bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of combined anti-VEGF and photodynamic therapy for bilateral diffuse uveal melanocytic proliferation
Authors: Miyata Manabu , Ooto Sotaro , Hata Masayuki , Takahashi Ayako , Tsujikawa Akitaka
Published: October 2021

Rationale:

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare retinal exudative disease with physical disorders and no established treatment standard. We describe treatment courses in 3 cases of BDUMP.

Patients concerns:

Three male patients complained active vision loss. One male patient in his 70s (patient 1) was treated with prednisolone, mesalazine, and ciclosporin for hypoplastic anemia and ulcerous colitis. One male patient in his 60s (patient 2) was on prednisolone therapy for adult Still disease. Another male patient in his 70s (patient 3) was on prednisolone therapy for polymyalgia rheumatica, giant cell arteritis, and pancreatic body tumor.

Diagnoses:

Retinal specialists diagnosed these patients with BDUMP based on characteristic fundus findings of multiple red patches and retinal exudate.

Interventions:

Two patients (patients 1 and 2) with poor response to anti-vascular endothelial growth factor (VEGF) monotherapy and/or triamcinolone acetonide sub-Tenon injection were treated with combined anti-VEGF therapy and photodynamic therapy. One patient (patient 3) was treated with 3 rounds of monthly anti-VEGF monotherapy.

Outcomes:

Retinal exudates were resolved in all patients. No recurrence of retinal exudates was observed for at least 10 months, 2 years, or 4 months after the therapy in patients 1, 2, and 3, respectively. However, best-corrected visual acuity of the right eye was low (20/200) compared with that of the left eye (20/22) in patient 2 despite exudate resolution, due to permanent outer retinal damage secondary to long-term retinal exudate.

Lessons subsections:

Combined anti-VEGF therapy and photodynamic therapy may be a feasible therapeutic option for treatment-resistant exudate in patients with BDUMP. Early diagnosis of BDUMP and prompt administration of combination therapy are crucial.
Serum matrix metalloproteinase-9 concentration as a marker of disease activity in patients with inflammatory bowel disease
Authors: Shamseya Ayman M. , Hussein Wafaa M. , Elnely Dalia A. , Adel Fadwa , Header Doaa A.
Published: October 2021

Background and aim

Diagnosing inflammatory bowel disease (IBD), determining the appropriate treatment and follow-up of patients rely mainly on endoscopy and biopsy. Finding a sensitive, specific, cost-effective and less-invasive biomarker is the focus of much of the current research in this field. The aim was to investigate the relation between serum matrix metalloproteinase-9 (MMP-9) levels and disease activity in patients with IBD, correlating with clinical and endoscopic indices of disease activity and with treatment received.

Patients and methods

Sixty patients (30 with ulcerative colitis, 30 with Crohn’s disease) and 20 controls were included. Serum MMP-9 levels were measured for all patients and controls by ELISA. Clinical activity was determined by partial Mayo score for patients with ulcerative colitis and Crohn’s Disease Activity Index for patients with Crohn’s disease, and endoscopic activity was assessed using Ulcerative Colitis Endoscopic Index of Severity for patients with ulcerative colitis and Simple Endoscopic Score of Crohn’s disease for patients with Crohn’s disease.

Results

Serum MMP-9 was higher in patients with active ulcerative colitis than in patients with inactive disease and the control group. Serum MMP-9 was also higher in patients with active Crohn’s disease than in patients with inactive disease and the control group. In both ulcerative colitis and Crohn’s disease groups, there was a significant difference between serum MMP-9 levels in patients receiving conventional treatment and those on biological treatment, with lower levels of the marker detected in the sera of patients subgroups receiving biologics.

Conclusion

Serum MMP-9 can be used to differentiate between active and inactive IBD (including both ulcerative colitis and Crohn’s disease).
Nonalcoholic fatty liver disease and risk of incident hypertension: a systematic review and meta-analysis
Authors: Ciardullo Stefano , Grassi Guido , Mancia Giuseppe , Perseghin Gianluca
Published: October 2021

Several studies reported an association between nonalcoholic fatty liver disease (NAFLD) and the risk of incident hypertension. The objective of this systematic review and meta-analysis was to obtain a precise and reliable estimate of the nature and magnitude of this association. We systematically searched Ovid-MEDLINE up to March 2021 for observational studies in which NAFLD was diagnosed in adults using blood-based panels, imaging techniques or liver biopsy and with a follow-up ≥1 year. Measures of association from individual studies were meta-analyzed using random-effects models. Of the 1108 titles initially scrutinized, we included 11 cohort studies with data on 390 348 participants (52% male) and a mean follow-up of 5.7 years. In the overall analysis, NAFLD was associated with a moderately increased risk of incident hypertension (hazard ratio 1.66; 95% confidence interval (CI), 1.38-2.01; test for overall effect z = 5.266; P < 0.001). There was significant heterogeneity among the studies (P < 0.001). Sensitivity analyses showed that estimates were not affected by geographical location, duration of follow-up and adjustment for baseline blood pressure values. On the other hand, the magnitude of the association was lower in studies that adjusted for baseline adiposity compared with those that did not, explaining part of the observed heterogeneity. No significant publication bias was detected by funnel plot analysis and Egger’s and Begg’s tests. This large meta-analysis indicates that NAFLD is associated with a ~1.6-fold increased risk of developing hypertension. Further studies are needed to investigate the role of NAFLD severity in terms of inflammation and fibrosis on incident hypertension.
Renal protection during 177lutetium DOTATATE molecular radiotherapy in children: a proposal for safe amino acid infusional volume during peptide receptor radionuclide therapy
Authors: Taylor Catherine A. , Shankar Ananth , Gaze Mark N. , Peet Connie , Gains Jennifer E. , Wan Simon , Voo Stefan , Priftakis Dimitrios , Bomanji Jamshed B.
Published: October 2021

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues such as 177-lutetium DOTATATE is an effective treatment modality for neuroendocrine tumours, paragangliomas, and neuroblastomas. However, renal and haematopoietic toxicities are the major limitations of this therapeutic approach. The renal toxicity of PRRT is mediated by renal proximal tubular reabsorption and interstitial retention of the radiolabelled peptides resulting in excessive renal irradiation that can be dose-limiting. To protect the kidneys from PRRT-induced radiation nephropathy, basic amino acids are infused during PRRT as they competitively bind to the proximal tubular cells and prevent uptake of the radionuclide. In adults, 1 L of a basic amino acid solution consisting of arginine and lysine is infused over 4 h commencing 30 min prior to PRRT. However, this volume of amino acids infused over 4 h is excessive in small children and can result in hemodynamic overload. This is all the more relevant in paediatric oncology, as many of the children may have been heavily pretreated and so may have treatment-related renal and or cardiac impairment. We have therefore developed the following guidelines for safe paediatric dosing of renal protective amino acid infusions during PRRT. Our recommendations have been made taking into consideration the renal physiology in small children and the principles of safe fluid management in children.
Can 18F-FDG PET/CT alone or combined with radiology be used to reliably grade cartilage bone neoplasms for surgical decision making?
Authors: Gundavda Manit K. , Agarwal Manish G. , Singh Natasha , Gupta Rajat , Reddy Rajeev , Bary Ashik
Published: October 2021

Objective

Treatment of chondrosarcomas is grade based; intralesional curettage for grade 1 and resection for grade 2 or more. Currently used methods to determine grades before surgery are not highly accurate and create a dilemma for the surgeon. We have used a PET-CT combined with imaging to answer the following study questions: (1) Does SUVmax value from an 18F-FDG PET/CT correlate with the grade of chondrosarcoma? (2) Can a cutoff SUVmax value be used to differentiate between various grades of chondroid neoplasms with sufficient sensitivity and specificity? (3) Does SUVmax guide the clinician and add value to radiology in offering histologic grade-dependent management?

Methods

SUVmax values of patients with suspected chondrosarcoma were retrospectively correlated with the final histology grade for the operated patients. Radiologic parameters and radiology aggressiveness scores (RAS) were reevaluated and tabulated.

Results

Totally 104 patients with chondroid tumors underwent 18F-FDG PET/CT assessment. In total 73 had tissue diagnosis available as a pretreatment investigation. Spearman correlation indicated that there was a significant positive association between SUVmax and the final histology grading of chondroid tumors (correlation coefficient = 0.743; P < 0.01). SUVmax cutoff of 13.3 was 88.9% sensitive and 100% specific for diagnosing dedifferentiated chondrosarcomas. An RAS cutoff value of 3 or more could diagnose IHGCS with a sensitivity of 80.7% and specificity of 93.75%. Adding an SUVmax cutoff of 3.6 improves the sensitivity to 89.5%.

Conclusion

SUVmax value can reliably help diagnose dedifferentiated chondrosarcoma and when added to the radiology score can improve the accuracy of grading chondrosarcoma.
Neonatal Thrombocytopenia Due to Dual Alloimmune and Autoimmune Mechanisms
Authors: Mantas Pedro , Félix Nuno , Oliveira Elisabete , Malcata Conceição , Palaré Maria J. , Ferrão Anabela
Published: October 2021

Alloantibody-mediated and autoantibody-mediated immune destruction are common causes of early neonatal thrombocytopenia. The authors report a case of severe, early-onset thrombocytopenia with mucocutaneous bleeding in an otherwise well-appearing full-term neonate. Recurrence of thrombocytopenia following initial treatment and its persistence after 2 weeks of life suggested a dual immune mechanism. This is a rare case of immune thrombocytopenia caused by human platelet antigen-5b alloimmunization and passive transfer of maternal antiplatelet antibodies. Appropriate, timely treatment and absence of severe bleeding complications, namely intracranial hemorrhage, conferred a good overall prognosis.
Onboarding New Graduate Nurses Using Assessment-Driven Personalized Learning to Improve Knowledge, Critical Thinking, and Nurse Satisfaction
Authors: Valdes Elise G. , Sembar M. Colleen , Sadler Felicia
Published: October 2021

Effective onboarding is key to new nurse success; however, many programs lack evidence-based support. The current study compared knowledge, critical thinking, and nurse satisfaction between cohorts before and after implementation of personalized learning for onboarding. Results showed better knowledge, critical thinking, and nurse satisfaction in the personalized learning cohort compared to prior cohorts. Nurse educators should use evidence-based personalized learning for onboarding to fully support new nurses as they transition from the classroom to practice.
TRPS1 Expression in Breast Carcinomas
Authors: Parkinson Bryce , Chen Wei , Shen Tiansheng , Parwani Anil V. , Li Zaibo
Published: October 2021

TRPS1 has been recently demonstrated as a highly sensitive and specific marker for breast carcinomas. To further explore TRPS1’s utility in breast carcinoma, we systematically evaluated TRPS1 expression on tissue microarrays from 160 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-positive, 94 ER−/HER2+, 117 triple-negative breast carcinomas, and 618 other primary carcinomas (cholangiocarcinoma, endometrial, colorectal, and hepatocellular carcinomas), and whole tissue sections from 64 HER2+, 76 triple-negative, and 67 metaplastic breast carcinomas. The results showed TRPS1 was highly expressed in breast carcinomas (100% of HER2+ and 97.4% of triple negative on whole tissue sections), but almost completely negative in other tested tumor types. TRPS1 was also highly expressed in metaplastic carcinoma (91%), significantly higher than GATA3 (55.2%). The different expression between TRPS1 and GATA3 was most prominent in chondroid/mesenchymal subtypes (100% vs. 36.4%), followed by spindle cell carcinoma (66.7% vs. 44.4%). In addition, TRPS1 was expressed in normal breast ductal epithelial cells with less staining than in carcinoma cells, and TRPS1 showed aberrant membranous staining in HER2+ breast carcinomas that suggests a potential cross-reactivity with HER2 protein.
Discharge Rehabilitation Measures Predict Activity Limitations in Patients With Stroke 6 Months After Inpatient Rehabilitation
Authors: Minor Maria , Jaywant Abhishek , Toglia Joan , Campo Marc , O’Dell Michael W.
Published: October 2021

Objective

The aim of this study was to identify rehabilitation measures at discharge from acute inpatient stroke rehabilitation that predict activity limitations at 6 mos postdischarge.

Design

This is a retrospective analysis of a prospective, longitudinal, observational cohort study. It was conducted in an acute inpatient rehabilitation unit at an urban, academic medical center. Activity limitations in patients (N = 141) with stroke of mild-moderate severity were assessed with the activity measure for post-acute care at inpatient stroke rehabilitation discharge and 6-mo follow-up. Rehabilitation measures at discharge were investigated as predictors for activity limitations at 6 mos.

Results

Measures of balance (Berg Balance Scale), functional limitations in motor-based activities (functional independence measure–motor subscore), and motor impairment (motricity index), in addition to discharge activities measure for post-acute care scores, strongly predicted activity limitations in basic mobility and daily activities at 6 mos (51% and 41% variance explained, respectively). Functional limitations in cognition (functional independence measure–cognitive subscore) and executive function impairment (Trail Making Test–part B), in addition to the discharge activities measure for post-acute care score, modestly predicted limitations in cognitively based daily activities at 6 mos (12% of variance).

Conclusions

Standardized rehabilitation measures at inpatient stroke rehabilitation discharge can predict future activity limitations, which may improve prediction of outcome post-stroke and aid in postdischarge treatment planning.
Cardiovascular risk score associations with frailty in men and women with or at risk for HIV
Authors: Kuniholm Mark H. , Vásquez Elizabeth , Appleton Allison A. , Kingsley Lawrence , Palella Frank J. , Budoff Matthew , Michos Erin D. , Fox Ervin , Jones Deborah , Adimora Adaora A. , Ofotokun Igho , D'souza Gypsyamber , Weber Kathleen M. , Tien Phyllis C. , Plankey Michael , Sharma Anjali , Gustafson Deborah R.
Published: October 2021

Objective:

To understand the relationship between cardiovascular disease (CVD) risk and frailty among men (MWH) and women living with HIV (WWH), or at risk for HIV.

Design:

We considered 10-year coronary heart disease and atherosclerotic CVD risk by Framingham risk score (FRS, 2001 National Cholesterol Education Program Adult Treatment Program III) and Pooled Cohort Equations (PCE, 2013 American College of Cardiology/American Heart Association) in relation to the Fried Frailty Phenotype (FFP) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS).

Methods:

FFP was ascertained in MACS from 2004 to 2019 and in WIHS from 2005 to 2006 and 2011–2019. FFP score at least three of five components defined frailty. Repeated measures logistic regression (both cohorts) and Cox proportional hazards regression (MACS) were performed, controlled for education, income, cholesterol medication and hepatitis C virus serostatus, and among MWH and WWH, CD4+ cell count/μl, antiretroviral therapy, and HIV viral load.

Results:

There were 5554 participants (1265 HIV seronegative/1396 MWH; 768 seronegative/1924 WWH) included. Among men, high-risk FRS was associated with increased risk of incident frailty among seronegative [adjusted hazard ratio (aHR)) = 2.12, 95% confidence interval (CI):1.22–3.69] and MWH (aHR = 2.19, 95% CI: 1.33–3.61). Similar associations were seen with high-risk PCE and incident frailty among SN (aHR = 1.88, 95% CI: 1.48–2.39) and MWH (aHR = 1.59, 95% CI: 1.26–2.00). Among women, high-risk PCE was associated with frailty in SN [adjusted odds ratio (aOR) = 1.43, 95% CI: 1.02–2.00] and WWH (aOR = 1.36, 95% CI: 1.08–1.71); however, high-risk FRS was not (seronegative: aOR = 1.03, 95% CI: 0.30–3.49; WWH: aOR = 0.86, 95% CI: 0.23–3.20).

Conclusion:

Higher CVD risk was associated with increased frailty regardless of HIV serostatus among men and women. These findings may inform clinical practices of screening for frailty.
HIV care outcomes among transgender persons with HIV infection in the United States, 2006–2021
Authors: Becasen Jeffrey S. , Morris Joseph D. , Denard Christa L. , Mullins Mary M. , Kota Krishna Kiran , Higa Darrel H.
Published: October 2021

Objectives:

HIV prevalence is an estimated 14% among transgender women (TW) and 3% among transgender men (TM). HIV care is vital for viral suppression but is hindered by transphobia and HIV stigma. We assessed HIV care outcomes among transgender persons (TG) with HIV in the United States.

Design:

Systematic review and meta-analysis of peer-reviewed journal articles.

Methods:

We searched multiple electronic databases and Centers for Disease Control and Prevention's HIV Prevention Research Synthesis database for 2006–September 2020. Eligible reports were US-based studies that included TG and reported HIV care outcomes. Random-effects models were used to calculate HIV care outcome rates. The protocol is registered with PROSPERO (CRD42018079564).

Results:

Few studies reported outcomes for TM; therefore, only TW meta-analysis results are reported. Fifty studies were identified having low-to-medium risk-of-bias scores. Among TW with HIV, 82% had ever received HIV care; 72% were receiving care, and 83% of those were retained in HIV care. Sixty-two percent were currently virally suppressed. Among those receiving HIV care or antiretroviral therapy (ART), 67% were virally suppressed at last test. Sixty-five percent were linked to HIV care 3 months or less after diagnosis. Seventy-one percent had ever been prescribed ART. Approximately 66% were taking ART, and 66% were ART-adherent. Only 56% were currently adherent the previous year.

Conclusions:

HIV care outcomes for TW were not ideal, and research gaps exists for TM. High heterogeneity was observed; therefore, caution should be taken interpreting the findings. Integrating transgender-specific health needs are needed to improve outcomes of transgender persons across the HIV care continuum.
Diagnosis delays in the UK according to pre or postmigration acquisition of HIV
Authors: Stirrup Oliver , Tostevin Anna , Ragonnet-Cronin Manon , Volz Erik , Burns Fiona , Delpech Valerie , Dunn David
Published: October 2021

Objectives:

The aim of this study was to evaluate whether infection occurred pre or postmigration and the associated diagnosis delay in migrants diagnosed with HIV in the UK.

Design:

We analyzed a cohort of individuals diagnosed with HIV in the UK in 2014–2016 born in Africa or elsewhere in Europe. Inclusion criteria were arrival within 15 years before diagnosis, availability of HIV pol sequence, and viral subtype shared by at least 10 individuals.

Methods:

We examined phylogenies for evidence of infection after entry into the UK and incorporated this information into a Bayesian analysis of timing of infection using biomarkers of CD4+ cell count, avidity assays, proportion of ambiguous nucleotides in viral sequences, and last negative test dates where available.

Results:

One thousand, two hundred and fifty-six individuals were included. The final model indicated that HIV was acquired postmigration for most MSM born in Europe (posterior expectation 65%, 95% credibility interval 64–67%) or Africa (65%, 62–69%), whereas a minority (20–30%) of men and women with heterosexual transmission acquired HIV postmigration. Estimated diagnosis delays were lower for MSM than for those with heterosexual transmission, and were lower for those with postmigration infection across all subgroups. For MSM acquiring HIV postmigration, the estimated mean time to diagnosis was less than one year, but for those who acquired HIV premigration, the mean time from infection to diagnosis was more than five years for all subgroups.

Conclusion:

Acquisition of HIV postmigration is common, particularly among MSM, calling for prevention efforts aimed at migrant communities. Delays in diagnosis reinforce the need for targeted testing initiatives.
Peripheral artery disease and physical function in women with and without HIV
Authors: Cedarbaum Emily R. , Ma Yifei , Adimora Adaora A. , Bamman Marcas , Cohen Mardge H. , Fischl Margaret A. , Gustafson Deborah , Matsushita Kunihiro , Ofotokun Igho , Plankey Michael , Seaberg Eric C. , Sharma Anjali , Tien Phyllis C.
Published: October 2021

Objectives:

Peripheral artery disease (PAD) is associated with decreased physical function and increased mortality in the general population. We previously found that PAD is common in middle-aged women with and without HIV infection, but its association with functional decline is unclear. We examine the contribution of PAD to functional decline in the Women's Interagency HIV Study, controlling for traditional cardiovascular risk factors and HIV-related factors.

Methods:

Analysis included 1839 participants (72% with HIV) with measured ankle–brachial index (ABI) and 4 m gait speed. ABI values categorized PAD severity. Linear models with repeated measures estimated the association of PAD severity with log-transformed gait speed after controlling for demographic, behavioral, and metabolic risk factors, and HIV/hepatitis C virus status.

Results:

Median age was 50 years and more than 70% were Black. Compared with normal ABI, there was a dose–response relationship between increasing PAD severity and slower gait speed in univariable analyses: 6% slower gait speed for low-normal ABI [95% confidence interval (CI): 4–9%], 10% for borderline PAD (95% CI: 6–13%), 14% for mild PAD (95% CI: 9–18%), and 16% for moderate–severe PAD (95% CI: 5–25%). PAD severity remained associated with slower gait speed in multivariable analyses. HIV/hepatitis C virus co-infection was independently associated with 9% (95% CI: 4–14%) slower gait speed compared with those with neither infection. Among women with HIV, neither CD4+ cell count nor HIV-RNA level was associated with gait speed.

Conclusion:

In middle-aged women with and without HIV infection, greater PAD severity is associated with progressively slower gait speed. Early detection of subclinical PAD may decrease the risk of lower extremity functional impairment and its long-term health consequences.
The use of ultrasound in the acute setting: Lessons learned after 30 years
Authors: Rozycki Grace F.
Published: October 2021

This article describes the key events in the evolution of the surgeon's use of ultrasound for the evaluation of patients. The lessons learned may be relevant in the future as the issues encountered with the adoption of ultrasound by surgeons may be revisited.
Variations in clot phenotype following injury: The MA-R ratio and fragile clots
Authors: Harrington James , Zarzaur Ben L. , Fox Erin E. , Wade Charles E. , Holcomb John B. , Savage Stephanie A.
Published: October 2021

INTRODUCTION

Trauma-induced coagulopathy is a continuum ranging from hypercoagulable to hypercoagulable phenotypes. In single-center studies, the maximum amplitude (MA) to r-time (R) (MA-R) ratio has identified a phenotype of injured patients with high mortality risk. The purpose of this study was to determine the relationship between MA-R and mortality using multicenter data and to investigate fibrinogen consumption in the development of this specific coagulopathy phenotype.

METHODS

Using the Pragmatic Randomized Optimal Platelet and Plasma Ratios data set, patients were divided into blunt and penetrating injury cohorts. MA was divided by R time from admission thromboelastogram to calculate MA-R. MA-R was used to assess odds of early and late mortality using multivariable models. Multivariable models were used to assess thrombogram values in both cohorts. Refinement of the MA-R cut point was performed with Youden index. Repeat multivariable analysis was performed with a binary CRITICAL and NORMAL MA-R.

RESULTS

In initial analysis, MA-R quartiles were not associated with mortality in the penetrating cohort. In the blunt cohort, there was an association between low MA-R and early and late mortality. A refined cut point of 11 was identified (CRITICAL: MA-R, ≤11; NORMAL: MA-R, >11). CRITICAL MA-R was associated with mortality in both penetrating and blunt subgroups. In further injury subgroup analysis, CRITICAL patients had significantly decreased fibrinogen levels in the blunt subgroup only. In both blunt and penetrating injury, there was no difference in time to initiation of thrombin burst (lagtime). However, both endogenous thrombin potential and peak thrombin levels were significantly lower in CRITICAL patients.

CONCLUSIONS

MA-R identifies a trauma-induced coagulopathy phenotype characterized in blunt injury by impaired thrombin generation that is associated with early and late mortality. The endotheliopathy and tissue factor release likely plays a role in the cascade of impaired thrombin burst, possible early fibrinogen consumption and the weaker clot identified by MA-R.

LEVEL OF EVIDENCE

Therapeutic/care management, level II.
Lithium toxicity at therapeutic doses as a fallout of COVID-19 infection: a case series and possible mechanisms
Authors: Pai Naveen Manohar , Malyam Vidhyavathi , Murugesan Manisha , Ganjekar Sundarnag , Moirangthem Sydney , Desai Geetha
Published: October 2021

Lithium, a mood stabilizer used in the treatment of bipolar disorder is known for its anti-inflammatory properties with the discussion of its potential use in COVID-19 infection. The SARS-CoV-2 virus causing COVID-19 infection is known to enter the target cells through angiotensin converting enzyme-2 receptors present in abundance in the lung and renal tissue. Recent research supports the evidence for direct renal injury by viral proteins. Here we report two patients with bipolar disorder presenting with lithium toxicity in the presence of COVID-19 infection. Two patients with bipolar disorder, maintaining remission on lithium prophylaxis, presented to the psychiatric emergency with recent-onset fever and altered sensorium. Both the patient’s investigations revealed lithium toxicity, elevated serum creatinine, urea and inflammatory markers. Hypernatremia, hyperkalaemia, and hyperchloremia were seen in one patient. Lithium and other psychotropic medications were stopped immediately, and COVID-19 treatment was initiated. Patient with clinical signs of lithium toxicity, hypernatremia, hyperkalaemia, and hyperchloremia developed ventricular tachycardia. He survived and regained consciousness after 2 weeks of aggressive conservative management. However, another patient died of acute respiratory failure on day 3. Possible direct infection of the kidney by SARS-CoV-2 viral proteins can manifest with acute kidney injury and lithium toxicity among patients on long-term lithium therapy. Health professionals treating COVID-19 infection among individuals on lithium therapy should be aware of the possibility of lithium toxicity in the background of renal injury.
Performance assessment of a new indirect rapid diagnostic test for plague detection in humans and other mammalian hosts
Authors: Bezerra Matheus Filgueira , dos Santos Wagner José Tenório , Rocha Igor Vasconcelos , Nadaes Natalia Rocha , Dantas-Torres Filipe , Silva Sales Kamila Gaudêncio da , de Melo Neto Osvaldo Pompilio , da Silva Marise Sobreira Bezerra , Silva Edimilson Domingos , de Almeida Alzira Maria Paiva , de Souza Reis Christian Robson
Published: October 2021

Plague is a flea-borne zoonosis that affects a wide range of mammals and still causes outbreaks in human populations yearly across several countries. While crucial for proper treatment, early diagnosis is still a major challenge in low- and middle-income countries due to poor access to laboratory infrastructure in rural areas. To tackle this issue, we developed and evaluated a new F1-based rapid diagnostic test (RDT) as an alternative method for plague diagnosis in humans and other mammals in the field. In this study, 187 serum samples from humans, dogs, rodents and rabbits were retrospectively assessed using the Plague RDT method. To calculate its performance rates, results were confronted to those obtained by hemagglutination (HA) and ELISA, considered as the reference standards. Remarkably, the results from RDT were in full agreement with those from the ELISA and HA assays, resulting in 100% (CI 95% = 95.5-100%) of sensitivity and 100% (CI 95% = 96.6-100%) of specificity. Accordingly, the Cohen’s Kappa test coefficient was 1.00 (almost perfect agreement). Moreover, the RDT showed no cross-reaction when tested with sera from individuals positive to other pathogens, such as Yersinia pseudotuberculosis, Yersinia enterocolitica, Anaplasma platys, Erliquia canis and Leishmania infantum. Although preliminary, this study brings consistent proof-of-concept results with high performance rates of the Plague RDT when compared to other methods well-established in the plague routine serodiagnosis. Although further human and animal population-based studies will be necessary to validate these findings, the data presented here show that the Plague RDT is highly sensitive and specific, polyvalent to several mammal species and simple to use in field surveillance or point-of-care situations with instant results.
Association of Body Anthropometry and Obstructive Sleep Apnea in Children: Impact of Hispanic Ethnicity
Authors: Bhattacharjee Emily B , Sun Xiaoying , Malhotra Atul , Tantisira Kelan G , Landeo-Gutierrez Jeremy S , Jain Sonia , Bhattacharjee Rakesh
Published: October 2021

Objectives

Obesity is a risk factor for obstructive sleep apnea (OSA) in children. Childhood obesity rates vary amongst different ethnic groups. Here we explore the interaction of Hispanic ethnicity and obesity on OSA risk.

Methods

Retrospective cross-sectional analysis of consecutive children undergoing polysomnography and anthropometry using bioelectrical impedance from 2017-2020. Demographics obtained from the medical chart. Children who had also undergone cardiometabolic testing were identified to assess the relationship of cardiometabolic markers with OSA and anthropometry.

Results

Data from 1217 children revealed Hispanic children were more likely to have moderate-severe OSA (36.0%) compared to Non-Hispanic children (26.5%), p<0.001. Hispanic children had greater BMI, BMI percentile and percent body fat, p<0.0001. In children that underwent cardiometabolic testing, Hispanic children had significantly greater serum ALT levels. Following adjustment of age and sex, Hispanic ethnicity was not found to moderate the association of anthropometry with OSA, anthropometry with cardiometabolic markers, and OSA with cardiometabolic markers.

Conclusions

OSA is more likely in Hispanic children; this relationship is likely driven by obesity status rather than ethnicity. Among children undergoing cardiometabolic testing, Hispanic children were observed to have greater ALT concentrations however ethnicity did not impact the association of anthropometry and ALT or other cardiometabolic markers.
Predictors of SARS-CoV-2 infection following high-risk exposure
Authors: Andrejko Kristin L. , Pry Jake , Myers Jennifer F. , Openshaw John , Watt James , Birkett Nozomi , DeGuzman Jennifer L. , Li Sophia S. , Barbaduomo Camilla M. , Fang Anna T. , Tran Vivian H. , Javadi Mahsa H. , Frost Paulina M. , Dong Zheng N. , Jain Seema , Lewnard Joseph A.
Published: October 2021

Background

Non-pharmaceutical interventions (NPIs) are recommended for COVID-19 mitigation. However, the effectiveness of NPIs in preventing SARS-CoV-2 transmission remains poorly quantified.

Methods

We conducted a test-negative design case-control study enrolling cases (testing positive for SARS-CoV-2) and controls (testing negative) with molecular SARS-CoV-2 diagnostic test results reported to California Department of Public Health between 24 February-26 September, 2021. We used conditional logistic regression to assess predictors of case status among participants who reported contact with an individual known or suspected to have been infected with SARS-CoV-2 (“high-risk exposure”) within ≤14 days of testing.

Results

643 of 1280 cases (50.2%) and 204 of 1263 controls (16.2%) reported high-risk exposures ≤14 days before testing. Adjusted odds of case status were 2.94-fold (95% confidence interval: 1.66-5.25) higher when high-risk exposures occurred with household members (vs. other contacts), 2.06-fold (1.03-4.21) higher when exposures occurred indoors (vs. not indoors), and 2.58-fold (1.50-4.49) higher when exposures lasted ≥3 hours (vs. shorter durations) among unvaccinated and partially-vaccinated individuals; excess risk associated with such exposures was mitigated among fully-vaccinated individuals. Mask usage by participants or their contacts during high-risk exposures reduced adjusted odds of case status by 48% (8-72%). Adjusted odds of case status were 68% (32-84%) and 77% (59-87%) lower for partially- and fully-vaccinated participants, respectively, than for unvaccinated participants. Benefits of mask usage were greatest when exposures lasted ≥3 hours, occurred indoors, or involved non-household contacts.

Conclusions

NPIs reduced the likelihood of SARS-CoV-2 infection following high-risk exposure. Vaccine effectiveness was substantial for partially and fully vaccinated persons.

KEY POINTS

SARS-CoV-2 infection risk was greatest for unvaccinated participants when exposures to known or suspected cases occurred indoors or lasted ≥3 hours.

Face mask usage when participants were exposed to a known or suspect case reduced odds of infection by 48%.
Generation time of the Alpha and Delta SARS-CoV-2 variants
Authors: Hart WS , Miller E , Andrews NJ , Waight P , Maini PK , Funk S , Thompson RN
Published: October 2021

Background

In May 2021, the Delta SARS-CoV-2 variant became dominant in the UK. This variant is associated with increased transmissibility compared to the Alpha variant that was previously dominant. To understand ongoing transmission and interventions, a key question is whether the Delta variant generation time (the time between infections in infector- infectee pairs) is typically shorter–i.e., transmissions are happening more quickly–or whether infected individuals simply generate more infections.

Methods

We analysed transmission data from a UK Health Security Agency household study. By fitting a mathematical transmission model to the data, we estimated the generation times for the Alpha and Delta variants.

Results

The mean intrinsic generation time (the generation time if there had been a constant supply of susceptibles throughout infection) was shorter for the Delta variant (4·6 days, 95% CrI 4·0-5·4 days) than the Alpha variant (5·5 days, 95% CrI 4·6-6·4 days), although within uncertainty ranges. However, there was a larger difference in the realised mean household generation time between the Delta (3·2 days, 95% CrI 2·4-4·2 days) and Alpha (4·5 days, 95% CrI 3·7-5·4 days) variants. This is because higher transmissibility led to faster susceptible depletion in households, in addition to the reduced intrinsic generation time.

Conclusions

The Delta variant transmits more quickly than previously circulating variants. This has implications for interventions such as contact tracing, testing and isolation, which are less effective if the virus is transmitted quickly. Epidemiological models of interventions should be updated to include the shorter generation time of the Delta variant.
Reduced context updating but intact visual priors in autism
Authors: Randeniya R. , Vilares I. , Mattingley J. B. , Garrido M. I.
Published: October 2021

A general consensus persists that sensory-perceptual differences in autism, such as hypersensitivities to light or sound, result from an overreliance on new (rather than prior) sensory observations. However, conflicting Bayesian accounts of autism remain unresolved as to whether such alterations are caused by more precise sensory observations (precise likelihood model) or by forming a less precise model of the sensory context (hypo-priors model). We used a decision-under-uncertainty paradigm that manipulated uncertainty in both likelihoods and priors. Contrary to model predictions we found no differences in reliance on likelihood in autistic group (AS) compared to neurotypicals (NT) and found no differences in subjective prior variance between groups. However, we found reduced context adjustment in the AS group compared to NT. Further, the AS group showed heightened variability in their relative weighting of sensory information (vs. prior) on a trial-by-trial basis. When participants were aligned on a continuum of autistic traits, we found no associations with likelihood reliance or prior variance but found an increased likelihood precision with autistic traits. These findings together provide empirical evidence for intact priors, precise likelihood, reduced context updating and heightened variability during sensory learning in autism.
Variations in cell-surface ACE2 levels alter direct binding of SARS-CoV-2 Spike protein and viral infectivity: Implications for measuring Spike protein interactions with animal ACE2 orthologs
Authors: Kazemi Soheila , López-Muñoz Alberto Domingo , Hollý Jaroslav , Jin Ling , Yewdell Jonathan W. , Dolan Brian P.
Published: October 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, the most severe pandemic in a century. The virus gains access to host cells when the viral Spike protein (S-protein) binds to the host cell-surface receptor angiotensin-converting enzyme 2 (ACE2). Studies have attempted to understand SARS-CoV-2 S-protein interaction with vertebrate orthologs of ACE2 by expressing ACE2 orthologs in mammalian cells and measuring viral infection or S-protein binding. Often these cells only transiently express ACE2 proteins and levels of ACE2 at the cell surface are not quantified. Here, we describe a cell-based assay that uses stably transfected cells expressing ACE2 proteins in a bi-cistronic vector with an easy to quantify reporter protein to normalize ACE2 expression. We found that both binding of the S-protein receptor-binding domain (RBD) and infection with a SARS-CoV-2 pseudovirus is proportional to the amount of human ACE2 expressed at the cell surface, which can be inferred by quantifying the level of reporter protein, Thy1.1. We also compared different ACE2 orthologs which were expressed in stably transfected cells expressing equivalent levels of Thy1.1. When ranked for either viral infectivity or RBD binding, mouse ACE2 had a weak to undetectable affinity for S-protein while human ACE2 was the highest level detected and feline ACE2 had an intermediate phenotype. The generation of stably transfected cells whose ACE2 level can be normalized for cross-ortholog comparisons allows us to create a reusable cellular library useful for measuring emerging SARS-CoV-2 variant’s ability to potentially infect different animals.

Importance

SARS-CoV-2 is a zoonotic virus responsible for the worst global pandemic in a century. An understanding of how the virus can infect other vertebrate species is important for controlling viral spread and understanding the natural history of the virus. Here we describe a method to generate cells stably expressing equivalent levels of different ACE2 orthologs, the receptor for SARS-CoV-2, on the surface of a human cell line. We find that both binding of the viral Spike protein receptor binding domain (RBD) and infection of cells with a SARS-CoV-2 pseudovirus are proportional to ACE2 levels at the cell surface. Adaptation of this method will allow for the creation of a library of stable transfected cells expressing equivalent levels of different vertebrate ACE2 orthologs which can be repeatedly used for identifying vertebrate species which may be susceptible to infection with SARS-CoV-2 and its many variants.
Hippocampal spatio-temporal cognitive maps adaptively guide reward generalization
Authors: Garvert Mona M. , Saanum Tankred , Schulz Eric , Schuck Nicolas W. , Doeller Christian F.
Published: October 2021

The brain forms cognitive maps of relational knowledge, an organizing principle thought to underlie our ability to generalize and make inferences. However, how can a relevant map be selected in situations where a stimulus is embedded in multiple relational structures? Here, we find that both spatial and temporal cognitive maps influence generalization in a choice task, where spatial location determines reward magnitude. Mirroring behavior, the hippocampus not only builds a map of spatial relationships but also encodes temporal distances. As the task progresses, participants’ choices become more influenced by spatial relationships, reflected in a strengthening of the spatial and a weakening of the temporal map. This change is driven by orbitofrontal cortex, which represents the evidence that an observed outcome is generated from the spatial rather than the temporal map and updates hippocampal representations accordingly. Taken together, this demonstrates how hippocampal cognitive maps are used and updated flexibly for inference.
Hingepoint emergence in mammalian spinal neurulation
Authors: de Goederen Veerle , Vetter Roman , McDole Katie , Iber Dagmar
Published: October 2021

Neurulation is the process in early vertebrate embryonic development during which the neural plate folds to form the neural tube. Spinal neural tube folding in the posterior neuropore changes over time, first showing a median hingepoint, then both the median hingepoint and dorsolateral hingepoints, followed by dorsolateral hingepoints only. The biomechanical mechanism of hingepoint formation in the mammalian neural tube is poorly understood. Here, we employ a mechanical finite element model to study neural tube formation. The computational model mimics the mammalian neural tube using microscopy data from mouse and human embryos. While intrinsic curvature at the neural plate midline has been hypothesized to drive neural tube folding, intrinsic curvature was not sufficient for tube closure in our simulations. We achieved neural tube closure with an alternative model combining mesoderm expansion, non-neural ectoderm expansion and neural plate adhesion to the notochord. Dorsolateral hingepoints emerged in simulations with low mesoderm expansion and zippering. We propose that zippering provides the biomechanical force for dorsolateral hingepoint formation in settings where the neural plate lateral sides extend above the mesoderm. Together, these results provide a new perspective on the biomechanical and molecular mechanism of mammalian spinal neurulation.
Disruption of Epithelial Integrity Drives Mesendoderm Differentiation in Human Induced Pluripotent Stem Cells by Enabling BMP and ACTIVIN Sensing
Authors: Rattier Diane , Legier Thomas , Vannier Thomas , Maina Flavio , Dono Rosanna
Published: October 2021

The processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between tissue organization and morphogens by using human induced pluripotent stem cells (hiPSCs) down-regulated for the morphogen regulator GLYPICAN-4, in which defects in tight junctions result in areas of disrupted epithelial integrity. Remarkably, this phenotype does not affect hiPSC stemness, but impacts on cell fate acquisition processes. Strikingly, cells within disrupted areas become competent to perceive BMP4 and ACTIVIN A/NODAL gastrulation signals and thus, differentiate into mesendoderm. Yet, disruption of epithelial integrity prolongs temporal activation of BMP4 and ACTIVIN A/NODAL downstream effectors and correlates with enhanced hiPSC endoderm/mesoderm differentiation potential. Altogether, our results disclose epithelial cell integrity as a key determinant of TGF-β activity and highlight a new mechanism guiding morphogen sensing and spatial cell fate change within an epithelium.
Coordinated DNA and Histone Dynamics Drive Accurate Histone H2A.Z Exchange
Authors: Poyton Matthew F. , Feng Xinyu A. , Ranjan Anand , Lei Qin , Wang Feng , Zarb Jasmin S. , Louder Robert K. , Park Giho , Jo Myung Hyun , Ye Joseph , Liu Sheng , Ha Taekjip , Wu Carl
Published: October 2021

Nucleosomal histone H2A is exchanged for its variant H2A.Z by the SWR1 chromatin remodeler, but the mechanism and timing of histone exchange remain unclear. Here, we quantify DNA and histone dynamics during histone exchange in real-time using a three-color single-molecule FRET assay. We show that SWR1 operates with timed precision to unwrap DNA with large displacement from one face of the nucleosome, remove H2A-H2B from the same face, and rewrap DNA, all within 2.3 seconds. Such productive DNA unwrapping requires full SWR1 activation and differs from unproductive, smaller-scale DNA unwrapping caused by SWR1 binding alone. On an asymmetrically positioned nucleosome, SWR1 intrinsically senses long-linker DNA to preferentially exchange H2A.Z on the distal face as observed in vivo. The displaced H2A-H2B dimer remains briefly associated with the SWR1-nucleosome complex and is dissociated by histone chaperones. These findings reveal how SWR1 coordinates DNA unwrapping with histone dynamics to rapidly and accurately place H2A.Z at physiological sites on chromatin.

One-Sentence Summary

Multicolor single-molecule FRET reveals how SWR1 unwraps DNA to exchange nucleosomal H2A-H2B for H2A.Z-H2B.