bluuebunny/crossref_metadata_2025 huggingface dataset:
Ex vivo normothermic preservation of amputated limbs with a hemoglobin-based oxygen carrier perfusate
Authors: Figueroa Brian A. , Said Sayf A. , Ordenana Carlos , Rezaei Majid , Orfahli Lynn M. , Dubé Gregory P. , Papay Francis , Brunengraber Henri , Dasarathy Srinivasan , Rampazzo Antonio , Gharb Bahar Bassiri
Published: September 2021

BACKGROUND

Ex vivo normothermic limb perfusion (EVNLP) preserves amputated limbs under near-physiologic conditions. Perfusates containing red blood cells (RBCs) have shown to improve outcomes during ex vivo normothermic organ perfusion, when compared with acellular perfusates. To avoid limitations associated with the use of blood-based products, we evaluated the feasibility of EVNLP using a polymerized hemoglobin-based oxygen carrier-201 (HBOC-201).

METHODS

Twenty-four porcine forelimbs were procured from Yorkshire pigs. Six forelimbs underwent EVNLP with an HBOC-201-based perfusate, six with an RBC-based perfusate, and 12 served as static cold storage (SCS) controls. Ex vivo normothermic limb perfusion was terminated in the presence of systolic arterial pressure of 115 mm Hg or greater, fullness of compartments, or drop of tissue oxygen saturation by 20%. Limb contractility, weight change, compartment pressure, tissue oxygen saturation, oxygen uptake rates (OURs) were assessed. Perfusate fluid-dynamics, gases, electrolytes, metabolites, methemoglobin, creatine kinase, and myoglobin concentration were measured. Uniformity of skin perfusion was assessed with indocyanine green angiography and infrared thermography.

RESULTS

Warm ischemia time before EVNLP was 35.50 ± 8.62 minutes (HBOC-201), 30.17 ± 8.03 minutes (RBC) and 37.82 ± 10.45 (SCS) (p = 0.09). Ex vivo normothermic limb perfusion duration was 22.5 ± 1.7 hours (HBOC-201) and 28.2 ± 7.3 hours (RBC) (p = 0.04). Vascular flow (325 ± 25 mL·min−1 vs. 444.7 ± 50.6 mL·min−1; p = 0.39), OUR (2.0 ± 1.45 mL O2·min−1·g−1 vs. 1.3 ± 0.92 mL O2·min−1·g−1 of tissue; p = 0.80), lactate (14.66 ± 4.26 mmol·L−1 vs. 13.11 ± 6.68 mmol·L−1; p = 0.32), perfusate pH (7.53 ± 0.25 HBOC-201; 7.50 ± 0.23 RBC; p = 0.82), flexor (28.3 ± 22.0 vs. 27.5 ± 10.6; p = 0.99), and extensor (31.5 ± 22.9 vs. 28.8 ± 14.5; p = 0.82) compartment pressures, and weight changes (23.1 ± 3.0% vs. 13.2 ± 22.7; p = 0.07) were not significantly different between HBOC-201 and RBC groups, respectively. In HBOC-201 perfused limbs, methemoglobin levels increased, reaching 47.8 ± 12.1% at endpoint. Methemoglobin saturation did not affect OUR (ρ = −0.15, r2 = 0.022; p = 0.45). A significantly greater number of necrotic myocytes was found in the SCS group at endpoint (SCS, 127 ± 17 cells; HBOC-201, 72 ± 30 cells; RBC-based, 56 ± 40 cells; vs. p = 0.003).

CONCLUSION

HBOC-201- and RBC-based perfusates similarly support isolated limb physiology, metabolism, and function.
Plasma metagenomic sequencing to detect and quantify bacterial DNA in ICU patients suspected of sepsis: A proof-of-principle study
Authors: Kisat Mehreen T. , Odenheimer-Bergman Ahuva , Markus Havell , Joseph Bellal , Srivatsan Sridhar N. , Contente-Cuomo Tania , Khalpey Zain , Keim Paul , O’Keeffe Terence , Askari Reza , Salim Ali , Rhee Peter , Murtaza Muhammed
Published: September 2021

BACKGROUND

Timely recognition of sepsis and identification of pathogens can improve outcomes in critical care patients but microbial cultures have low accuracy and long turnaround times. In this proof-of-principle study, we describe metagenomic sequencing and analysis of nonhuman DNA in plasma. We hypothesized that quantitative analysis of bacterial DNA (bDNA) levels in plasma can enable detection and monitoring of pathogens.

METHODS

We enrolled 30 patients suspected of sepsis in the surgical trauma intensive care unit and collected plasma samples at the time of diagnostic workup for sepsis (baseline), and 7 days and 14 days later. We performed metagenomic sequencing of plasma DNA and used computational classification of sequencing reads to detect and quantify total and pathogen-specific bDNA fraction. To improve assay sensitivity, we developed an enrichment method for bDNA based on size selection for shorter fragment lengths. Differences in bDNA fractions between samples were evaluated using t test and linear mixed-effects model, following log transformation.

RESULTS

We analyzed 72 plasma samples from 30 patients. Twenty-seven samples (37.5%) were collected at the time of infection. Median total bDNA fraction was 1.6 times higher in these samples compared with samples with no infection (0.011% and 0.0068%, respectively, p < 0.001). In 17 patients who had active infection at enrollment and at least one follow-up sample collected, total bDNA fractions were higher at baseline compared with the next sample (p < 0.001). Following enrichment, bDNA fractions increased in paired samples by a mean of 16.9-fold. Of 17 samples collected at the time when bacterial pathogens were identified, we detected pathogen-specific DNA in 13 plasma samples (76.5%).

CONCLUSION

Bacterial DNA levels in plasma are elevated in critically ill patients with active infection. Pathogen-specific DNA is detectable in plasma, particularly after enrichment using selection for shorter fragments. Serial changes in bDNA levels may be informative of treatment response.

LEVEL OF EVIDENCE

Epidemiologic/Prognostic, Level V.
A Primer on EEG Spectrograms
Authors: Ng Marcus C. , Jing Jin , Westover M. Brandon
Published: September 2021

As continuous brain monitoring becomes a routine part of clinical care, continuous EEG has allowed better detection and characterization of nonconvulsive seizures, and patterns along the ictal–interictal continuum in critically ill patients. However, this increased workload has led many to turn to quantitative EEG whose central tool is the “spectrogram.” Although in relatively wide use, many clinicians lack a detailed understanding of how spectrograms relate to the underlying “raw” EEG signal. This article provides an approachable set of first principles to help clinicians understand how spectrograms encode information about the raw EEG and how to interpret spectrograms to efficiently infer underlying EEG patterns.
Causal Associations of Self-Reported Walking Pace with Telomere Length in 405,981 middle-aged adults: a UK Biobank study
Authors: Dempsey Paddy C. , Musicha Crispin , Rowlands Alex V. , Davies Melanie , Khunti Kamlesh , Razieh Cameron , Timmins Iain , Zaccardi Francesco , Codd Veryan , Nelson Christopher P. , Yates Tom , Samani Nilesh J
Published: September 2021

Objectives

Walking pace is a strong marker of functional and health status. We investigated whether walking pace is also associated with leucocyte telomere length (LTL), which is causally associated with several diseases and has been proposed as a marker of biological age.

Methods

We used baseline data from UK Biobank participants recruited from March-2006 to July-2010. Walking pace was self-reported as slow, steady/average, or brisk. Accelerometer-assessed measures of total physical activity and intensity were included to support interpretation of walking pace data. LTL was measured by qPCR assay. Bi-directional Mendelian randomization (MR) analyses were undertaken to inform likely causal directions.

Results

The analysed cohort comprised 405,981 adults (54% women) with mean age of 56.5 years (SD, 8.1) and body mass index 27.2 kg/m2 (SD, 4.7). Steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with a Z-standardised LTL difference of 0.066 (0.053-0.078) and 0.101 (0.088-0.113), respectively. Associations remained but were attenuated following full covariate adjustment: 0.038 (0.025-0.051) and 0.058 (0.045-0.072), respectively. Accelerometer data (n=86,002) demonstrated a non-linear association between LTL and habitual movement intensity, but not total activity. MR analysis supported a causal association of walking pace on LTL, with an increase in Z-standardised LTL of 0.192 (0.077, 0.306) for each difference in walking pace category. No evidence of a causal association was observed for LTL on walking pace.

Conclusion

Faster walking pace may be causally associated with longer LTL, which could explain some of the beneficial effects of brisk walking on health status.
Patient-Centered Approach Might Effectively Tackle The Definition Of Progression In Chronic Neurological Diseases: Results From The EmBioProMS Trial In Progressive Multiple Sclerosis
Authors: Abdelhak Ahmed , Krumbholz Markus , Senel Makbule , Havla Joachim , Zettl Uwe K. , Kleiter Ingo , Skripuletz Thomas , Stahmann Alexander , Huss Andre , Antweiler Kai , Gingele Stefan , Kowarik Markus C. , Hoshi Muna-Miriam , Hengstebeck Sandra , Friede Tim , Ludolph Albert C. , Kümpfel Tania , Ziemann Ulf , Tumani Hayrettin
Published: September 2021

Background

Proper identification of disability accumulation in the routine clinical care of progressive multiple sclerosis (PMS) patients is usually a challenging task. Patient-reported outcome measurements (PROMs) can provide a practical, cost-efficient, and remotely accessible tool to assess disease progression.

Methods

EmBioProMS is a prospective, multicentric cohort, conducted in 7 specialized MS centers in Germany. PROMs were evaluated at inclusion and compared between patients with retrospective evidence of disease progression in the last two years and those with stable disease. Patients with either primary or secondary progressive MS according to the McDonald criteria 2017 were included in the analysis, while patients with incomplete PROMs scores, MS relapses, other neurological or systemic inflammatory diseases were excluded. The disease progression was assessed using a combined outcome parameter, including EDSS score, timed 25-foot walk test, and nine-hole-peg test.

Results

185 patients were included in the final analysis (SPMS, n=77; PPMS, n=108). The median age and disease duration were 55 years and 13 years, respectively. Disease progression was diagnosed in 114 of 185 patients (61.6%). BDI-II, MSIS-29, and FSMC scores were worse in patients with evidence of disease progression in the last two years. Patients with any of the included PROMs above the 90th percentile had an odds ratio of 3.8 (95% confidence interval: 1.4–10.6, P=0.01) for having progression in the last two years in a binomial regression model adjusted for age, sex, disease duration, treatment status, center effect, and Expanded Disability Status Scale (EDSS). Similar results were observed in patients with PROM scores in the 80th and 70th percentile (OR: 2.9 and 3.7, P=0.015 and 0.003, respectively).

Conclusion

PROMs can be a simple and effective way to detect disability worsening in a chronic neurological disease like PMS and, therefore, substantially contribute to better classification and prognostication of the disease course through objective and structural patient-doctor communication.

Trial Registration

German Clinical Trials Register (Deutsches Register Klinischer Studien - DRKS), DRKS00020132
Psychosis in Alzheimer’s Disease is Associated with Excitatory Neuron Vulnerability and Post-Transcriptional Mechanisms Altering Synaptic Protein Levels
Authors: DeChellis-Marks MR , Wei Y , Ding Y , Wolfe CM , Krivinko JM , MacDonald ML , Lopez OL , Sweet RA , Kofler J
Published: September 2021

Alzheimer’s disease with psychosis (AD+P) is a phenotypic variant of the disease which is associated with a much more rapid deterioration compared to Alzheimer’s disease without psychosis (AD-P). The neurobiological basis of AD+P is poorly understood. AD is thought to be a disease of the synapse, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD-P. We previously demonstrated that multiple neuropathologies only account for approximately 18% of the variance in the occurrence of psychosis in AD. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD-P [Mean (SD) AD+P 0.295 (0.061); AD-P 0.324 (0.052), p = 0.026]. Network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. Including cell type proportions and differentially expressed modules with neuropathology measures explained 67.5% of the variance in psychosis occurrence in our AD cohort.
Two Data-Driven Approaches to Identifying the Spectrum of Problematic Opioid Use: A Pilot Study within a Chronic Pain Cohort
Authors: Schirle Lori , Jeffery Alvin , Yaqoob Ali , Sanchez-Roige Sandra , Samuels David
Published: September 2021

ASTRACT

Background

Although electronic health records (EHR) have significant potential for the study of opioid use disorders (OUD), detecting OUD in clinical data is challenging. Models using EHR data to predict OUD often rely on case/control classifications focused on extreme opioid use. There is a need to expand this work to characterize the spectrum of problematic opioid use.

Methods

Using a large academic medical center database, we developed 2 datadriven methods of OUD detection: (1) a Comorbidity Score developed from a Phenome-Wide Association Study of phenotypes associated with OUD and (2) a Textbased Score using natural language processing to identify OUD-related concepts in clinical notes. We evaluated the performance of both scores against a manual review with correlation coefficients, Wilcoxon rank sum tests, and area-under the receiver operating characteristic curves. Records with the highest Comorbidity and Text-based scores were re-evaluated by manual review to explore discrepancies.

Results

Both the Comorbidity and Text-based OUD risk scores were significantly elevated in the patients judged as High Evidence for OUD in the manual review compared to those with No Evidence (p = 1.3E-5 and 1.3E-6, respectively). The risk scores were positively correlated with each other (rho = 0.52, p < 0.001). AUCs for the Comorbidity and Text-based scores were high (0.79 and 0.76, respectively). Follow-up manual review of discrepant findings revealed strengths of data-driven methods over manual review, and opportunities for improvement in risk assessment.

Conclusion

Risk scores comprising comorbidities and text offer differing but synergistic insights into characterizing problematic opioid use. This pilot project establishes a foundation for more robust work in the future.
Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial
Authors: Bergman Peter , Blennow Ola , Hansson Lotta , Mielke Stephan , Nowak Piotr , Chen Puran , Söderdahl Gunnar , Österborg Anders , Edvard Smith C. I. , Wullimann David , Vesterbacka Jan , Lindgren Gustaf , Blixt Lisa , Friman Gustav , Wahren-Borgström Emilie , Nordlander Anna , Gomez Angelica Cuapio , Akber Mira , Valentini Davide , Norlin Anna-Carin , Thalme Anders , Bogdanovic Gordana , Muschiol Sandra , Nilsson Peter , Hober Sophia , Loré Karin , Chen Margaret Sällberg , Buggert Marcus , Ljunggren Hans-Gustaf , Ljungman Per , Aleman Soo ,   the COVAXID-collaborator group (shown separately)
Published: September 2021

Background

Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate the safety and efficacy after two doses of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls.

Methods

539 study subjects (449 patients and 90 controls) were included in the clinical trial. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/chimeric antigen receptor T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection.

Findings

Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72·2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43·4%) and CLL (63·3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively.

Interpretation

The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. The rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups and/or subgroups to improve immunity.

Funding

Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, Swedish Research Council, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.
Young onset diabetes in Asian Indians is associated with lower measured and genetically determined beta-cell function: an INSPIRED study
Authors: Siddiqui Moneeza K , Anjana RM , Dawed Adem Y , Martoeau Cyrielle , Srinivasan Sundararajan , Saravanan Jebarani , Madanagopal Sathish K , Veluchamy Abirami , Pradeepa Rajendra , Sattar Naveed , Venkatesan Radha , Palmer Colin N A , Pearson Ewan R , Mohan Viswanathan
Published: September 2021

Background

South Asians have higher risk of type 2 diabetes compared to white Europeans and a younger age of onset. Reasons for the younger age of onset in relation to beta-cell function and insulin sensitivity are under-explored.

Methods

Two cohorts of Asian Indians, ICMR-INDIAB (Indian Council of Medical Research-INdia DIABetes Study) and DMDSC (Dr. Mohan’s Diabetes Specialties Centre) and one of white Europeans, ESDC (East Scotland Diabetes Cohort) were used. We examined the comparative prevalence of healthy, overweight, and obese BMI in young onset diabetes. We explored the role of clinically measured beta-cell function in diabetes onset in Asian Indians. Finally, the comparative distribution of a partitioned polygenic score (pPS) for risk of diabetes due to poor beta cell function was examined.

Results

Prevalence of young onset with normal BMI was 9.3% amongst white Europeans and 24%-39% amongst Asian Indians. In young diagnosed Asian Indians, after adjustment for family history of T2DM, sex, insulin sensitivity and HDL-c, stimulated C-peptide was 492pmol/mL (IQR: 353,616,P<0.0001) lower in lean compared to obese individuals. Asian Indians have lower genetically determined beta-cell function than white Europeans(P <0.0001). The pPS was associated with age of diagnosis in Asian Indians but not in white Europeans. The pPS explained 2% of variation in clinically measured beta cell function and 1.2%, 0.97%, and 0.36% of variance in age of diabetes amongst Asian Indians with normal, overweight, and obese BMI respectively.

Conclusions

Asian Indians have over two times the prevalence of lean BMI in young onset diabetes compared to white Europeans. This phenotype of lean, young onset diabetes appears driven in part by lower beta cell function. We demonstrate that Asian Indians with diabetes also have lower genetically determined beta cell function.
Serial evaluation of anti-SARS-CoV-2 IgG antibody and breakthrough infections in BNT162b2 Vaccinated migrant workers from Bangladesh
Authors: Hoque Ashraful , Rahman Md Marufur , Das Anindita
Published: September 2021

Background

While Bangladesh has started its mass COVID-19 vaccination drive, it is struggling to cover its huge population similar to other low- and middle-income countries due to the lack of vaccine availability. One of the major remittance sources for Bangladesh is its migrant workers who are required to receive mRNA vaccines to return to their jobs. Despite reports of higher efficacy of mRNA vaccine against COVID-19, breakthrough infection cases are arising especially with the emergence of Delta variant. It is highly important to understand the post-vaccination immune response and breakthrough infections in different populations so that the necessity of booster dosage can be assessed properly.

Methods

We observed post BNT162b2 full vaccination immune response in a small older group (mean age= 59.5±5.44 years) of migrant workers (n=10) for six months at the Sheikh Hasina National Institute of Burn and Plastic Surgery, Dhaka, Bangladesh. The plasma samples from the participants were collected after 14 days, 2 months, 3 months, 4 months, 5 months, and 6 months of receiving the 2nd dose of the BNT162b2 vaccine. Anti S1 RBD IgG responses were measured as optical density ratios using a commercially available ELISA kit.

Results

All 10 of the participants were male migrant workers and none of them had a history of previous COVID-19 infection. The median antibody response [IQ1:IQ3] was 9.05 [7.53; 10.0] on day 14 then it increases to 13.6 [12.0; 14.0] at the second month which gradually decreased to a median of 8.63 [8.34; 9.37] on the 6th-month post-vaccination. There were two breakthrough infection cases after receiving the second dose and the antibody responses were highly increased in the following months. Two of the breakthrough cases were diagnosed with mild COVID-19 as the symptom duration was less than 3 days with no respiratory complications and no hospital admission were required.

Conclusions

The BNT162b2 mRNA vaccine produces a strong immune response that sustains at least 6 months after getting fully vaccinated. But even after getting fully vaccinated people are susceptible to breakthrough infections that are not severe and boost the immune response greatly offering a hybrid immunity from both vaccine and natural infection. Hence, it is still important to fully vaccinate a greater number of people rather than thinking of offering booster dosage to a privileged population out of the fear of breakthrough cases. If the LMICs can quickly cover at least 80% of their population with usual priority targets (healthcare workers, migrant workers, older people, etc.) then a global risk reduction and pandemic control would be possible that will allow additional variant-specific boosters for targeted populations if evidence support.
Low linoleic acid foods with added DHA given to Malawian children with severe acute malnutrition improves cognition: a randomized, triple blinded, controlled clinical trial
Authors: Stephenson Kevin , Callaghan-Gillespie Meghan , Maleta Kenneth , Nkhoma Minyanga , George Matthews , Park Hui Gyu , Lee Reginald , Humpheries-Cuff Iona , Lacombe R J Scott , Wegner Donna R , Canfield Richard L , Brenna J Thomas , Manary Mark J
Published: September 2021

Background

There is concern that the PUFA composition of ready-to-use therapeutic food (RUTF) for treatment of severe acute malnutrition (SAM) is suboptimal for neurocognitive recovery.

Objective

We tested the hypothesis that RUTF made with reduced amounts of linoleic acid, achieved using high oleic (HO) peanuts, with or without added DHA, improves cognition when compared to standard RUTF (S-RUTF).

Methods

A triple-blind, randomized, controlled clinical feeding trial was conducted among children with uncomplicated SAM in Malawi with 3 types of RUTF; DHA-HO-RUTF, HO-RUTF and S-RUTF. The primary outcomes, measured in a subset of subjects, were the Malawi Developmental Assessment Tool (MDAT) global and 4 domain (gross motor, fine motor, language and social) z-scores and a modified Willatts problem solving assessment (PSA) intention score for 3 standardized problems, measured 6 months and immediately after completing RUTF therapy, respectively. Plasma fatty acid content, anthropometry and eye tracking were secondary outcomes. Comparisons were made between the novel PUFA RUTFs and S-RUTF.

Results

Among the 2565 SAM children enrolled, global MDAT z-score was -0.69 ± 1.19 and - 0.88 ± 1.27 for children receiving DHA-HO-RUTF and S-RUTF, respectively (difference 0.19, 95% CI 0.01 to 0.38). The gross motor and social domains had higher z-scores among children receiving either DHA-HO-RUTF than S-RUTF. The PSA problem 3 scores did not differ by dietary group (Odds ratio 0.92, 95% CI 0.67 to 1.26 for DHA-HO-RUTF). After 4 weeks of treatment, plasma phospholipid EPA and α-linolenic acid were greater in children consuming DHA-HO-RUTF or HO-RUTF when compared to S-RUTF (for all 4 comparisons P values < 0.001), but only plasma DHA was greater in DHA-HO-RUTF than S-RUTF (P <0.001).

Conclusions

Treatment of uncomplicated SAM with DHA-HO-RUTF resulted in an improved MDAT score, conferring a cognitive benefit six months after completing diet therapy. This treatment should be explored in operational settings.
Prevalence and incidence of stress, depression, and anxiety symptoms among Brazilians in quarantine across the early phases of the COVID-19 crisis
Authors: Blacutt Miguel , Filgueiras Alberto , Stults-Kolehmainen Matthew
Published: September 2021

Objective

The present study aimed to measure the prevalence and incidence of stress, depression, and anxiety symptoms in Brazilians during the COVID-19 pandemic.

Method

We assessed 103 (54 women, 49 men) participants online in three periods of the pandemic: March 2020 (T1), April 2020 (T2), and June 2020 (T3). Prevalence and incidence were identified when mental health scores were two standard deviations above the mean compared to normative data. Mental health indicators were measured using the Perceived Stress Scale, the Filgueiras Depression Index, and the State-Trait Anxiety Inventory – State Subscale.

Results

At T1, 89% of individuals were below cut-off scores for stress, anxiety, and depression, which dropped to 35% by T3. Stress prevalence was 1.9% at T1, 7.8% at T2, and 28.2% at T3. Depression prevalence was 0% at T1, 23.3% at T2, and 25.2% at T3. State anxiety prevalence was 10.7% at T1, 11.7% at T2, and 45.6% at T3. Stress incidence increased by 7.8% from T1 to T2, and 23.3% from T2 to T3. Depression incidence increased by 23.3% from T1 to T2, and 15.5% from T2 to T3. Anxiety incidence increased by 9.7% from T1 to T2, and 39.8% from T2 to T3. Stress severity scores significantly increased from 16.1±8.7 at T1 to 23.5±8.4 at T2, and 30.3±6.0 at T3. Depression severity scores significantly increased from 48.5±20.5 at T1 to 64.7±30.2 at T2, and 75.9±26.1 at T3. Anxiety increased from 49.0±13.4 at T1 to 53.5±12.5 at T2 and 62.3±13.4 at T3. Females had significantly higher anxiety scores than males by T3 (66.7±11.8 vs. 57.4±13.5).

Conclusion

Prevalence and incidence of stress, depression, and anxiety significantly increased throughout the pandemic. The largest increase in stress and anxiety occurred between T2 and T3, and between T1 and T2 for depression. Severity of stress, depression, and anxiety increased throughout the study.
Expanding The Use Of Friedewald Equation In Lipid Profile Testing Among HIV Positive And Negative Elderly Persons
Authors: Jude Emunyu , Brian Semigga , Stephen Kisembo , Brenda Namukwaya , Bridget Namubiru , Charles Bakyayita , Omony Emmanuel
Published: September 2021

Hypercholesterolemia and hypocholesterolemia are associated with mortality which warrants routine lipid profile testing. This financially burdens the already overwhelmed health sector especially in developing countries. Additionally, lipid profile test reagent stock-out or failure to afford all tests affects result interpretation. In 1972, James Friedewald published a statistical model to calculate low density lipo-protein. The study aim was to determine the percentage error of the James Friedewald equation in calculating all lipid profile test parameters. A retrospective study from 2018 was performed at Mildmay Uganda involving lipid profile results of 103 persons (48 HIV-positive and 55 HIV-negative) 50 years and older enrolled in a previous cross-sectional study. The Friedewald equation was used to calculate total cholesterol, high density lipoprotein, triglycerides and low density lipo-protein. The percentage error of calculated values in reference to measured values was ascertained. Pearson correlation between measured and calculated results was determined among all persons and classified by HIV status. The total error of calculated analytes was 7% (low density lipo-protein), 17% (high density lipo-protein), 39% (triglycerides) and 4% (total cholesterol). Pearson correlations were 0.98 (all persons), 0.98 (HIV-negative) and 0.98 (HIV-positive) for low density lipo-protein, 0.89 (all persons), 0.90 (HIV-positive) and 0.88 (HIV-negative) for high density lipo-protein, 0.75 (all persons), 0.76 (HIV-negative) and 0.77 (HIV-positive) for triglycerides, 0.99 (all persons), 0.98 (HIV-negative) and 0.99 (HIV-positive) for total cholesterol. In conclusion, Friedewald equation reliably calculated low density lipo-protein, total cholesterol (most accurate) and high density lipo-protein while triglycerides calculation was erroneous among persons aged ≥ 50 years.
Experienced hearing aid users’ perspectives of assessment and communication within audiology: A qualitative study using digital methods
Authors: Parmar Bhavisha , Mehta Kinjal , Vickers Deborah , Bizley Jennifer K.
Published: September 2021

Objective

To explore experienced hearing aid users’ perspectives of audiological assessments and the patient-audiologist communication dynamic during clinical interactions.

Design

A qualitative study was implemented incorporating both an online focus group and online semi-structured interviews. Sessions were audio-recorded and transcribed verbatim. Iterative-inductive thematic analysis was carried out to identify themes related to assessment and communication within audiology practice.

Study samples

Seven experienced hearing aid users took part in an online focus group and 14 adults participated in semi-structured interviews (age range: 22 - 86 years; 9 males, 11 females).

Results

Themes related to assessment included the unaided and aided testing procedure and relating tests to real world hearing difficulties. Themes related to communication included the importance of communication strategies, explanation of test results and patient centred care in audiology.

Conclusion

To ensure that hearing aid services meet the needs of the service users, we should explore user perspectives and proactively adapt service delivery. This approach should be ongoing, in response to advances in hearing aid technology. Within audiology, experienced hearing aid users’ value 1) comprehensive, relatable hearing assessment, 2) clear, concise, deaf aware patient-audiologist communication, 3) accessible services and 4) a personalised approach to recommend suitable technology and address patient specific aspects of hearing loss.
Genome-wide pleiotropy analysis identifies novel blood pressure variants and improves its polygenic risk scores
Authors: Zhu Xiaofeng , Zhu Luke , Wang Heming , Cooper Richard S , Chakravarti Aravinda
Published: September 2021

Systolic and diastolic blood pressure (S/DBP) are highly correlated modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and pleiotropy analysis of systolic and diastolic blood pressure (BP) summary statistics from the UKB-ICBP BP genome-wide association study (GWAS) and construct a composite genetic risk score (GRS) by including pleiotropic variants. The composite GRS captures greater (1.11-3.26 fold) heritability for BP traits and increases (1.09- and 2.01-fold) Nagelkerke’s R2 for hypertension (HTN) and cardiovascular disease (CVD). We replicated 118 novel BP pleiotropic variants including 18 novel BP loci using summary statistics from the Million Veteran Program (MVP) study. An additional 219 novel BP signals and 40 novel loci were identified after meta-analysis of the UKB-ICBP and MVP summary statistics but without further independent replication. Our study provides further insight into BP regulation and provides a novel way to construct a GRS by including pleiotropic variants for other complex diseases.
University of Texas at Arlington (UTA) in-house COVID-19 testing program
Authors: Rudewick Roy , Gunby Taylor , Smith Anajane G. , Guo Zibiao , Middleton Angela J. , Cox Necole , Haseltine Florence P.
Published: September 2021

The pandemic caused by the spread of the virus SARS-CoV-2 threatened to severely disrupt the activities of student-athletes. (REF) In order to provide a safe environment for athletic competition, the National Collegiate Athletic Association (NCAA) mandated testing of student-athletes. The goal was to rapidly identify student-athletes and the athletic staff member who either tested positive for SARS-CoV-2 or were in contact with individuals who tested positive. Rapid identification of infected individuals and their contacts allowed the University to implement quarantine standards and quarantine facilities quickly as needed. The University of Texas at Arlington (UTA) developed an in-house testing program and was quickly able to meet the NCAA requirements, allowing UTA to continue its athletic participation with minimal forfeiture of scheduled games. The purpose of this paper is to report the implementation UTA’s COVID prevention program for the university’s athletic program. This program will provide valuable information to other universities’ planning for the management of COVID prevention in their athletic programs. Challenges and solutions are identified.
Combined Impact of Prior SARS-CoV-2 Infection and Vaccination on Antibody Presence
Authors: Shuford Jennifer A , Swartz Michael D , Lakey David L , Aguillard Kimberly A , Pont Stephen J , Valerio-Shewmaker Melissa A , Boerwinkle Eric
Published: September 2021

As COVID-19 continues to spread rapidly and vaccine uptake stagnates, questions remain about the amount of SARS-CoV-2 antibodies present in the population induced by either SARS-CoV-2 infection, by a COVID-19 vaccine, or both.

The TEXAS Coronavirus Antibody REsponse Survey (CARES) is a statewide seroprevalence program which utilizes the Roche S-test to detect antibodies to the SARS-CoV-2 spike protein and the Roche N-test to detect antibodies to the SARS-CoV-2 nucleocapsid protein, to monitor the combined impact of prior infection and the COVID-19 vaccine. The current sample size having both S- and N-test data and reported vaccination status is 8,846.

Participants with prior infection (i.e. N+) and with either partial or full vaccination have the highest proportion of those showing the maximum value of the S-test (80.95% and 83.07%, respectively). Using a permutation test, there is no statistically significant difference between the median S-test value for those that have had prior infection and are partially vaccinated versus those that have had prior infection and are fully vaccinated. These groups both show significantly higher median amount compared to the other three groups: N+/not vaccinated, N-/partially vaccinated, and N-/fully vaccinated (all p-values < 0.0001).

Unvaccinated individuals with prior infection have one of the lowest median S-test values. For participants with previous SARS-CoV-2 infection and a COVID-19 vaccine, the median S-test value is high and is not statistically different between those who are partially vaccinated and those who are fully vaccinated.
QuaID: Enabling Earlier Detection of Recently Emerged SARS-CoV-2 Variants of Concern in Wastewater
Authors: Sapoval Nicolae , Liu Yunxi , Lou Esther G. , Hopkins Loren , Ensor Katherine B , Schneider Rebecca , Stadler Lauren B , Treangen Todd J
Published: September 2021

As clinical testing declines, wastewater monitoring can provide crucial surveillance on the emergence of SARS-CoV-2 variants of concern (VoC) in communities. Multiple recent studies support that wastewater-based SARS-CoV-2 detection of circulating VoC can precede clinical cases by up to two weeks. Furthermore, wastewater based epidemiology enables wide population-based screening and study of viral evolutionary dynamics. However, highly sensitive detection of emerging variants remains a complex task due to the pooled nature of environmental samples and genetic material degradation. In this paper we propose quasi-unique mutations for VoC identification, implemented in a novel bioinformatics tool (QuaID) for VoC detection based on quasi-unique mutations. The benefits of QuaID are three-fold: (i) provides up to 3 week earlier VoC detection compared to existing approaches, (ii) enables more sensitive VoC detection, which is shown to be tolerant of >50% mutation drop-out, and (iii) leverages all mutational signatures, including insertions & deletions.
Anticarcinogenic effects from plasma elderly trained: the role of mitochondrial function
Authors: Peres Alessandra , Dorneles Gilson Pires , Branchini Gisele , Bordignon Fernanda , Romão Pedro R T , Minuzzi Luciele , Lira Fabio S , Cavalcante Mateus , Elsner Viviane
Published: September 2021

This study aimed to evaluate the effects of a multimodal exercise training on systemic cytokine levels of the elderly, and the impact of post-exercise training plasma on prostate cancer cell viability and proliferationin vitro. Fasting blood samples were collected from eight institutionalized elderly before and after eight weeks of multimodal exercise training (twice a week). The levels of interleukin(IL)-1ra, IL-1β, IL-2, IL-6, IL-10, IL-17, interferon (IFN)-α, tumor necrosis factor (TNF)-α, fibroblast growth factor (FGF)-1, platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-α were evaluated in the peripheral blood. PC3 prostate cancer cell lines were incubated with 10% plasma acquired before and after exercise training from each participant. Multimodal exercise training increased the plasma levels of IL-2, IL-10, IFN-α, and FGF-1, and decreased TNF-α concentrations. PC3 cells presented decreased cell viability evaluated by MTT and lactate dehydrogenase activity as well as lower rates of cell proliferation after the incubation with post-training plasma samples. Furthermore, the incubation of PC-3 cells with post-training plasma decreased the mitochondrial membrane polarization and increased mitochondrial reactive oxygen species (ROS) production without changes in cytosolic ROS. Post-training plasma did not change apoptosis or necrosis rates in the PC-3 cell line. In conclusion, we showed that systemic adaptations in plasma mediators of institutionalized elderly might alter cell viability and proliferation by targeting mitochondrial ROS in a prostate cancer cell line.
Dense Optic Nerve Head Deformation Estimated using CNN as a Structural Biomarker of Glaucoma Progression
Authors: Salehi Ali , Balasubramanian Madhusudhanan
Published: September 2021

Purpose

To present a new structural biomarker for detecting glaucoma progression based on structural transformation of the optic nerve head (ONH) region.

Methods

A dense ONH deformation was estimated using deep learning methods namely DDCNet-Multires, FlowNet2, and FlowNet-Correlation, and legacy computational methods namely the topographic change analysis (TCA) and proper orthogonal decomposition (POD) methods using longitudinal confocal scans of the ONH for each study eye. A candidate structural biomarker of glaucoma progression in a study eye was estimated as average magnitude of flow velocities within the ONH region. The biomarker was evaluated using longitudinal confocal scans of 12 laser-treated and 12 contralateral normal eyes of 12 primates from the LSU Experimental Glaucoma Study (LEGS); and 36 progressing eyes and 21 longitudinal normal eyes from the UCSD Diagnostic Innovations in Glaucoma Study (DIGS). Area under the ROC curves (AUC) was used to assess the diagnostic accuracy of the candidate biomarker.

Results

AUROC (95% CI) for LEGS were: 0.83 (0.79, 0.88) for DDCNet-Multires; 0.83 (0.78, 0.88) for FlowNet2; 0.83 (0.78, 0.88) for FlowNet-Correlation; 0.94 (0.91, 0.97) for POD; and 0.86 (0.82, 0.91) for TCA methods. For DIGS: 0.89 (0.80, 0.97) for DDCNet-Multires; 0.82 (0.71, 0.93) for FlowNet2; 0.93 (0.86, 0.99) for FlowNet-Correlation; 0.86 (0.76, 0.96) for POD; and 0.86 (0.77, 0.95) for TCA methods. Lower diagnostic accuracy of the learning-based methods for LEG study eyes were due to image alignment errors in confocal sequences.

Conclusion

Deep learning methods trained to estimate generic deformation were able to detect ONH deformation from confocal images and provided a higher diagnostic accuracy when compared to the classical optical flow and legacy biomarkers of glaucoma progression. Because it is difficult to validate the estimates of dense ONH deformation in clinical population, our validation using ONH sequences under controlled experimental conditions confirms the diagnostic accuracy of the biomarkers observed in the clinical population. Performance of these deep learning methods can be further improved by fine-tuning these networks using longitudinal ONH sequences instead of training the network to be a general-purpose deformation estimator.
Advancing convergent mixed methods design using the Diamond Approach for clinical multiple case studies: an example using data on time to treatment in aneurysmal subarachnoid haemorrhage
Authors: Nguyen Thuy Phuong , Stirling Christine , Kitsos Gemma , Jose Kim , Nichols Linda , Chandra Ronil V. , Rehman Sabah , Smith Karen , Mosley Ian , Lai Leon , Asadi Hamed , Dubey Arvind , Froelich Jens , Thrift Amanda , Gall Seana
Published: September 2021

Using a new approach to the analysis and synthesis of a clinically focused mixed-methods multiple case study of aneurysmal subarachnoid haemorrhage (aSAH), we explored barriers and facilitators to timely treatment. In this paper we provide guidance for the multiple steps of analysis and synthesis of qualitative and quantitative data from across and within 27 case studies. Results showed that median (IQR) time to treatment was 15.1 (9.0, 24.1) hours. Only 37% of cases had treatment within 12-hours of onset. Early recognition of aSAH, good coordination, and availability of resources for treatment were main facilitators for treatment within 12 hours from onset. Lack of recognition of aSAH at onset and lack of resources for immediate in-hospital treatment were major barriers.
Common genetic alterations of SPOP-MATH domain in prostate cancer tissues and association with pathological tumor characteristics*
Authors: Abumsimir Berjas , Mrabti Mohammed , Laraqui Abdelilah , Saif Imane , Lamsisi Maryame , Ennaji Youssef , Ameur Ahmed , Koraishi Saad Ibnsouda , Ennaji Moulay Mustapha
Published: September 2021

SPOP gene has a critical role in prostate cancer development and found high mutated in the prostate tumor through various populations. MATH domain represents an important site for SPOP-DNA linkage and other sensitive gene-gene interactions. To investigate the genetic alterations of the MATH domain of SPOP gene in prostate cancer biopsies and correlation with clinical and pathological parameters; DNA samples from 50 prostate cancer tissues were genotyped and confirmed by Sanger sequencing. The frequency and distribution of high frequent mutations were determined and correlated with the patient’s tumor characteristics. Among 50 samples 34 (68%) were carrying one or more common mutations. Novel frame shift deletion mutation: c.255delA (p.Leu86Phefs) was detected in eight patients (16%), in addition to five novel missense mutations with moderate frequency (6%) namely: c.209G>C (p.Arg70Pro), c.215A>C (p.Asn72Thr), c.334G>A (p.Glu112Lys), c.373T>C (p.Phe125Leu), and c.388G>A (p.Asp130Asn), All missense mutations located in MATH domain. The effects of novel mutations described in the MATH domain are uncertain. No significant differences between carriers and noncarriers of common mutations detected regarding Gleason score, prostate-specific antigen concentration PSA, and tumor stage [p > 0.05]. Clinical significance of mutations detected on prostate tumors progression can be investigated in future analysis. Our findings revealed novel SPOP alterations in prostate cancer tissues probably associated with cancer development.
A Machine Learning Approach to Identifying Delirium from Electronic Health Records
Authors: Kim Jae Hyun , Hua May , Whittington Robert A. , Lee Junghwan , Liu Cong , Ta Casey N. , Marcantonio Edward R. , Goldberg Terry E. , Weng Chunhua
Published: September 2021

Background

Despite the well-known impact of delirium on long-term clinical outcomes, identification of delirium in electronic health records (EHR) remains difficult due to inadequate assessment or documentation of delirium. The purpose of this research is to present a classification model that identifies delirium using retrospective EHR data. The classification model would support the additional identification of delirium cases otherwise undocumented during routine practice.

Methods

Delirium was confirmed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Age, sex, Elixhauser comorbidity index, drug exposures, and diagnoses were used as features to train the logistic regression and multi-layer perceptron models. The clinical notes from the EHR were parsed to supplement the features that were not recorded in the structured data. The model performance was evaluated with a 5-fold cross-validation area under the receiver operating characteristic curve (AUC).

Results

Seventy-six patients (17 cases and 59 controls) with at least one CAM-ICU evaluation result during ICU stay from January 30, 2018 to February 20, 2018 were included in the model. The multi-layer perceptron model achieved the best performance in identifying delirium; mean AUC of 0.967 ± 0.019. The mean positive predictive value (PPV), mean negative predicted value (NPV), mean sensitivity, and mean specificity of the MLP model were 0.9, 0.88, 0.56, and 0.95, respectively.

Conclusion

A simple classification model showed a mean AUC over 0.95. This model promises to identify delirium cases with EHR data, thereby enable a sustainable infrastructure to build a retrospective cohort of delirium in the ICU. The cohort would be useful for the evaluation of long-term sequelae of delirium in ICU.
Single cell multi-omics reveals early elevated function and multiple fates within human progenitor exhausted CD8+ T cells
Authors: Cai Curtis , Samir Jerome , Pirozyan Mehdi R. , Adikari Thiruni N. , Gupta Money , Leung Preston , Hughes Brendan , Van der Byl Willem , Rizzetto Simone , Elthala Auda , Keoshkerian Elizabeth , Palgen Jean-Louis , Peters Timothy , Nguyen Thi H. O. , Louie Raymond , Kedzierska Katherine , Gaudieri Silvana , Bull Rowena A. , Lloyd Andrew R. , Luciani Fabio
Published: September 2021

T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of subjects with primary infection using single cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome we discovered progenitors of early-exhaustion with intermediate expression of PD-1. Intra clonal analysis revealed distinct trajectories with multiple fates suggesting evolutionary plasticity of precursor cells. These findings challenge current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T-cell differentiation in human infections.

One sentence summary

Progenitors of T-cell exhaustion in acute HCV infection