inequities.
Compassionate Removal of Heated High-Flow Nasal Cannula for End of Life
Authors: Brackett Hareklia , Forman Andrea , Foster Laura A. , Fischer Stacy M.
Published: June 2021

Patients often receive burdensome care at the end of life in the form of interventions that may need to be removed. Heated high-flow oxygen delivered through a nasal cannula (HHFNC) is one such intervention that can be delivered in the hospital yet is rarely available outside of this setting. During the COVID-19 (coronavirus disease 2019) pandemic, health care systems continue to face the possibility of rationing critical life-sustaining equipment that may include HHFNC. We present a clinical protocol designed for weaning HHFNC to allow a natural death and ensuring adequate symptom management throughout the process. This was a retrospective chart review of 8 patients seen by an inpatient palliative care service of an academic tertiary referral hospital who underwent terminal weaning of HHFNC using a structured protocol to manage dyspnea. Eight patients with diverse medical diagnoses, including COVID-19 pneumonia, underwent terminal weaning of HHFNC according to the clinical protocol with 4 down-titrations of approximately 25% for both fraction of inspired oxygen and liter flow with preemptive boluses of opioid and benzodiazepine. Clinical documentation supported good symptom control throughout the weaning process. This case series provides preliminary evidence that the clinical protocol proposed has the ability to ensure comfort through terminal weaning of HHFNC.
Using the Nurse Coaching Process to Support Bereaved Staff During the COVID-19 Crisis
Authors: Rosa William E. , Levoy Kristin , Battista Vanessa , Dahlin Constance , Thaxton Cheryl , Greer Kelly
Published: June 2021

Nurses are confronting a number of negative mental health consequences owing to high burdens of grief during COVID-19. Despite increased vaccination efforts and lower hospitalization and mortality rates, the long-term effects of mass bereavement are certain to impact nurses for years to come. The nurse coaching process is an evidence-based strategy that nurse leaders can use to assist staff in mitigating negative mental health outcomes associated with bereavement. The End-of-Life Nursing Education Consortium brought together a team of palliative nursing experts early in the pandemic to create resources to support nurses across settings and promote nurse well-being. This article shares a timely resource for health systems and nursing administration that leverages the nurse coaching process to support bereaved staff in a safe and therapeutic environment.
Objective Measures of Retinal Image Degradation Due to Refractive Corrections
Authors: Westheimer Gerald
Published: June 2021

SIGNIFICANCE

There is a need for a measure, as simple and yet as informative as possible, to describe objectively the retinal image quality when a patient views targets at various distances through spectacle, contact, or intraocular corrections with optics more elaborate than single vision.

PURPOSE

The purposes of this study are to examine the current status of quantitative descriptions of retinal image blur and find optimal characterization of image degradation.

METHODS

A variety of indexes of image degradation are computed for a typical eye and polychromatic light, in and out of focus, and as exemplars of sophisticated wave shaping, when the pupil transmission has been modified to a truncated Bessel amplitude function and to a “fractal” phase function.

RESULTS

Figures are shown for the optical transfer, point- and edge-spread functions, and Koenig bar and optotype letter blur for the various imaging and defocus conditions, and the relative values of several blur indexes are compared graphically and in a correlation table.

CONCLUSIONS

No single index captures the many ways in which the image can deviate from the diffraction-limited ideal. Among the incomplete descriptors of image degradation, the light distribution at a sharp edge stands out as optimally informative and economical, and, when condensed to just two values, one representing central image sharpness and the other outlying light spread, allows for a quick survey of the imaging deficit.
Diminution of the Primary Cilia From the Intrahepatic Cholangiocytes in a Pediatric Choledochal Cyst
Authors: Mitra Suvradeep , Ayyanar Pavithra , Mahalik Santosh K. , Patra Susama , Purkait Suvendu , Satapathy Amit K.
Published: June 2021

Choledochal cyst (CC) is a cystic disease predominantly involving the extrahepatic biliary tree. Biliary atresia (BA), another disorder of the extrahepatic biliary tree, is sometimes considered to be in the same spectrum as pediatric CC. Recently, the absence and/or the structural abnormality of the primary cilia in the intrahepatic cholangiocytes have been implicated in the pathogenesis of BA. We aimed to evaluate the expression of primary ciliary proteins in the intrahepatic cholangiocytes in cases of pediatric CC and compare it with normal control and BA. We performed immunohistochemistry for primary ciliary proteins (acetylated-α-tubulin and double-cortin domain containing 2) on the liver biopsies of control liver (n=5), pediatric CC (n=13), and BA (n=14). We also compared the expression with various clinical, biochemical, histopathologic (portal fibroinflammation and ductal plate malformation), and immunohistochemical (proliferative index) data. There was significant loss of primary cilia from the intrahepatic cholangiocytes in cases of CC and BA as compared with the normal control by both immunostains (CC: P=0.003 and 0.001, respectively; BA: P=0.001 and 0.001, respectively). There was no significant difference between the CC and BA in terms of ciliary protein loss. The loss of the ciliary proteins occurred irrespective of the proliferative (MIB-1 labeling) index, portal fibroinflammation, or ductal plate malformation. The loss of cilia did not correlate with the clinical follow-up in cases of pediatric CC. The loss of primary cilia from the intrahepatic cholangiocytes may be crucial in the etiopathogenesis of pediatric CC.
Intraoperative Frozen Section Biopsy of Uterine Smooth Muscle Tumors
Authors: Lok Johann , Tse Ka Yu , Lee Elaine Yuen Phin , Wong Richard Wing Cheuk , Cheng Ivy Shui Ying , Chan Alice Ngot Htain , Leung Charlotte Ka Lun , Cheung Annie Nga Yin , Ip Philip Pun Ching
Published: June 2021

Frozen sections of uterine smooth muscle tumors are infrequently required, and related diagnostic difficulties are seldom discussed. We analyzed the clinicopathologic features of 112 frozen sections of uterine smooth muscle tumors and determined the accuracy, reasons for deferrals, and causes of interpretational errors. Most patients (median age, 45 y) presented with pelvic mass symptoms (53%). The main reasons for a frozen section examination were an abnormal gross appearance including loss of the usual whorled pattern of leiomyoma (36 cases, 32.1%), and intraoperative discovery of an abnormal growth pattern and extrauterine extension of a uterine tumor (28 cases, 25%). There were 9 leiomyosarcomas and 103 leiomyomas, including 18 benign histologic variants. An accurate diagnosis of malignancy was achieved in all leiomyosarcomas, with the exception of a myxoid leiomyosarcoma. In 99 cases (88%), the frozen section diagnosis concurred with the permanent section diagnosis (false positives, 0.9%; false negatives, 0%). Misinterpretation of stromal hyalinization as tumor cell necrosis in a leiomyoma with amianthoid-like fibers was a major discrepancy. Two minor discrepancies did not lead to a change in management. The diagnosis was deferred in 10 cases (8.9%) because of stromal alterations, unusual cellular morphology, uncertain type of necrosis, and abnormal growth patterns. Thus, although various stromal and cellular alterations can cause diagnostic uncertainty, leading to deferrals, frozen section diagnosis of uterine smooth muscle tumors has a high accuracy rate. While a definitive frozen section diagnosis of malignancy may be made when there is unequivocal atypia, indisputable mitotic figures, and tumor cell necrosis, it is important to remember that nonmyogenic mesenchymal tumors may also mimic uterine smooth muscle tumors. In a frozen section setting, it would be sufficient to issue a diagnosis of “malignant mesenchymal tumor.” For tumors that do not meet the criteria for malignancy, issuing a frozen section diagnosis of “atypical mesenchymal tumor and defer the histologic subtyping to the permanent sections” is appropriate.
Loss of p57 Expression in Conceptions Other Than Complete Hydatidiform Mole
Authors: Xing Deyin , Miller Karin , Beierl Katie , Ronnett Brigitte M.
Published: June 2021

Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs—2 diandric triploid and 1 triandric tetraploid—and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum β-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.
ICU Admission in Children With Acute Lymphoblastic Leukemia in Sweden: Prevalence, Outcome, and Risk Factors
Authors: Ranta Susanna , Broman Lars Mikael , Abrahamsson Jonas , Berner Jonas , Fläring Urban , Hed Myrberg Ida , Kalzén Håkan , Karlsson Lene , Mellgren Karin , Nilsson Anna , Norén-Nyström Ulrika , Palle Josefine , von Schewelov Katarina , Svahn Johan E. , Törnudd Lisa , Heyman Mats , Harila-Saari Arja
Published: June 2021

OBJECTIVES:

Despite progress in the treatment of childhood acute lymphoblastic leukemia, severe complications are common, and the need of supportive care is high. We explored the cumulative prevalence, clinical risk factors, and outcomes of children with acute lymphoblastic leukemia, on first-line leukemia treatment in the ICUs in Sweden.

DESIGN:

A nationwide prospective register and retrospective chart review study.

SETTING:

Children with acute lymphoblastic leukemia were identified, and demographic and clinical data were obtained from the Swedish Childhood Cancer Registry. Data on intensive care were collected from the Swedish Intensive Care Registry. Data on patients with registered ICU admission in the Swedish Childhood Cancer Registry were supplemented through questionnaires to the pediatric oncology centers.

PATIENTS:

All 637 children 0–17.9 years old with acute lymphoblastic leukemia diagnosed between June 2008 and December 2016 in Sweden were included.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Twenty-eight percent of the children (178/637) were admitted to an ICU at least once. The Swedish Intensive Care Registry data were available for 96% of admissions (241/252). An ICU admission was associated with poor overall survival (hazard ratio, 3.25; 95% CI, 1.97–5.36; p ≤ 0.0001). ICU admissions occurred often during early treatment; 48% (85/178) were admitted to the ICU before the end of the first month of acute lymphoblastic leukemia treatment (induction therapy). Children with T-cell acute lymphoblastic leukemia or CNS leukemia had a higher risk of being admitted to the ICU in multivariable analyses, both for early admissions before the end of induction therapy and for all admissions during the study period.

CONCLUSIONS:

The need for intensive care in children with acute lymphoblastic leukemia, especially for children with T cell acute lymphoblastic leukemia and CNS leukemia, is high with most admissions occurring during early treatment.
Use of dietary supplements containing polyvalent cations and antacids among people with HIV and its impact on viral suppression
Authors: Peng An-Ting , Huang Sung-Hsi , Sun Hsin-Yun , Huang Yi-Chia , Chuang Yu-Chung , Wu Pei-Ying , Chen Ling-Ya , Chang Hsi-Yen , Luo Yu-Zhen , Liu Wen-Chun , Kuo Han-Yueh , Hung Chien-Ching
Published: June 2021

Dietary supplements and medications containing polyvalent cations can interact with integrase strand transfer inhibitors (INSTIs) and decrease exposure to INSTIs. In this cross-sectional study of 513 people with HIV (PWH) who were on stable antiretroviral therapy, 57.5% and 6.6% reported concurrent use of dietary supplements and antacids, respectively. In the multivariable analysis, the use of antacids, but not dietary supplements containing polyvalent cations, was associated with HIV viremia in PWH who received INSTI-based ART.
The Longitudinal Effects of Blood Pressure and Hypertension on Neurocognitive Performance in People Living With HIV
Authors: Guzman Vanessa A. , Cham Heining , Gutierrez Jose , Byrd Desiree , Morris Emily P. , Tureson Kayla , Morgello Susan , Mindt Monica R. ,   for the Manhattan HIV Brain Bank
Published: June 2021

Background:

Hypertension (HTN) and HIV are salient risk factors for cerebral small vessel disease and neurocognitive (NC) impairment, yet the effects of HTN on NC performance in persons living with HIV remain poorly understood. This is the first study to examine the longitudinal associations between blood pressure (BP), HTN, and pulse pressure (PP) with NC performance in persons living with HIV.

Setting:

New York City.

Methods:

Analysis of medical, NC, and virologic data from 485 HIV+ participants was collected by the Manhattan HIV Brain Bank, a prospective, observational, longitudinal study of neuroHIV. A series of multilevel linear growth curve models with random intercepts and slopes were estimated for BP, HTN status, and PP to predict the change in NC performance.

Results:

The baseline prevalence of HTN was 23%. Longitudinal changes in diastolic and systolic pressure were associated with a 10.5-second and 4-second increase in the Grooved Pegboard Test nondominant hand performance, respectively. A longitudinal change in diastolic BP was also associated with a 0.3-point decline in correct categories and 3-point increase in perseverative responses and total errors on the Wisconsin Card Sorting Test. Increasing odds of prevalent and/or incident HTN were associated with a 0.1-point decrease in correct categories and a 0.8-point increase in total errors on the Wisconsin Card Sorting Test. There was no association between PP and NC performance.

Conclusions:

The results indicate linear longitudinal relations for BP and HTN with poorer NC test performance, particularly in psychomotor and executive functions in persons with HIV.
Alexithymia is associated with reduced vitamin D levels, but not polymorphisms of the vitamin D binding-protein gene
Authors: Terock Jan , Hannemann Anke , Weihs Antoine , Janowitz Deborah , Grabe Hans J.
Published: June 2021

Objective

Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions, which is associated with various psychiatric disorders, including depression and posttraumatic stress disorder (PTSD). Its pathogenesis is incompletely understood but previous studies suggested that genetic as well as metabolic factors, are involved. However, no results on the role of vitamin D and the polymorphisms rs4588 and rs7041 of the vitamin D binding protein (VDBP) have been published so far.

Methods

Serum levels of total 25(OH)D were measured in two general-population samples (total n = 5733) of the Study of Health in Pomerania (SHIP). The Toronto Alexithymia Scale-20 (TAS-20) was applied to measure alexithymia. Study participants were genotyped for rs4588 and rs7041. Linear and logistic regression analyses adjusted for sex, age, waist circumference, physical activity, season and study and, when applicable, for the batch of genotyping and the first three genetic principal components, were performed. In sensitivity analyses, the models were additionally adjusted for depressive symptoms.

Results

25(OH)D levels were negatively associated with TAS-20 scores (β = −0.002; P < 0.001) and alexithymia according to the common cutoff of TAS-20>60 (β = −0.103; P < 0.001). These results remained stable after adjusting for depressive symptoms. The tested genetic polymorphisms were not significantly associated with alexithymia.

Conclusions

Our results suggest that low vitamin D levels may be involved in the pathophysiology of alexithymia. Given that no associations between alexithymia and rs4588 as well as rs7041 were observed, indicates that behavioral or nutritional features of alexithymic subjects could also explain this association.
Haploinsufficiency of the HIRA gene may not always produce severe neurodevelopmental consequences
Authors: Curtis David
Published: June 2021

A recent report describes neurodevelopmental disorder in a total of three unrelated patients with de novo truncating variants in the HIRA gene. 200 632 subjects who have undergone exome sequencing by the UK Biobank were investigated to identify any variants predicted to cause HIRA haploinsufficiency. Four were found, three with frameshift variants and one with a stop variant. One of these subjects had depression but the others did not have any major neuropsychiatric phenotypes. Variants causing haploinsufficiency of HIRA are very rare but when they do occur it seems that they are not always associated with neurodevelopmental disorder.
Interplay between central carbon metabolism and metal homeostasis in mycobacteria and other human pathogens
Authors: Serafini Agnese
Published: June 2021

Bacterial nutrition is a fundamental aspect of pathogenesis. While the host environment is in principle nutrient-rich, hosts have evolved strategies to interfere with nutrient acquisition by pathogens. In turn, pathogens have developed mechanisms to circumvent these restrictions. Changing the availability of bioavailable metal ions is a common strategy used by hosts to limit bacterial replication. Macrophages and neutrophils withhold iron, manganese, and zinc ions to starve bacteria. Alternatively, they can release manganese, zinc, and copper ions to intoxicate microorganisms. Metals are essential micronutrients and participate in catalysis, macromolecular structure, and signalling. This review summarises our current understanding of how central carbon metabolism in pathogens adapts to local fluctuations in free metal ion concentrations. We focus on the transcriptomics and proteomics data produced in studies of the iron-sparing response in

Mycobacterium tuberculosis

, the etiological agent of tuberculosis, and consequently generate a hypothetical model linking trehalose accumulation, succinate secretion and substrate-level phosphorylation in iron-starved

M. tuberculosis

. This review also aims to highlight a large gap in our knowledge of pathogen physiology: the interplay between metal homeostasis and central carbon metabolism, two cellular processes which are usually studied separately. Integrating metabolism and metal biology would allow the discovery of new weaknesses in bacterial physiology, leading to the development of novel and improved antibacterial therapies.
Seasonal Disease in the United States Has the Hallmarks of an Entrained Circannual Clock
Authors: Schober Andrew F. , Rzhetsky Andrey , Rust Michael J.
Published: June 2021

Infectious human diseases are often characterized by seasonal variation in incidence which produces recurring annual peaks with precise timing. Changing weather conditions such as temperature and humidity are known to affect virus transmission, but we consider the possibility that an intrinsic rhythm in susceptibility, entrained to annual cues, also contributes to seasonality. These two mechanisms produce different predictions about how the timing and amplitude of seasonal disease depend on environmental forcing. Using databases of health insurance claims and weather across U.S. counties, we find that the timing of winter-peaking diseases, but not their amplitude, scales with latitude. This latitude scaling is shared across many diagnosis codes involving multiple pathogens. Regression against simple models suggests an underlying limit cycle that, in temperate zones, is entrained to annual changes in irradiance, possibly a human circannual clock.

Significance statement

Peak timing but not amplitude of seasonal disease scales with latitude, suggesting a circannual rhythm in host susceptibility.
Regular testing of asymptomatic healthcare workers identifies cost-efficient SARS-CoV-2 preventive measures
Authors: Sanchez-Taltavull Daniel , Castelo-Szekely Violeta , Murugan Shaira , Rollenske Tim , Ganal-Vonarburg Stephanie C. , Büchi Isabel , Keogh Adrian , Li Hai , Salm Lilian , Spari Daniel , Yilmaz Bahtiyar , Zimmermann Jakob ,   UVCM-COVID researchers, Gerfin Michael , Roldan Edgar , Beldi Guido
Published: June 2021

Protecting healthcare professionals is crucial in maintaining a functioning health-care system. The risk of infection and optimal preventive strategies for health-care workers during the COVID-19 pandemic remain poorly understood. Here we report the results of a weekly testing regime that has been performed since the beginning of the COVID-19 pandemic to identify pre- and asymptomatic healthcare workers. Based on these observations we have developed a mathematical model of SARS-CoV-2 transmission that integrates the sources of infection from inside and outside the hospital. The data were used to study how regular testing and a desynchronisation protocol are effective in preventing transmission of COVID-19 infection at work, and compared both strategies in terms of workforce availability and cost-effectiveness. We showed that case incidence among healthcare workers is higher than would be explained solely by community infection. Furthermore, while testing and desynchronisation protocols are both effective in preventing nosocomial transmission, regular testing maintains work productivity with implementation costs.
Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India
Authors: Dhar Mahesh S , Marwal Robin , Radhakrishnan VS , Ponnusamy Kalaiarasan , Jolly Bani , Bhoyar Rahul C. , Sardana Viren , Naushin Salwa , Rophina Mercy , Mellan Thomas A , Mishra Swapnil , Whittaker Charles , Fatihi Saman , Datta Meena , Singh Priyanka , Sharma Uma , Ujjainiya Rajat , Batheja Nitin , Divakar Mohit Kumar , Singh Manoj K , Imran Mohamed , Senthivel Vigneshwar , Maurya Ranjeet , Jha Neha , Mehta Priyanka , Vivekanand A , Sharma Pooja , Arvinden VR , Chaudhary Urmila , Soni Namita , Thukral Lipi , Flaxman Seth , Bhatt Samir , Pandey Rajesh , Dash Debasis , Faruq Mohammed , Lall Hemlata , Gogia Hema , Madan Preeti , Kulkarni Sanket , Chauhan Himanshu , Sengupta Shantanu , Kabra Sandhya ,   The Indian SARS-CoV-2 Genomics Consortium (INSACOG), Gupta Ravindra K. , Singh Sujeet K , Agrawal Anurag , Rakshit Partha
Published: June 2021

Delhi, the national capital of India, has experienced multiple SARS-CoV-2 outbreaks in 2020 and reached a population seropositivity of over 50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant B.1.617.2 (Delta) replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and partial reduction of immunity elicited by prior infection (median estimates; ×1.5-fold, 20% reduction). Seropositivity of an employee and family cohort increased from 42% to 86% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.

One-Sentence Summary

Delhi experienced an overwhelming surge of COVID-19 cases and fatalities peaking in May 2021 as the highly transmissible and immune evasive Delta variant replaced the Alpha variant.
The INDSCI-SIM model for COVID-19 in India
Authors: Hazra Dhiraj Kumar , Pujari Bhalchandra S. , Shekatkar Snehal M. , Mozaffer Farhina , Sinha Sitabhra , Guttal Vishwesha , Chaudhuri Pinaki , Menon Gautam I.
Published: June 2021

Estimating the burden of COVID-19 in India is difficult because the extent to which cases and deaths have been undercounted is hard to assess. The INDSCI-SIM model is a 9-component, age-stratified, contact-structured compartmental model for COVID-19 spread in India. We use INDSCI-SIM, together with Bayesian methods, to obtain optimal fits to reported cases and deaths across the span of the first wave of the Indian pandemic, over the period Jan 30, 2020 to Feb 15, 2021. We account for lock-downs and other non-pharmaceutical interventions, an overall increase in testing as a function of time, the under-counting of cases and deaths, and a range of age-specific infection-fatality ratios. We first use our model to describe data from all individual districts of the state of Karnataka, benchmarking our calculations using data from serological surveys. We then extend this approach to aggregated data for Karnataka state. We model the progress of the pandemic across the cities of Delhi, Mumbai, Pune, Bengaluru and Chennai, and then for India as a whole. We estimate that deaths were undercounted by a factor between 2 and 5 across the span of the first wave, converging on 2.2 as a representative multiplier that accounts for the urban-rural gradient across the country. We also estimate an overall under-counting of cases by a factor of between 20 and 25 towards the end of the first wave. Our estimates of the infection fatality ratio (IFR) are in the range 0.05 - 0.15, broadly consistent with previous estimates but substantially lower than values that have been estimated for other LMIC countries. We find that approximately 40% of India had been infected overall by the end of the first wave, results broadly consistent with those from serosurveys. These results contribute to the understanding of the long-term trajectory of COVID-19 in India.
Does Hemispheric Asymmetry Reduction in Older Adults (HAROLD) in motor cortex reflect compensation?
Authors: Knights Ethan , Morcom Alexa ,   Cam-CAN, Henson Richard N.
Published: June 2021

Older adults tend to display greater brain activation in the non-dominant hemisphere during even basic sensorimotor responses. It is debated whether this Hemispheric Asymmetry Reduction in Older Adults (HAROLD) reflects a compensatory mechanism. Across two independent fMRI experiments involving an adult-lifespan human sample (N = 586 and N = 81; approximately half female) who performed right hand finger responses, we distinguished between these hypotheses using behavioural and multivariate Bayes (MVB) decoding approaches. Standard univariate analyses replicated a HAROLD pattern in motor cortex, but in- and out-of-scanner behavioural results both demonstrated evidence against a compensatory relationship, in that reaction time measures of task performance in older adults did not relate to ipsilateral motor activity. Likewise, MVB showed that this increased ipsilateral activity in older adults did not carry additional information, and if anything, combining ipsilateral with contralateral activity patterns reduced action decoding in older adults (at least in Experiment 1). These results contradict the hypothesis that HAROLD is compensatory, and instead suggest that the age-related, ipsilateral hyper-activation is non-specific, in line with alternative hypotheses about age-related reductions in neural efficiency/differentiation or inter-hemispheric inhibition.

Significance Statement

A key goal in the cognitive neuroscience of ageing is to provide a mechanistic explanation of how brain-behaviour relationships change with age. One interpretation of the common finding that task-based hemispheric activity becomes more symmetrical in older adults, is that this shift reflects a compensatory mechanism, with the non-dominant hemisphere needing to “help out” with computations normally performed by the dominant hemisphere. Contrary to this view, our behavioural and brain data indicate that the additional activity in ipsilateral motor cortex in older adults is not reflective of better task performance nor better neural representations of finger actions.
Hybridization chain reaction enables a unified approach to multiplexed, quantitative, high-resolution immunohistochemistry and in situ hybridization
Authors: Schwarzkopf Maayan , Liu Mike C. , Schulte Samuel J. , Ives Rachel , Husain N. , Choi Harry M.T. , Pierce Niles A.
Published: June 2021

RNA in situ hybridization (RNA-ISH) based on the mechanism of hybridization chain reaction (HCR) enables multiplexed, quantitative, high-resolution RNA imaging in highly autofluorescent samples including whole-mount vertebrate embryos, thick brain slices, and formalin-fixed paraffin-embedded (FFPE) tissue sections. Here, we extend the benefits of 1-step, multiplexed, quantitative, isothermal, enzyme-free HCR signal amplification to immunohistochemistry (IHC), enabling accurate and precise protein relative quantitation with subcellular resolution in an anatomical context. More-over, we provide a unified framework for simultaneous quantitative protein and RNA imaging with 1-step HCR signal amplification performed for all target proteins and RNAs simultaneously.

Signal amplification based on the mechanism of hybridization chain reaction enables multiplexed, quantitative, high-resolution imaging of protein and RNA targets in highly autofluorescent tissues.
Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration into human lung cells
Authors: Caohuy Hung , Eidelman Ofer , Chen Tinghua , Yang Qingfeng , Bera Alakesh , Walton Nathan , Pollard Harvey B.
Published: June 2021

To initiate SARS-CoV-2 infection, the Receptor Binding Domain (RBD) on the viral spike protein must first bind to the host receptor ACE2 protein on pulmonary and other ACE2-expressing cells. We hypothesized that cardiac glycoside drugs might block the binding reaction between ACE2 and the Spike (S) protein, and thus block viral penetration into target cells. To test this hypothesis we developed a biochemical assay for ACE2:Spike binding, and tested cardiac glycosides as inhibitors of binding. Here we report that ouabain, digitoxin, and digoxin are high-affinity competitive inhibitors of ACE2 binding to the Wuhan S1 and the European [E614G] S1 proteins. These drugs also inhibit ACE2 binding to the Wuhan RBD, as well as to RBD proteins containing the S. Africa [E484K], Mink [Y453F] and UK [N501Y] mutations. As hypothesized, we also found that ouabain and digitoxin blocked penetration by SARS-CoV-2 Spike-pseudotyped virus into human lung cells. These data indicate that cardiac glycosides may block viral penetration into the target cell by first inhibiting ACE2:Spike binding. Clinical concentrations of ouabain and digitoxin are relatively safe for short term use for subjects with normal hearts. It has therefore not escaped our attention that these common cardiac medications could be deployed worldwide as inexpensive repurposed drugs for anti-COVID-19 therapy.
Display of the self-sufficient CYP102A1 on the surface of E. coli-derived Outer Membrane Vesicles
Authors: Devriese Delphine , Surmont Pieter , Lynen Frederic , Devreese Bart
Published: June 2021

The cytochrome P450 (CYP) monooxygenase superfamily offers the unique ability to catalyze regio-and stereospecifical oxidation of a non-activated C-H bond. CYPs found applications in the synthesis of pharmaceuticals and drug metabolites as well as in bioremediation. They are typically used in whole-cell bioconversion processes, due to their low stability and the need for a redox partner and cofactor. Unfortunately, substrate uptake and/or product transport limitations are frequently encountered and side reactions occur due to other enzymes in the cellular environment. Here, we present a proof-of-principle of a novel cell-free cytochrome P-450 nanocatalyst based on surface display on bacterial outer membrane vesicles. The self-sufficient CYP 102A1 from Bacillus megaterium was engineered to be translocated on the outer membrane vesicles of Escherichia coli. The resulting vesicles can simply be isolated from the culture supernatant. Moreover, no expensive and elaborate enzyme purification is required. This approach shows great promise as an alternative strategy to recombinantly produce CYP enzymes for a variety of applications, such as in fine chemical production and in the development of biosensors.
Mutation saturation for fitness effects at human CpG sites
Authors: Agarwal Ipsita , Przeworski Molly
Published: June 2021

Whole exome sequences have now been collected for millions of humans, with the related goals of identifying pathogenic mutations in patients and establishing reference repositories of data from unaffected individuals. As a result, we are approaching an important limit, in which datasets are large enough that, in the absence of natural selection, every highly mutable site will have experienced at least one mutation in the genealogical history of the sample. Here, we focus on putatively-neutral, synonymous CpG sites that are methylated in the germline and experience mutations to T at an elevated rate of ~10-7 per site per generation; in a sample of 390,000 individuals, ~99% of such CpG sites harbor a C/T polymorphism. These CpG sites provide a natural mutation saturation experiment for fitness effects: as we show, at current sample sizes, not seeing a polymorphism is indicative of strong selection against that mutation. We rely on this idea in order to directly identify a subset of highly deleterious CpG transitions, including ~27% of possible loss-of-function mutations, and up to 21% of possible missense mutations, depending on the type of site in which they occur. Unlike methylated CpGs, most mutation types, with rates on the order of 10-8 or 10-9, remain very far from saturation. We discuss what this contrast implies about interpreting the potential clinical relevance of mutations from their presence or absence in reference databases and for inferences about the fitness effects of new mutations.
A Method for Checking Recombinant Protein Quality to Troubleshoot for Discordant Immunoassays
Authors: Tran-Nguyen Thi K.
Published: June 2021

Discordant results of recombinant protein-based enzyme-linked immunosorbent assays (ELISA) and other antigen detection tests are a common and vexing problem in scientific research and clinical laboratories. The reproducibility of immunoassays based on antibody specificity can be adversely affected by cryptic changes in the composition of the analyte (e.g., the protein antigen). By use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry analyses, we found varying levels of purity and the extent of post-translational modifications (PTMs), particularly of N-linked glycosylation and phosphorylation, among varied lots of recombinant glucose-regulated protein 78 (GRP78) expressed in Escherichia coli. We expect these lotto-lot variabilities of both purity and PTMs led to inconsistent results stemming from ELISA assays that measured GRP78 autoantibody levels in patient plasma specimens. We present these analyses to draw readers’ attention to a potentially common, yet seldom appreciated problem, in laboratory assays using recombinant proteins as antigens for antibody detection, and propose a workflow to detect and troubleshoot for this typical problem.
Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma
Authors: Broestl Lauren , Grandison Lucia , Shenoy Saraswati , Tallman Miranda M. , Rhee Gina , Yang Wei , Sponagel Jasmin , Kfoury-Beaumont Najla , Hill Cameron M. , Mao Diane D. , Kim Albert H. , Stewart Sheila A. , Venere Monica , Luo Jingqin , Rubin Joshua B.
Published: June 2021

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in both wildtype and transformed murine astrocytes and patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned by gonadal sex. These data suggest that sex differences in p21 induced senescence contribute to the female survival advantage in GBM.