bluuebunny/crossref_metadata_2025 huggingface dataset:
High unmet treatment needs in patients with chronic kidney disease and type 2 diabetes: real-world evidence from a US claims database
Authors: Fried Linda , Schmedt Niklas , Folkerts Kerstin , Bowrin Kevin , Raad Hanaya , Batech Michael , Kovesdy Csaba
Published: April 2022

Background

Chronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease

(ESKD). Treatment guidelines recommend renin–angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort).

Methods

In this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs.

Results

We identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found.

Conclusion

Our results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden.
Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19
Authors: Pepperrell Toby , Ellis Leah , Wang Junzheng , Hill Andrew
Published: April 2022

Pfizer and the Medicines Patent Pool (MPP) have reached a voluntary licensing agreement for Paxlovid (nirmatrelvir+ritonavir), a novel antiviral for coronavirus disease 2019 (COVID-19) taken orally in the first 5 days from symptom onset. The Pfizer-MPP deal enables 95 low- and middle-income countries (L/MICs) to access affordable biosimilars. Generics are delayed awaiting bioequivalence testing and may be ineffective in L/MICs with reduced testing capacity, which comprise only 10% of global diagnoses. Thirty-nine percent of diagnoses originate in MICs forced to pay high prices due to exclusion from the Pfizer-MPP deal. The cost-effectiveness of Paxlovid could be limited compared with the creation of sustainable vaccine infrastructure in these nations, delaying socioeconomic pandemic recovery. Furthermore, Paxlovid may not be cost-effective in vaccinated populations, and concerns remain over ritonavir drug interactions with COVID-19 comorbidity medications. We call for expanded coverage by the Paxlovid-MPP deal and greater access to testing.
Gaps in Hepatitis A and Hepatitis B Vaccination Among Hepatitis C Antibody–Positive Individuals Experiencing Homelessness
Authors: Partida Diana , Powell Jesse , Gonzalez Daniel , Khalili Mandana
Published: April 2022

Vaccination for both hepatitis A (HAV) and hepatitis B (HBV) is recommended in hepatitis C infection (HCV). Among HCV antibody–positive persons experiencing homelessness, we identified high rates of HAV (34%) and HBV vaccine (35%) eligibility, highlighting critical gaps in HCV preventative services. Following education, 54% and 72% underwent HAV and HBV vaccination, respectively.
Determinants of LGBTQ+ Corporate Policies
Authors: Artiga González Tanja , Calluzzo Paul , Dong G Nathan , Granic Georg D
Published: April 2022

We study the determinants of firms’ LGBTQ+ policies and their relation to general CSR policies. Common factors explain LGBTQ+ policies related to firms’ primary stakeholders and those aimed at public LGBTQ+ efforts: younger firms, those with more financial resources, more educated workforces, catering to retail customers, and located in liberal areas have more LGBTQ+-friendly policies. LGBTQ+ initiatives encounter less societal agreement than CSR initiatives. Illustrating the distinctiveness of LGBTQ+ issues in the CSR space, we find that firms’ LGBTQ+ friendliness only weakly correlates with overall CSR performance. Lastly, we show that firms’ LGBTQ+ policies respond to pressure from shareholder proposals. (JEL G32, G34, G38)
Neural correlates with individual differences in temporal prediction during auditory-motor synchronization
Authors: Miyata Kohei , Yamamoto Tetsuya , Fukunaga Masaki , Sugawara Sho , Sadato Norihiro
Published: April 2022

Temporal prediction ability is vital for movement synchronization with external rhythmic stimuli (sensorimotor synchronization); however, little is known regarding individual variations in temporal prediction ability and its neural correlates. We determined the underlying neural correlates of temporal prediction and individual variations during auditory-motor synchronization. We hypothesized that the non-primary motor cortices, such as the premotor cortex and supplementary motor area, are the key brain regions that correlate individual variations in prediction ability. Functional magnetic resonance imaging (7T) was performed for 18 healthy volunteers who tapped to 3 types of auditory metronome beats: isochronous, tempo change, and random. The prediction ability was evaluated using prediction/tracking ratios that were computed based on cross-correlations between tap timing and pacing events. Participants with a higher prediction/tracking ratio (i.e. stronger predictive tendency) tapped to metronome beats more accurately and precisely. The prediction/tracking ratio was positively correlated with the activity in the bilateral dorsal premotor cortex (PMd), suggesting that the bilateral PMd explains the individual variation in prediction ability. These results indicate that the PMd is involved in generating a model for temporal prediction of auditory rhythm patterns and its activity would reflect model accuracy, which is critical for accurate and precise sensorimotor synchronization.
Predicting Time to Death After Withdrawal of Life-Sustaining Measures Using Vital Sign Variability: Derivation and Validation
Authors: Scales Nathan B. , Herry Christophe L. , van Beinum Amanda , Hogue Melanie L. , Hornby Laura , Shahin Jason , Dhanani Sonny , Seely Andrew J. E.
Published: April 2022

OBJECTIVES:

To develop a predictive model using vital sign (heart rate and arterial blood pressure) variability to predict time to death after withdrawal of life-supporting measures.

DESIGN:

Retrospective analysis of observational data prospectively collected as part of the Death Prediction and Physiology after Removal of Therapy study between May 1, 2014, and May 1, 2018.

SETTING:

Adult ICU.

PATIENTS:

Adult patients in the ICU with a planned withdrawal of life-supporting measures and an expectation of imminent death.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Vital sign waveforms and clinical data were prospectively collected from 429 patients enrolled from 20 ICUs across Canada, the Czech Republic, and the Netherlands. Vital sign variability metrics were calculated during the hour prior to withdrawal. Patients were randomly assigned to the derivation cohort (288 patients) or the validation cohort (141 patients), of which 103 and 54, respectively, were eligible for organ donation after circulatory death. Random survival forest models were developed to predict the probability of death within 30, 60, and 120 minutes following withdrawal using variability metrics, features from existing clinical models, and/or the physician’s prediction of rapid death. A model employing variability metrics alone performed similarly to a model employing clinical features, whereas the combination of variability, clinical features, and physician’s prediction achieved the highest area under the receiver operating characteristics curve of all models at 0.78 (0.7–0.86), 0.79 (0.71–0.87), and 0.8 (0.72–0.88) for 30-, 60- and 120-minute predictions, respectively.

CONCLUSIONS:

Machine learning models of vital sign variability data before withdrawal of life-sustaining measures, combined with clinical features and the physician’s prediction, are useful to predict time to death. The impact of providing this information for decision support for organ donation merits further investigation.
Regulator of G-Protein Signaling 5 Protein Deficiency Differentially Influences Blood Pressure, Vascular and Behavioral Effects in Aged Male Mice
Authors: D'Souza Manoranjan S. , Luu Anh N. , Guisinger Trevor C. , Seeley Sarah L. , Waldschmidt Ryan A. , Chrissobolis Sophocles
Published: April 2022

Aging and elevated activity of the renin–angiotensin–system (RAS) are associated with hypertension, vascular and emotional behavioral abnormalities, like anxiety and depression. Many actions of the main effector hormone of the RAS, angiotensin II (Ang II), are mediated by Ang II type 1 receptor whose activity is modulated by the regulator of G-protein signaling 5 (RGS5) protein. We assessed the role of RGS5 on blood pressure, vascular and emotional behavioral outcomes in aged male mice in the presence and absence of chronically elevated Ang II levels. We used aged (∼21-month old) male RGS5-deficient (RGS5−/−) and wild-type (RGS5+/+) mice treated with vehicle (saline) or Ang II (1 mg/kg/d for 21 days). RGS5 deficiency increased baseline and cerebral vascular superoxide levels in the presence of chronically elevated Ang II levels, suggesting that RGS5 deficiency leads to elevated blood pressure and deleterious cerebral vascular outcomes in aged mice. RGS5 deletion had no effect on Ang II–induced increases in systolic blood pressure. Chronically elevated Ang II levels increased spontaneous locomotor activity in RGS5+/+ but not RGS5−/− mice. RGS5 deficiency and Ang II treatment had no effect on anxiety- and depression-like behavior. This is the first study to assess the effects of deficiency of an RGS protein in the vasculature or on emotional behavioral outcomes in aged mice. We report that RGS5 has protective effects on blood pressure and the cerebral vasculature in aged mice. Clinically, these data suggest that RAS blockers may significantly reduce cerebrovascular disease risk in aged males lacking RGS5.
Impact of the Gastrointestinal Tract Microbiota on Cardiovascular Health and Pathophysiology
Authors: Gunaydin Akyildiz Aysenur , Biondi-Zoccai Giuseppe , De Biase Daniela
Published: April 2022

The microbiota of the gastrointestinal tract (GIT) is an extremely diverse community of microorganisms, and their collective genomes (microbiome) provide a vast arsenal of biological activities, particularly enzymatic ones, which are far from being fully elucidated. The study of the microbiota (and the microbiome) is receiving great interest from the biomedical community because it carries the potential to improve risk prediction models, refine primary and secondary prevention efforts, and also design more appropriate and personalized therapies, including pharmacological ones. A growing body of evidence, although sometimes impaired by the limited number of subjects involved in the studies, suggests that GIT dysbiosis, that is, the altered microbial composition, has an important role in causing and/or worsening cardiovascular disease (CVD). Bacterial translocation and the alteration of levels of microbe-derived metabolites can thus be important to monitor and modulate because they may lead to initiation and progression of CVD and to its establishment as chronic state. We hereby aim to provide readers with details on available resources and experimental approaches that are used in this fascinating field of biomedical research and on some novelties on the impact of GIT microbiota on CVD.
Laser Therapy for Recalcitrant Vulvar Lichen Sclerosus: A Review of the Literature
Authors: Marnach Mary L. , Casey Petra M.
Published: April 2022

Vulvar lichen sclerosus (LS) is a chronic vulvar dermatosis potentially impacting quality of life and sexual function. While most women with LS respond to topical corticosteroids and/or calcineurin inhibitors, some require additional therapy. Systemic therapies have been used successfully in oral and vulvovaginal lichen planus with minimal data in the setting of LS. Likewise, while vaginal laser therapy has shown potential benefit for genitourinary syndrome of menopause, there is a paucity of data in the setting of LS. We review retrospective and prospective studies along with randomized controlled trials utilizing vulvovaginal laser for LS therapy.
OCULAR FEATURES ASSOCIATED WITH MUTATIONS IN ATOH7 GENE OVERLAP THOSE WITH FAMILIAL EXUDATIVE VITREORETINOPATHY
Authors: Naruse Sho , Kondo Hiroyuki
Published: April 2022

Background/Purpose:

To report the ocular findings in three patients with a mutation in the ATOH7 gene.

Methods:

The clinical findings were collected from the medical records including those for magnetic resonance imaging. Three patients of two families who had poor vision since infancy were studied. Genetic testing of the ATOH7 gene was performed.

Results:

The three patients had varying degrees of intraocular vascular proliferation associated with advanced retinal detachments as falciform retinal folds or total retinal detachments. This state is referred to as congenital retinal nonattachment. One eye of a sibling had fluorescein angiographic findings of excessive branching of the retinal vessels and fluorescent dye leakage that were consistent with those of familial exudative vitreoretinopathy. Bilateral hypoplasia of the optic nerve was found in all three patients by magnetic resonance imaging. Genetic analysis showed a known in-frame deletion of the ATOH7 gene in all three patients.

Conclusion:

This is the first report of a patient with a mutation in the ATOH7 gene that had typical vascular patterns of familial exudative vitreoretinopathy in the peripheral retina. The ocular features associated with mutations in the ATOH7 gene overlap those with familial exudative vitreoretinopathy at the early and advanced stages.
C-DU(KE) Calculator: A Clinical Tool for Risk Stratification in Infectious Keratitis
Authors: Mousa Hazem M. , Feghali James , Song Ailin , Soifer Matias , Jammal Alessandro A. , Perez Victor L.
Published: April 2022

Purpose:

The aim of this study was to identify characteristics of infectious keratitis predictive of poor outcome to develop a web-based predictive calculator.

Method:

A retrospective chart review was performed at the Duke Eye Center. Two hundred fifteen adult patients with culture-proven infectious keratitis presenting between January 1, 2016, and December 31, 2020, were separated into a derivation set (136 patients, 53 positives; 83 controls) and a temporal validation set (79 patients, 26 positives; 53 controls). The poor outcome group consisted of patients requiring penetrating keratoplasty for visually significant scarring, penetrating keratoplasty for ulcer progression, or evisceration/enucleation for endophthalmitis. Univariable analysis was performed followed by stepwise multivariable logistic regression to obtain a predictive model in the derivation data set. Culture-naïve and postculture models were constructed. Discrimination and calibration were assessed using the area under the curve (AUC) and calibration plots, respectively.

Results:

The culture-naïve model consisted of corticosteroid drop use postsymptom onset [Odds Ratio (OR) = 2.3, P = 0.054], decreased vision (OR = 2.4, P = 0.001), and increased ulcer area (OR = 1.017, P = 0.017). The postculture model additionally included fungal keratitis (OR = 5.4, P = 0.006) and elapsed time from symptoms to organism-sensitive therapy (OR = 1.027, P = 0.014). The models were summarized by the acronym C-DU(KE). The AUCs for the culture-naïve model were 0.794 in the derivation set and 0.850 in the validation set. The AUCs for the postculture model were 0.898 in the derivation set and 0.946 in the validation set. Calibration plots indicated goodness of fit in the data sets for both models. The calculator was deployed under the URL: https://duke-eye-calculator.shinyapps.io/Corneal_Ulcers/.

Conclusions:

The C-DU(KE) calculator permits a data-driven prediction of outcome in infectious keratitis that can supplement clinical judgment.
Postnatal Cytomegalovirus Infection: Is it Important? A 10-Year Retrospective Case-control Study of Characteristics and Outcomes in Very Preterm and Very Low Birth Weight Infants
Authors: Minihan Lily , Lee Oei Ju , Bajuk Barbara , Palasanthiran Pamela
Published: April 2022

Background:

To determine the characteristics and outcomes of postnatal cytomegalovirus (pCMV) infection in preterm infants in a neonatal intensive care unit (NICU).

Methods:

A retrospective, matched case-control study in a tertiary NICU. Infants born between January 2009 and December 2019, <32 weeks’ gestational age (GA) and/or birth weight (BW) <1500 g with pCMV infection were matched 1:1 with cytomegalovirus-(CMV)-negative infants by year of admission, gender, GA and BW. Primary outcome was death ≤36 weeks’ postmenstrual age or bronchopulmonary dysplasia (BPD). Secondary outcomes were length of ventilation (LOV), length of stay (LOS) and neurodevelopmental impairment (NDI) at corrected age 1 and 2 years.

Results:

Forty-eight pCMV-positive infants (median GA 25.3 weeks, BW 695 g, age 58 days) were identified from 1659 infants (incidence 2.9%). The most common symptoms of pCMV infection were abdominal distension (43.8%), sepsis-like syndrome (29.2%), thrombocytopenia (60.5%) and conjugated hyperbilirubinemia (60.9%). Compared with controls, there were no significant differences in the composite outcome of death or BPD (56.3% vs. 37.5%; P = 0.1) or NDI at 1 and 2 years (51.9% vs. 44%; P = 0.8; 71.4% vs. 50%; P = 0.4). pCMV-positive infants had a significantly longer median LOV (23.5 vs. 12 days)* and LOS (140 vs. 110.5 days)*. Eleven (22.9%) infants received antivirals. Ten improved and 1 died. Two untreated infants died (1 from pCMV infection).

Conclusions:

Clinically identifiable pCMV infections are significant and associated with increased respiratory support and prolonged hospital stay in vulnerable infants. pCMV screening and preventive measures against transmission merit consideration.

*P < 0.05.
Coagulation Abnormalities and Management in Hospitalized Pediatric Patients With COVID-19
Authors: Noni Maria , Koukou Dimitra-Maria , Tritzali Maroula , Kanaka-Gantenbein Christina , Michos Athanasios , Spoulou Vana
Published: April 2022

Background:

The incidence and severity of coagulation abnormalities have not been extensively studied in pediatric populations with coronavirus disease 2019 (COVID-19). Moreover, their association with an increased risk for thromboembolic events remains unclear, and there is a lack of evidence for optimal prophylactic antithrombotic management. The aim of our study was to present our experience in evaluation, management, and long-term outcomes of coagulation abnormalities in pediatric hospitalized patients with COVID-19.

Methods:

A prospective study was performed in all children hospitalized for COVID-19 during a 6-month period focusing on patients’ coagulation abnormalities, the normalization of the coagulation profile with or without anticoagulation prophylaxis and the clinical outcome of the disease.

Results:

Two hundred twenty-three patients (median age: 11.4 months) were enrolled in the study. Coagulation abnormalities were detected in 92.4% of patients with increased D-dimer levels to be the most common abnormality detected in 84.3% of patients. Prophylactic anticoagulation was initiated only in 7 (3.1%) selected patients with severe COVID-19 and at least 2 risk factors for venous thromboembolism (VTE) and in all patients with previous history of VTE. Follow-up coagulation profile in 85 patients showed that changes over time had a tendency towards normalization irrespectively of the initiation of anticoagulant thromboprophylaxis. No thrombotic complications were observed 3 months upon discharge.

Conclusions:

Although abnormal findings in coagulation profile were very common, they were not associated with risk for VTE even in severe cases. A trend of normalization early in the course of the disease was observed regardless of the use of anticoagulant thromboprophylaxis.
Guillain-Barré Syndrome Associated With Acute Toxoplasmosis in a 3-Year-old Boy
Authors: Satostegui Margarita , Altcheh Jaime , Moroni Samanta , Moscatelli Guillermo
Published: April 2022

Few clinical cases of Guillain-Barré syndrome have been described following acute Toxoplasma gondii infection, all in adult patients. We report a case of a 3-year-old boy who developed this syndrome with a good response to antiparasitic treatment.
Association Between Self-care and Resilience
Authors: van Rijn Michelle M. , Jaarsma Tiny , de Man-van Ginkel Janneke M. , Weldam Saskia W.M.
Published: April 2022

Background

Self-care (SC) is a cornerstone in heart failure management and is related to patient outcomes. The continuous and complex demands of SC can be experienced as stressful and may require patients to apply resilient behaviors as they manage their conditions. Resilience may be a helpful factor in performing SC.

Objective

The aim of this study was to determine the association between resilience and SC in patients with heart failure.

Methods

A cross-sectional study was performed between January 2020 and January 2021. Participants were asked to complete a questionnaire addressing baseline characteristics, the 2-item Patient Health Questionnaire, the Resilience Evaluation Scale, and the Self-Care of Chronic Illness Inventory, which measures 3 concepts of SC: SC maintenance, SC monitoring, and SC management. Multiple regression analysis was performed to determine whether resilience was associated with SC.

Results

Eighty-six patients were included, and 74 patients completed the questionnaire. In the univariate analysis, an association was found between resilience and SC maintenance, resulting in an increase in SC for patients with higher resilience (β = 0.24; 95% confidence interval, 0.03–0.96). In the multivariate analysis adjusted and corrected for confounders, no significant associations between resilience and all SC scales were found.

Conclusion

This study could not demonstrate significant associations between resilience and all SC scales. This study contributes to the body of knowledge on factors that can mediate or moderate SC. Further longitudinal research should be performed to study cause-effect relationships.
Self-reported Sleep Quality Before and After Atrial Fibrillation Ablation
Authors: Wood Kathryn A. , Higgins Melinda K. , Barnes Angel H.
Published: April 2022

Background

Poor sleep quality is highly prevalent in atrial fibrillation (AF) with reported links between worse sleep quality and higher AF severity. Little research has examined whether sleep quality changes after AF ablation despite it being a routinely performed procedure.

Objective

The aim of this study was to evaluate self-reported sleep quality before and after AF ablation and to examine whether sleep quality differs by AF severity or sex.

Methods

This longitudinal pilot study assessed sleep using the Pittsburgh Sleep Quality Index at preablation and at 1, 3, and 6 months after ablation. Atrial fibrillation disease severity was assessed by the Canadian Cardiology Society Severity of AF scale. Outcomes were analyzed using descriptive statistics, Spearman ρ correlations, and multilevel longitudinal models.

Results

The sample (N = 20) was 55% female with a mean age of 65 (±7) years. Poor sleep quality (mean Pittsburgh Sleep Quality Index scores > 5) was evident at all time points. Improvement was noted at 3 months (moderate effect size d = 0.49); and negligible further improvement, from 3 to 6 months post ablation. Improvement was seen primarily in male subjects (large effect size d = 0.89 at 3 months), with smaller improvements for female subjects. Although Severity of AF scale scores were not correlated with sleep quality, Severity of AF scale severity scores did significantly improve over time.

Conclusions

Patients with AF have poor sleep quality that improves for the first 3 months after AF ablation, with men showing more improvement than women. A more accurate understanding of the sleep challenges after AF ablation could lead to development of more realistic patient education and improve patient self-management.
Disparities in COVID-19 Mortality Rates: Implications for Rural Health Policy and Preparedness
Authors: Grome Heather N. , Raman Rameela , Katz Benjamin D. , Fill Mary-Margaret , Jones Timothy F. , Schaffner William , Dunn John
Published: April 2022

Context:

It is well established that rural communities face geographic and socioeconomic challenges linked to higher rates of health disparities across the United States, though the coronavirus disease 2019 (COVID-19) impact on rural communities is less certain.

Objective:

To understand the COVID-19 pandemic's impact on rural communities in Tennessee, investigate differences in rural-urban mortality rates after controlling for confounding variables, and inform state pandemic response policy.

Design:

A cross-sectional analysis of cumulative COVID-19 morality rates.

Setting/Participants:

Tennessee county-level COVID-19 mortality data from March 1, 2020, to January 31, 2021, were matched with county-level sociodemographic and health data from public datasets: Agency for Healthcare Research and Quality Social Determinants of Health, PLACES: Local Data for Better Health County Data, and the US Census Bureau. County status was defined using the 2013 National Center for Health Statistics Urban-Rural Classification.

Main Outcome Measures:

A negative binomial regression model estimated adjusted incidence rate ratio and 95% confidence intervals (CI) for rural compared with urban mortality. Unadjusted rate ratios and rate differences for COVID-19 mortality in rural versus urban counties were compared with those for influenza and pneumonia and all-cause mortality over the past 5 years.

Results:

During the study period, 9650 COVID-19 deaths occurred across 42 urban and 53 rural counties. Controlling for county-level sociodemographic characteristics, health care access, and comorbidities, incidence rate ratio was 1.13 (95% CI, 1.00-1.28, P < .05) for rural as compared with urban deaths. Unadjusted COVID-19 mortality risk difference between rural and urban counties was greater (61.85, 95% CI, 54.31-69.31) than 5-year influenza and pneumonia rural-urban risk difference (12.57, 95% CI, 11.16-13.00) during 2015-2019.

Conclusions:

COVID-19 mortality rates were greater for populations living in Tennessee's rural as compared with urban counties during the study period. This differential impact must be considered in public health decision making to mitigate COVID-19.
Prevalence and Risk Factors of Post–heart Transplant Tricuspid Regurgitation
Authors: Kim Hong Rae , Kim Ho Jin , Lee Sang Eun , Jung Sung-Ho , Yun Tae-Jin , Kim Jae Joong , Lee Jae Won
Published: April 2022

Background.

Tricuspid valve regurgitation (TR) is a common sequela immediately after heart transplantation, and its occurrence has decreased after the adoption of the bicaval anastomosis technique. However, the fate of the tricuspid valve in patients undergoing heart transplantation using the bicaval technique is uncertain.

Methods.

We identified patients who underwent orthotopic heart transplantation with bicaval technique at our institution between January 2001 and December 2018. Changes in TR on transthoracic echocardiography from the immediately posttransplantation period until 10 y posttransplant were investigated.

Results.

A total of 475 consecutive patients (mean age, 49.1 ± 12.7 y; 153 females) who underwent heart transplantation and followed-up for a median of 74.0 mo (interquartile range, 39.5–118.1) were examined. The severities of TR immediately after heart transplantation were less than mild in 194 patients (40.8%), mild in 253 patients (53.3%), moderate in 20 patients (4.2%), and severe in 8 patients (1.7%). The rates of significant TR at 1 mo, 1 y, 3 y, and 5 y were 4.6% (22 of 475), 2.0% (9 of 459), 1.6% (6 of 387), and 1.4% (4 of 289), respectively. Generalized mixed-effects model showed that the TR decreased over time within 1 y (odd ratio, 0.08; 95% confidence interval, 0.02-0.32; P < 0.001) and increased thereafter (odds ratio, 1.37; 95% confidence interval, 1.19-1.58; P < 0.001). There were no patients who required surgical tricuspid valve intervention.

Conclusions.

In patients undergoing heart transplantation with the bicaval technique, significant TR was less common than the rates reported in previous studies and showed a trend of improvement within a year after surgery.
Lung Transplantation Advanced Prediction Tool: Determining Recipient’s Outcome for a Certain Donor
Authors: Zafar Farhan , Hossain Md Monir , Zhang Yin , Dani Alia , Schecter Marc , Hayes Don , Macaluso Maurizio , Towe Christopher , Morales David L.S.
Published: April 2022

Background.

Many risk-prediction models for lung transplantation are centered on recipient characteristics and do not account for impact of donor and transplant-related factors or only examine short-term outcomes (eg, predicted 1-y survival). We sought to develop a comprehensive model guiding recipient-donor matching.

Methods.

We identified double lung transplant recipients (≥12 y old) in the United Network for Organ Sharing Registry (2005–2020) to develop a risk scoring tool. Cohort was divided into derivation and validation sets. A total of 42 recipient, donor, and transplant factors were included in the analysis. Lasso method was used for variable selection. Survival was estimated using Cox-proportional hazard models. An interactive web-based tool was developed for clinical use.

Results.

A derivation cohort (n = 10 660) informed the model with 13-recipient, 4-donor, and 2-transplant variables. Adjusted risk scores were computed for every transplant and grouped into 3 clusters. Model-estimated survival probabilities were similar to the observed in the validation cohort (n = 4464) for all clusters. The mortality increases for medium- and high-risk groups was similar in both derivation and validation cohorts (C statistics for 1-, 5-, and 10-y survival were 0.67, 0.64, and 0.72, respectively). The web-based application estimated 1-, 5-, 10-y survival and half-life for low- (92%, 73%, 52%; 10.5 y), medium- (89%, 62%, 38%; 7.3 y), and high-risk clusters (85%, 52%, 26%; 5.2 y).

Conclusions.

Advanced methods incorporating machine/deep learning led to a risk scoring model (including recipient, donor, and transplant factors) and a web-based clinical tool providing short- and long-term survival probabilities for recipient-donor matches. This will enable risk-based matching that could improve utilization of and benefit from a limited donor pool.
The Duration in Treatment With Electroconvulsive Therapy Among Patients Screening Positive or Negative for Borderline Personality Disorder Traits
Authors: Luccarelli James , McCoy Thomas H. , Yip Agustin G. , Seiner Stephen J. , Henry Michael E.
Published: April 2022

Objective

While emerging evidence suggests that electroconvulsive therapy (ECT) is an effective treatment for depressive symptoms in patients with co-occurring borderline personality disorder (BPD) traits, it is unclear whether the presence of BPD traits modulates the tolerability of ECT. This study estimates the association between BPD traits and retention in acute course ECT treatment.

Methods

This study used a retrospective cohort of patients receiving ECT between 2015 and 2020 and who were assessed using the McLean Screening Instrument for BPD, the Quick Inventory of Depressive Symptomatology Self-Report 16-item scale, and the Montreal Cognitive Assessment before initiating treatment.

Results

One thousand five hundred eight patients received ECT during the study period, of whom 277 (18.4%) screened positive for BPD traits. Borderline personality disorder traits were associated with a higher odds of remaining in ECT for at least 10 treatments (adjusted odds ratio, 1.502; 95% confidence interval, 1.11–2.02; P = 0.007). Among individual symptom domains, only endorsing chronically feeling empty was associated with duration in ECT treatment.

Conclusions

Among patients receiving ECT, screening positive for BPD traits was associated with a higher odds of receiving at least 10 ECT treatments. These results support the overall tolerability of ECT in patients with BPD traits.
Dengue-2 Cosmopolitan genotype detection and emergence in South America
Authors: Giovanetti Marta , Pereira Luiz Augusto , Santiago Gilberto A. , Fonseca Vagner , García Mendoza Maria Paquita , de Oliveira Carla , de Moraes Laise , Xavier Joilson , Tosta Stephane , Fristch Hegger , de Castro Barbosa Emerson , Strazza Rodrigues Evandra , Figueroa-Romero Dana , Padilla-Rojas Carlos , Cáceres-Rey Omar , Mendonça Ana Flávia , de Bruycker Nogueira Fernanda , Venancio da Cunha Rivaldo , Bispo de Filippis Ana Maria , Freitas Carla , Leonel Peterka Cassio Roberto , Campelo de Albuquerque Carlos Frederico , Franco Leticia , Méndez Rico Jairo Andrés , Muñoz-Jordán Jorge L. , Lemes da Silva Vinícius , Alcantara Luiz Carlos Junior
Published: April 2022

We report the first confirmed case of DENV-2 Cosmopolitan genotype isolated from a male patient from Aparecida de Goiania, Goías state, Midwest Brazil. Using nanopore sequencing, and phylogenetic analyses our findings provide the first preliminary insight regarding the introduction of this emerging genotype in Brazil and South America.

Article Summary Line

Molecular detection of Dengue virus type 2 Cosmopolitan genotype in South America
Predicting Clinical Endpoints and Visual Changes with Quality-Weighted Tissue-based Renal Histological Features
Authors: Tam Ka Ho , Soares Maria F. , Kers Jesper , Sharples Edward J. , Ploeg Rutger J. , Kaisar Maria , Rittscher Jens
Published: April 2022

Two common obstacles limiting the performance of data-driven algorithms in digital histopathology classification tasks are the lack of expert annotations and the narrow diversity of datasets. Multi-instance learning (MIL) can be used to address the former challenge for the analysis of whole slide images (WSI) but performance is often inferior to full supervision. We show that the inclusion of weak annotations can significantly enhance the effectiveness of MIL while keeping the approach scalable.

An analysis framework was developed to process periodic acid-Schiff (PAS) and Sirius Red (SR) slides of renal biopsies. The workflow segments tissues into coarse tissue classes. Handcrafted and deep features were extracted from these tissues and combined using a soft attention model to predict several slide-level labels: delayed graft function (DGF), acute tubular injury (ATI), and Remuzzi grade components. A tissue segmentation quality metric was also developed to reduce the adverse impact of poorly segmented instances. The soft attention model was trained using 5-fold cross-validation on a mixed dataset and tested on the QUOD dataset containing n=373 PAS and n=195 SR biopsies.

The average ROC-AUC over different prediction tasks was found to be 0.598±0.011, significantly higher than using only ResNet50 (0.545±0.012), only handcrafted features (0.542±0.011), and the baseline (0.532±0.012) of state-of-the-art performance. Weighting tissues by segmentation quality in conjunction with soft attention has led to further improvement (AUC = 0.618 ± 0.010). Using an intuitive visualisation scheme, we show that our approach may also be used to support clinical decision making as it allows pinpointing individual tissues relevant to the predictions.

2020 MSC

68T07, 92C50
A novel immersive virtual reality environment for the motor rehabilitation of stroke patients: A feasibility study
Authors: Fregna Giulia , Schincaglia Nicola , Baroni Andrea , Straudi Sofia , Casile Antonino
Published: April 2022

We designed and implemented an immersive virtual reality environment for upper limb rehabilitation, which possesses several notable features. First, by exploiting modern computer graphics its can present a variety of scenarios that make the rehabilitation routines challenging yet enjoyable for patients, thus enhancing their adherence to the therapy. Second, immersion in a virtual 3D space allows the patients to execute tasks that are closely related to everyday gestures, thus enhancing the transfer of the acquired motor skills to real-life routines. Third, in addition to the VR environment, we also developed a client app running on a PC that allows to monitor in real-time and remotely the patients’ routines thus opening the door to telerehabilitation scenarios.

Here, we report the results of a feasibility study in a cohort of 16 stroke patients. All our patients showed a high degree of comfort in our immersive VR system and they reported very high scores of ownership and agency in embodiment and satisfaction questionnaires. Furthermore, and notably, we found that behavioral performances in our VR tasks correlated with the patients’ clinical scores (Fugl-Meyer scale) and they can thus be used to assess improvements during the rehabilitation program. While further studies are needed, our results clearly support the feasibility and effectiveness of VR-based motor rehabilitation processes.

Significance statement

Approximately 80% of stroke patients suffer from a hemiparesis of the contralateral upper limb. Motor rehabilitation has been proven to be of key importance to regain, partially or totally, the impaired motor skills. Rehabilitation techniques are based on the repetitive and intense execution of simple motor behaviors. As such they can become taxing and cumbersome for the patients. This often produces non-adherence issues with an obvious negative impact on motor recovery.

Here we describe a novel immersive virtual environment for upper limb motor rehabilitation and we report the results that we obtained in a cohort of 16 stroke patients. Our system was designed to turn rehabilitation routines into engaging games and to allow the remote monitoring of the patients’ exercises thus allowing telerehabilitation.

All our patients showed a high degree of comfort in our immersive VR system and they reported very high scores of ownership and agency in embodiment and satisfaction questionnaires. Furthermore, and notably, we found that behavioral performances in our VR tasks correlated with the patients’ clinical scores (Fugl-Meyer scale) and they can thus be used to assess improvements during the rehabilitation program.
Distinct respiratory tract biological pathways characterizing ARDS molecular phenotypes
Authors: Sarma Aartik , Christenson Stephanie A. , Zha Beth Shoshana , Pisco Angela Oliveira , Neyton Lucile P.A. , Mick Eran , Sinha Pratik , Wilson Jennifer G. , Moazed Farzad , Leligdowicz Aleksandra , Maddali Manoj V. , Siegel Emily R. , Lyon Zoe M. , Zhou Hanjing , Jauregui Alejandra , Ghale Rajani , Caldera Saharai , Serpa Paula Hayakawa , Deiss Thomas , Love Christina , Byrne Ashley , Kalantar Katrina L. , DeRisi Joseph L. , Erle David J. , Krummel Matthew F. , Kangelaris Kirsten N. , Hendrickson Carolyn M. , Woodruff Prescott G. ,   COMET Consortium, Matthay Michael A. , Langelier Charles R. , Calfee Carolyn S.
Published: April 2022

Background

Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and responses to therapy have been identified. Classification as “hyperinflammatory” or “hypoinflammatory” depends on plasma biomarker profiling. Differences in pulmonary biology underlying these phenotypes are unknown.

Methods

We analyzed tracheal aspirate (TA) RNA sequencing (RNASeq) data from 41 ARDS patients and 5 mechanically ventilated controls to assess differences in lung inflammation and repair between ARDS phenotypes. In a subset of subjects, we also analyzed plasma proteomic data. We performed single-cell RNA sequencing (scRNASeq) on TA samples from 9 ARDS patients. We conducted differential gene expression and gene set enrichment analyses,in silicoprediction of pharmacologic treatments, and compared results to experimental models of acute lung injury.

Findings

In bulk RNASeq data, 1334 genes were differentially expressed between ARDS phenotypes (false detection rate < 0.1). Hyperinflammatory ARDS was characterized by an exaggerated innate immune response, increased activation of the integrated stress response, interferon signaling, apoptosis, and T-cell activation. Gene sets from experimental models of lipopolysaccharide lung injury overlapped more strongly with hyperinflammatory than hypoinflammatory ARDS, though overlap in gene expression between experimental and clinical samples was variable. ScRNASeq demonstrated a central role for T-cells in the hyperinflammatory phenotype. Plasma proteomics confirmed a role for innate immune activation, interferon signaling, and T-cell activation in the hyperinflammatory phenotype. Predicted candidate therapeutics for the hyperinflammatory phenotype included imatinib and dexamethasone.

Interpretation

Hyperinflammatory and hypoinflammatory ARDS phenotypes have distinct respiratory tract biology, which could inform targeted therapeutic development.

Funding

National Institutes of Health; University of California San Francisco ImmunoX CoLabs; Chan Zuckerberg Foundation; Genentech
Cardiovascular diseases worsen the maternal prognosis of COVID-19
Authors: Testa Carolina Burgarelli , de Godoi Luciana Graziela , de Figueiredo Lemos Bortolotto Maria Rita , Jiménez Monroy Nátaly Adriana , de Mattos Bruna Rodrigues , Rodrigues Agatha Sacramento , Vieira Francisco Rossana Pulcineli
Published: April 2022

Cardiovascular diseases are a risk factor for severe cases of COVID-19. There are no studies evaluating whether the presence of CVD in pregnant women and in postpartum women with COVID-19 is associated with a worse prognosis. In an anonymized open database of the Ministry of Health, we selected cases of pregnant and postpartum women who were hospitalized due to COVID-19 infection. Among the 1,876,953 reported cases, 3,562 confirmed cases of pregnant and postpartum women were included, of which 602 had CVD. Patients with CVD had an older age (p<0,001), a higher incidence of diabetes (p<0,001) and obesity (p<0,001), a higher frequency of systemic (p<0,001) and respiratory symptoms (p<0,001). CVD was a risk factor for ICU admission (p<0,001), ventilatory support (p=0.004) and orotracheal intubation in the third trimester (OR 1.30 CI95%1.04-1.62). The group CVD had a higher mortality (18.9% vs. 13.5%, p<0,001), with a 32% higher risk of death (OR 1.32 CI95%1.16-1.50). Moreover, the risk was increased in the second (OR 1.94 CI95%1.43-2.63) and third (OR 1.29 CI95%1.04-1.60) trimesters, as well as puerperium (OR 1.27 IC95%1.03-1.56). Hospitalized obstetric patients with CVD and COVID-19 are more symptomatic. Their management demand more ICU admission and ventilatory support and the mortality is higher.
Voice patterns as markers of schizophrenia: building a cumulative generalizable approach via a cross-linguistic and meta-analysis based investigation
Authors: Parola Alberto , Simonsen Arndis , Lin Jessica Mary , Zhou Yuan , Wang Huiling , Ubukata Shiho , Koelkebeck Katja , Bliksted Vibeke , Fusaroli Riccardo
Published: April 2022

Background and Hypothesis

Voice atypicalities are potential markers of clinical features of schizophrenia (e.g., negative symptoms). A recent meta-analysis identified an acoustic profile associated with schizophrenia (reduced pitch variability and increased pauses), but also highlighted shortcomings in the field: small sample sizes, little attention to the heterogeneity of the disorder, and to generalizing findings to diverse samples and languages.

Study Design

We provide a critical cumulative approach to vocal atypicalities in schizophrenia, where we conceptually and statistically build on previous studies. We aim at identifying a cross-linguistically reliable acoustic profile of schizophrenia and assessing sources of heterogeneity (symptomatology, pharmacotherapy, clinical and social characteristics). We relied on previous meta-analysis to build and analyze a large cross-linguistic dataset of audio recordings of 231 patients with schizophrenia and 238 matched controls (>4.000 recordings in Danish, German, Mandarin and Japanese). We used multilevel Bayesian modeling, contrasting meta-analytically informed and skeptical inferences.

Study Results

We found only a minimal generalizable acoustic profile of schizophrenia (reduced pitch variability), while duration atypicalities replicated only in some languages. We identified reliable associations between acoustic profile and individual differences in clinical ratings of negative symptoms, medication, age and gender. However, these associations vary across languages.

Conclusions

The findings indicate that a strong cross-linguistically reliable acoustic profile of schizophrenia is unlikely. Rather, if we are to devise effective clinical applications able to target different ranges of patients, we need first to establish larger and more diverse cross-linguistic datasets, focus on individual differences, and build self-critical cumulative approaches.
Quantifying phenotype and genotype distributions in single muscle fibres from patients carrying the pathogenic mtDNA variant m.3243A>G
Authors: Ahmed Syeda T , Taylor Robert W , Turnbull Doug M , Lawless Conor , Pickett Sarah J
Published: April 2022

Background

Pathogenic mitochondrial (mt)DNA variants cause neuromuscular disease with highly variable severity and phenotypic presentation, the reason for which is poorly understood. Cells are thought to tolerate the presence of pathogenic mtDNA variants up to a threshold proportion with little or no functional consequence, developing significant respiratory complex defects above this threshold. We developed a robust method to identify deficient muscle fibres, applied it to biopsies from 17 patients carrying the common m.3243A>G variant and examined the relationship between respiratory deficiency and m.3243A>G level in hundreds of single skeletal muscle fibres. We hypothesised that single-cell between-patient differences may explain the vast clinical heterogeneity of mtDNA disease.

Results

Immunohistochemical measurements of respiratory complexes I and IV and unsupervised machine learning identified muscle fibres with respiratory deficiency; the pattern of deficiency and proportion of deficient fibres (range 0-64%) varies between patients. Tissue homogenate m.3243A>G level is a poor surrogate for the broad and complex distributions of m.3243A>G level in single cells from individual patients. Estimated thresholds do not differ between patients, but sections with narrow m.3243A>G distributions have a lower proportion of deficient fibres.

Conclusions

Inter-individual differences in respiratory complex deficiency in muscle fibres from patients with m.3243A>G are more complex than previously thought and may be driven by differential segregation and expansion of mtDNA molecules. Our quantitative observations could constrain the range of feasible mechanisms responsible for phenotypic diversity in mitochondrial disease.