Search

Performance tracking devices in the form of wrist-worn watches are common in rowing; however, the accuracy of relevant output variables (i.e. stroke rate [SR] and velocity) during on-water training is unknown. To assess the quality of wrist-watch data output, 16 rowing athletes recorded 118 on-water rowing sessions using a Garmin Forerunner 735XT, which was compared to a Catapult Optimeye R4 tracking device. Garmin recording function was set to 'Every Second' (N = 68 sessions) or 'Smart' (N = 50 sessions). Catapult velocity was calculated as the average velocity per stroke, while a 15 s velocity moving average was determined for Garmin data. Catapult and Garmin were filtered for training-specific data (SR = 14–50 strokes per minute [spm]; velocity = 2.1–7.0 m/s−1). Efficacy and reliability of the Garmin was assessed via the difference between devices (% error), intra-class correlation coefficient (ICC ± 95% confidence interval (CI)) and coefficient of variation (CV%). Error in 15 s smoothed velocity was 3.8% ('Every Second') and 8.2% ('Smart'). Both recording functions demonstrated 'good' reliability (ICC = 0.75–0.9, CV < 10%) for SR and velocity; the exception was SR using 'Smart' recording. Our data suggests that when using the 'Every Second' recording function, data is filtered and velocity is smoothed over 15 s, the Garmin device can be reliable for SR and velocity measurement within 1 spm and <0.20 m/s−1 respectively. [ABSTRACT FROM AUTHOR]

This investigation explored differences in the pre-tournament preparation period relative to the movement demands of the Tokyo 2020 Olympic Games for the Australian male field-hockey team. Movement data was collected over 7 months prior to and during the 13-day Olympic tournament. Duration, distance (total; >80% individual peak velocity; >5 m.s−1), high-speed decelerations (>3.5 m.s−2), and total accelerations and decelerations (>2.5 m.s−2) were measured during each running-based session. A 13-day moving sum was calculated for each variable and compared to a player-specific "worst-case scenario" (WCS) for intra-tournament total movement demands. Summed 13-day movement demands exceeded the WCS for 6–58% of the preparation period across variables, for the entire squad. During the tournament, midfielders covered significantly greater sprint distance than Defenders (+84%,p = 0.020), with no other positional differences found. Greater variation in tournament movement demands was observed between players for accelerations, decelerations, and high-speed distance (CV = 19–46%) compared to duration and distance (CV = 4–9%). In conclusion, physical preparation exposed athletes to movement demands which surpassed WCS. Additionally, gross measures of training volume (duration and distance) are more generalisable to a squad; however, additional metrics such as sprint distance and high-speed decelerations are needed to better define positional and individual movement demands, and therefore, should be monitored by practitioners. [ABSTRACT FROM AUTHOR]

Objective: Few data exist on cognitive and depressive symptoms and vascular factors in American Indian (AI) elders. Since vascular risk factors increase risk for cognitive impairments, depression and dementia, and since AI elders are at high vascular risk, it is timely to assess the interplay of these factors in comprehensive studies of aging in this population. To begin, pilot studies must be conducted to show these types of data can be collected successfully.Design: A cross-sectional pilot study, the Southwest Heart Mind Study (SHMS).Setting: Tribal community in the Southwest United States.Participants: AI elders, aged ≥55 years.Main Outcome Measures: Cross-cultural demographic, social network and risk factor surveys; tests of cognition, depression and anxiety; physical measurements; blood biochemistries; and APOE genotyping.Results: SHMS elders were comparable to other rural elder populations on cognitive and depressive symptom scores. The average CogScore was 28.8 (out of 32), the average Geriatric Depression Scale (GDS) was 6.7 (of 30), and the average Hamilton Anxiety Scale was 1.2 (of 4). 32% possessed at least one APOEe4 allele. High vascular risk was evident: 76% were overweight or obese; 54% self-reported history of hypertension; 24% heart trouble; 32% type 2 diabetes; 35% depression; and 24% a family history of serious memory loss. More than 70% reported prescription medication use. 54% cared for someone besides self.Conclusions: A better understanding of the burden of vascular risk in relation to cognition and depression among Southwest Tribes is needed. [ABSTRACT FROM AUTHOR]

Der Beitrag widmet sich mit der Auseinandersetzung zwischen dem Deutschen Orden und dem Königreich Polen im frühen 15. Jahrhundert. Im Fokus stehen hierbei weniger die Austragung des Konflikts auf dem Konstanzer Konzil und die Berufung der Deputierten in der Diskussion auf die Autorität des Konzils. Vielmehr werden diplomatische Einflüsse ausübender „Drittakteure“ beleuchtet, wie etwa der Heilige Stuhl, der König und die Fürsten des Heiligen Römischen Reiches. Den groben zeitlichen Orientierungsrahmen bilden hier der sogenannte „Große Krieg“ 1409–1411 und der Frieden von Melnosee 1422.

We report on our investigation of low-energy pion-nucleon scattering from lattice QCD with Wilson type fermions. Our focus is on the isospin I = 3/2 channel, which couples to the Delta resonance. We discuss our calculations aiming at the extraction of the Delta resonance mass, width and effective coupling at pion mass 250 MeV, using the Lüscher finite-volume method to extract the phase shift δJ=3/2,l=1.

Excess N fertilization to achieve high crop yield is a grand old practice in developing countries. However, inorganic nutrient sources considerably replenish soil organic C (SOC). In the present study, we applied six different levels of N keeping P and K constant for maize, grown under maize (Zea mays) - dhaincha (Sesbania aculeata) cropping sequence. We recorded high crop yield, profuse root biomass and SOC stock with increasing N fertilization. Moreover, water holding capacity, microbial biomass carbon and particulate organic carbon improved significantly with increasing levels of N. Conversely, bulk density, mineral associated organic carbon and pH decreased with increasing application of inorganic N. Furthermore, a significant positive correlation was recorded between root biomass and soil organic carbon. A study of the sensitivity index showed particulate organic carbon and microbial biomass carbon to be good indicators of nutrient management practices. Dhaincha cultivation accelerated C and N mineralization in soil, which is reflected in increased biomass and crop yield. Hence, we conclude that inorganic N fertilization rate (7280 kg ha-1) in maize-dhaincha cropping sequence successfully maintains the SOC balance and optimize N stock in soil.

The present experiment was conducted with two common pulse crops namely black gram (Vigna mungo L.) and green gram (Vigna radiata L.) with the objective to study the morpho-physiological changes that took place in response to low moisture stress. Parameters such as plant height, leaf number, leaf area and pod number were studied under moisture stress condition as well as subsequent recovery stages. At harvest, yields of these two crops were recorded and various yield indexes like drought susceptibility index, drought tolerance index, mean and productivity rate were calculated. The study revealed that moisture stress has a significant impact on all these parameters in both crops. The effect was more significant in green gram compared to black gram. From the findings it is observed that moisture stress during flowering stage is detrimental for yield of the pulse crops and re-watering does not have a significant impact on yield improvement. Black gram variety T9 and green gram variety Pratap were identified as drought-tolerant varieties.

We present a high-statistics analysis of the ρ resonance in ππ scattering, using 2 + 1 flavors of clover fermions at a pion mass of approximately 320 MeV and a lattice size of approximately 3:6 fm. The computation of the two-point functions are carried out using combinations of forward, sequential, and stochastic propagators. For the extraction of the ρ-resonance parameters, we compare different fit methods and demonstrate their consistency. For the ππ scattering phase shift, we consider different Breit-Wigner parametrizations and also investigate possible nonresonant contributions. We find that the minimal Breit-Wigner model is suffcient to describe our data, and obtain amρ = 0:4609(16)stat(14)sys and gρππ = 5:69(13)stat(16)sys. In our comparison with other lattice QCD results, we consider the dimensionless ratios amρ/amN and amπ/amN to avoid scale setting ambiguities.

Context: Recent studies show increasing use of mechanical ventilation among people living with dementia. There are concerns that this trend may not be driven by patient preferences., Objectives: To better understand decision-making regarding mechanical ventilation in people living with dementia., Methods: This was an electronic health record-based retrospective cohort study of older adults with dementia (n = 295) hospitalized at one of two teaching hospitals between 2015 and 2019 who were supported with mechanical ventilation (n = 191) or died without mechanical ventilation (n = 104). Multivariable logistic regression was used to examine associations between patient characteristics and mechanical ventilation use., Results: The median age was 78 years (IQR 71-86), 41% were female, 28% resided in a nursing home, and 58% had clinical markers of advanced dementia (dehydration, weight loss, mobility limitations, or pressure ulcers). Among patients supported with mechanical ventilation, 70% were intubated within 24 hours of presentation, including 31% intubated before hospital arrival. Younger age, higher illness acuity, and absence of a treatment-limiting Physician Orders for Life-Sustaining Treatment document were associated with mechanical ventilation use; nursing home residence and clinical markers of advanced dementia were not. Most patients (89%) had a documented goals of care discussion (GOCD) during hospitalization., Conclusion: Future efforts to promote goal-concordant care surrounding mechanical ventilation use for people living with dementia should involve identifying barriers to goal-concordant care in pre-hospital settings, assessing the timeliness of in-hospital GOCD, and developing strategies for in-the-moment crisis communication across settings., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019, caused by SARS-CoV-2 (SCV-2) was stated as a pandemic on March 11 2020 by World Health Organization (WHO), and since then, it has become a major health issue worldwide. It mainly attacks the respiratory system with various accompanying complications, including cardiac injury, renal failure, encephalitis and Stroke. Materials and Methods: The current systematic review has been compiled to summarize the available literature on SCV-2 induced ischemic Stroke and its subtypes. Further, the mechanisms by which the virus crosses the blood-brain barrier (BBB) to enter the brain have also been explored. The role of CRP and D-dimer as potent prognostic markers was also explored. The literature search was carried out comprehensively on Google scholar, PubMed, SCOP US, Embase and Cochrane databases by following guidelines. Results: All the studies were reviewed thoroughly by authors and disagreements were resolved by consensus and help of the senior authors. The most common subtype of the IS was found to be large artery atherosclerosis in SCV-2 induced IS. Hypertension emerged as the most significant risk factor. The mechanism resulting in elevated levels of CRP and D-dimer have also been discussed. However, there is a scarcity of definitive evidence on how SCV-2 enters the human brain. The available literature based on various studies demonstrated that SCV-2 enters through the nasopharyngeal tract via olfactory cells to olfactory neurons, astrocytes and via choroid plexus through endothelial cells. Further, disruption of gut-brain axis has been also discussed. Conclusion: Data available in the literature is not adequate to come to a conclusion. Therefore, there is a need to carry out further studies to delineate the possible association between SCV-2 induced IS.

MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21-22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3' - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use., Competing Interests: Declaration of Competing Interest The Authors declare no competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Severe coronavirus disease 2019 (COVID-19) is associated with systemic hyper-inflammation. An adaptive interaction between gut microbiota and host immune systems is important for intestinal homeostasis and systemic immune regulation. The association of gut microbial composition and functions with COVID-19 disease severity is sparse, especially in India. We analysed faecal microbial diversity and abundances in a cohort of Indian COVID-19 patients to identify key signatures in the gut microbial ecology in patients with severe COVID-19 disease as well as in response to different therapies. The composition of the gut microbiome was characterized using 16Sr RNA gene sequences of genomic DNA extracted from faecal samples of 52 COVID-19 patients. Metabolic pathways across the groups were predicted using PICRUSt2. All statistical analyses were done using Vegan in the R environment. Plasma cytokine abundance at recruitment was measured in a multiplex assay., Results: The gut microbiome composition of mild and severe patients was found to be significantly different. Immunomodulatory commensals, viz. Lachnospiraceae family members and Bifidobacteria producing butyrate and short-chain fatty acids (SCFAs), were under represented in patients with severe COVID-19, with an increased abundance of opportunistic pathogens like Eggerthella. The higher abundance of Lachnoclostridium in severe disease was reduced in response to convalescent plasma therapy. Specific microbial genera showed distinctive trends in enriched metabolic pathways, strong correlations with blood plasma cytokine levels, and associative link to disease outcomes., Conclusion: Our study indicates that, along with SARS-CoV-2, a dysbiotic gut microbial community may also play an important role in COVID-19 severity through modulation of host immune responses., (© 2023. The Author(s).)

Context: Goals-of-care discussions are important for patient-centered care among hospitalized patients with serious illness. However, there are little data on the occurrence, predictors, and timing of these discussions., Objectives: To examine the occurrence, predictors, and timing of electronic health record (EHR)-documented goals-of-care discussions for hospitalized patients., Methods: This retrospective cohort study used natural language processing (NLP) to examine EHR-documented goals-of-care discussions for adults with chronic life-limiting illness or age ≥80 hospitalized 2015-2019. The primary outcome was NLP-identified documentation of a goals-of-care discussion during the index hospitalization. We used multivariable logistic regression to evaluate associations with baseline characteristics., Results: Of 16,262 consecutive, eligible patients without missing data, 5,918 (36.4%) had a documented goals-of-care discussion during hospitalization; approximately 57% of these discussions occurred within 24 hours of admission. In multivariable analysis, documented goals-of-care discussions were more common for women (OR=1.26, 95%CI 1.18-1.36), older patients (OR=1.04 per year, 95%CI 1.03-1.04), and patients with more comorbidities (OR=1.11 per Deyo-Charlson point, 95%CI 1.10-1.13), cancer (OR=1.88, 95%CI 1.72-2.06), dementia (OR=2.60, 95%CI 2.29-2.94), higher acute illness severity (OR=1.12 per National Early Warning Score point, 95%CI 1.11-1.14), or prior advance care planning documents (OR=1.18, 95%CI 1.08-1.30). Documentation of these discussions was less common for racially or ethnically minoritized patients (OR=0.823, 95%CI 0.75-0.90)., Conclusion: Among hospitalized patients with serious illness, documented goals-of-care discussions identified by NLP were more common among patients with older age and increased burden of acute or chronic illness, and less common among racially or ethnically minoritized patients. This suggests important disparities in goals-of-care discussions., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Severe COVID-19 frequently features a systemic deluge of cytokines. Circulating cytokines that can stratify risks are useful for more effective triage and management. Here, we ran a machine-learning algorithm on a dataset of 36 plasma cytokines in a cohort of severe COVID-19 to identify cytokine/s useful for describing the dynamic clinical state in multiple regression analysis. We performed RNA-sequencing of circulating blood cells collected at different time-points. From a Bayesian Information Criterion analysis, a combination of interleukin-8 (IL-8), Eotaxin, and Interferon-γ (IFNγ) was found to be significantly linked to blood oxygenation over seven days. Individually testing the cytokines in receiver operator characteristics analyses identified IL-8 as a strong stratifier for clinical outcomes. Circulating IL-8 dynamics paralleled disease course. We also revealed key transitions in immune transcriptome in patients stratified for circulating IL-8 at three time-points. The study identifies plasma IL-8 as a key pathogenic cytokine linking systemic hyper-inflammation to the clinical outcomes in COVID-19.

Objective: To assess the clinical and immunological benefits of passive immunization using convalescent plasma therapy (CPT)., Materials and Methods: A series of subclass analyses were performed on the previously published outcome data and accompanying clinical metadata from a completed randomized controlled trial (RCT) (Clinical Trial Registry of India, number CTRI/2020/05/025209). The subclass analyses were performed on the outcome data and accompanying clinical metadata from a completed RCT (patient recruitment between May 15, 2020 and October 31, 2020). Data on the plasma abundance of a large panel of cytokines from the same cohort of patients were also used to characterize the heterogeneity of the putative anti-inflammatory function of convalescent plasma (CP) in addition to passively providing neutralizing antibodies., Results: Although the primary clinical outcomes were not significantly different in the RCT across all age groups, significant immediate mitigation of hypoxia, reduction in hospital stay, and significant survival benefit were registered in younger (<67 years in our cohort) patients with severe coronavirus disease 2019 and acute respiratory distress syndrome on receiving CPT. In addition to neutralizing the antibody content of CP, its anti-inflammatory proteome, by attenuation of the systemic cytokine deluge, significantly contributed to the clinical benefits of CPT., Conclusion: Subgroup analyses revealed that clinical benefits of CPT in severe coronavirus disease 2019 are linked to the anti-inflammatory protein content of CP apart from the anti-severe acute respiratory syndrome coronavirus 2 neutralizing antibody content., (© 2022 Published by Elsevier Inc on behalf of Mayo Foundation for Medical Education and Research.)

Cellular deconvolution algorithms virtually reconstruct tissue composition by analyzing the gene expression of complex tissues. We present the decision tree machine learning algorithm, Kassandra, trained on a broad collection of >9,400 tissue and blood sorted cell RNA profiles incorporated into millions of artificial transcriptomes to accurately reconstruct the tumor microenvironment (TME). Bioinformatics correction for technical and biological variability, aberrant cancer cell expression inclusion, and accurate quantification and normalization of transcript expression increased Kassandra stability and robustness. Performance was validated on 4,000 H&E slides and 1,000 tissues by comparison with cytometric, immunohistochemical, or single-cell RNA-seq measurements. Kassandra accurately deconvolved TME elements, showing the role of these populations in tumor pathogenesis and other biological processes. Digital TME reconstruction revealed that the presence of PD-1-positive CD8 + T cells strongly correlated with immunotherapy response and increased the predictive potential of established biomarkers, indicating that Kassandra could potentially be utilized in future clinical applications., Competing Interests: Declaration of interests N.F. is the Chief Medical Officer of BostonGene, Corp. and a professor at the University of Texas MD Anderson Cancer Center. A. Zaitsev, M. Chelushkin, V.Z., B.S., D.D., E. Nuzhdina, A. Bagaev, and R.A. are inventors on patent applications related to Kassandra. All other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: Outcomes after cardiopulmonary resuscitation (CPR) remain poor. We have spent 10 years investigating an "informed assent" (IA) approach to discussing CPR with chronically ill patients/families. IA is a discussion framework whereby patients extremely unlikely to benefit from CPR are informed that unless they disagree, CPR will not be performed because it will not help achieve their goals, thus removing the burden of decision-making from the patient/family, while they retain an opportunity to disagree., Objectives: Determine the acceptability and efficacy of IA discussions about CPR with older chronically ill patients/families., Methods: This multi-site research occurred in three stages. Stage I determined acceptability of the intervention through focus groups of patients with advanced COPD or malignancy, family members, and physicians. Stage II was an ambulatory pilot randomized controlled trial (RCT) of the IA discussion. Stage III is an ongoing phase 2 RCT of IA versus attention control in in patients with advanced chronic illness., Results: Our qualitative work found the IA approach was acceptable to most patients, families, and physicians. The pilot RCT demonstrated feasibility and showed an increase in participants in the intervention group changing from "full code" to "do not resuscitate" within two weeks after the intervention. However, Stages I and II found that IA is best suited to inpatients. Our phase 2 RCT in older hospitalized seriously ill patients is ongoing; results are pending., Conclusions: IA is a feasible and reasonable approach to CPR discussions in selected patient populations., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Documented goals-of-care discussions are an important quality metric for patients with serious illness. Natural language processing (NLP) is a promising approach for identifying goals-of-care discussions in the electronic health record (EHR)., Objectives: To compare three NLP modeling approaches for identifying EHR documentation of goals-of-care discussions and generate hypotheses about differences in performance., Methods: We conducted a mixed-methods study to evaluate performance and misclassification for three NLP featurization approaches modeled with regularized logistic regression: bag-of-words (BOW), rule-based, and a hybrid approach. From a prospective cohort of 150 patients hospitalized with serious illness over 2018 to 2020, we collected 4391 inpatient EHR notes; 99 (2.3%) contained documented goals-of-care discussions. We used leave-one-out cross-validation to estimate performance by comparing pooled NLP predictions to human abstractors with receiver-operating-characteristic (ROC) and precision-recall (PR) analyses. We qualitatively examined a purposive sample of 70 NLP-misclassified notes using content analysis to identify linguistic features that allowed us to generate hypotheses underpinning misclassification., Results: All three modeling approaches discriminated between notes with and without goals-of-care discussions (AUC ROC : BOW, 0.907; rule-based, 0.948; hybrid, 0.965). Precision and recall were only moderate (precision at 70% recall: BOW, 16.2%; rule-based, 50.4%; hybrid, 49.3%; AUC PR : BOW, 0.505; rule-based, 0.579; hybrid, 0.599). Qualitative analysis revealed patterns underlying performance differences between BOW and rule-based approaches., Conclusion: NLP holds promise for identifying EHR-documented goals-of-care discussions. However, the rarity of goals-of-care content in EHR data limits performance. Our findings highlight opportunities to optimize NLP modeling approaches, and support further exploration of different NLP approaches to identify goals-of-care discussions., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Importance: High-quality goals-of-care communication is critical to delivering goal-concordant, patient-centered care to hospitalized patients with chronic life-limiting illness. However, implementation and documentation of goals-of-care discussions remain important shortcomings in many health systems., Objective: To evaluate the efficacy, feasibility, and acceptability of a patient-facing and clinician-facing communication-priming intervention to promote goals-of-care communication for patients hospitalized with serious illness., Design, Setting, and Participants: This randomized clinical trial enrolled patients from November 6, 2018, to February 18, 2020. The setting was 2 hospitals in an academic health care system in Seattle, Washington. Participants included hospitalized adults with chronic life-limiting illness, aged 65 years or older and with markers of frailty, or aged 80 years or older. Data analysis was performed from August 2020 to August 2021., Intervention: Patients were randomized to usual care with baseline questionnaires (control) vs the Jumpstart communication-priming intervention. Patients or surrogates in the intervention group and their clinicians received patient-specific Jumpstart Guides populated with data from questionnaires and the electronic health records (EHRs) that were designed to prompt and guide a goals-of-care discussion., Main Outcomes and Measures: The primary outcome was EHR documentation of a goals-of-care discussion between randomization and hospital discharge. Additional outcomes included patient-reported or surrogate-reported goals-of-care discussions, patient-reported or surrogate-reported quality of communication, and intervention feasibility and acceptability., Results: Of 428 eligible patients, this study enrolled 150 patients (35% enrollment rate; mean [SD] age, 59.2 [13.6] years; 66 women [44%]; 132 [88%] by patient consent and 18 [12%] by surrogate consent). Seventy-five patients each were randomized to the intervention and control groups. Compared with the control group, the cumulative incidence of EHR-documented goals-of-care discussions between randomization and hospital discharge was higher in the intervention group (16 of 75 patients [21%] vs 6 of 75 patients [8%]; risk difference, 13% [95% CI, 2%-24%]; risk ratio, 2.67 [95% CI, 1.10-6.44]; P = .04). Patient-reported or surrogate-reported goals-of-care discussions did not differ significantly between groups (30 of 66 patients [45%] vs 36 of 66 patients [55%]), although the intrarater consistency of patient and surrogate reports was poor. Patient-rated or surrogate-rated quality of communication did not differ significantly between groups. The intervention was feasible and acceptable to patients, surrogates, and clinicians., Conclusions and Relevance: In this randomized clinical trial, a patient-facing and clinician-facing communication priming intervention for seriously ill, hospitalized patients promoted EHR-documented goals-of-care discussions before discharge with good feasibility and acceptability. Communication-priming interventions should be reexamined in a larger randomized clinical trial to better understand their effectiveness in the inpatient setting., Trial Registration: ClinicalTrials.gov Identifier: NCT03746392.

A single center open label phase 2 randomised control trial (Clinical Trial Registry of India No. CTRI/2020/05/025209) was done to assess clinical and immunological benefits of passive immunization using convalescent plasma therapy. At the Infectious Diseases and Beleghata General Hospital in Kolkata, India, 80 patients hospitalized with severe COVID-19 disease and fulfilling the inclusion criteria (aged more than 18 years, with either mild ARDS having PaO2/FiO2 200-300 or moderate ARDS having PaO2/FiO2 100-200, not on mechanical ventilation) were recruited and randomized into either standard of care (SOC) arm (N = 40) or the convalescent plasma therapy (CPT) arm (N = 40). Primary outcomes were all-cause mortality by day 30 of enrolment and immunological correlates of response to therapy if any, for which plasma abundance of a large panel of cytokines was quantitated before and after intervention to assess the effect of CPT on the systemic hyper-inflammation encountered in these patients. The secondary outcomes were recovery from ARDS and time taken to negative viral RNA PCR as well as to report any adverse reaction to plasma therapy. Transfused convalescent plasma was characterized in terms of its neutralizing antibody content as well as proteome. The trial was completed and it was found that primary outcome of all-cause mortality was not significantly different among severe COVID-19 patients with ARDS randomized to two treatment arms (Mantel-Haenszel Hazard Ratio 0.6731, 95% confidence interval 0.3010-1.505, with a P value of 0.3424 on Mantel-Cox Log-rank test). No adverse effect was reported with CPT. In severe COVID-19 patients with mild or moderate ARDS no significant clinical benefit was registered in this clinical trial with convalescent plasma therapy in terms of prespecified outcomes., (© 2022. The Author(s).)

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact., Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics., Design, Setting, and Participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants)., Exposure: Receipt of CCP., Main Outcomes and Measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI., Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs., Conclusions and Relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Background and Objectives: The COVID-19 pandemic has spread across 87 million people with more than 1·8 million deaths in the world. As there is no definite treatment modality, the use of convalescent plasma has become increasingly popular worldwide. This study aimed to identify an appropriate strategy of donor recruitment and to evaluate the appropriateness of pre-set plasma donation guidelines., Material and Methods: In this prospective study conducted from May to September 2020, the donors were recruited under the following two circumstances: Group I, patients in the post-COVID-19 follow-up in the clinic, and Group II, patients recovered from COVID-19 recruited through mass and electronic media. A pre-set donor selection criteria and laboratory investigation was designed according to national and international guidelines. Approximately 500 ml of COVID-19 convalescent plasma (CCP) was collected from recovered individuals in each group by two different cell separators. The overall donor's attendance rate, deferral rate, adverse events and donor compliance was analysed and compared between the two groups., Results: There was a significant difference in attendance in relation to registration between the groups ( P  < 0·0001). Donor deferral was significantly higher in group II compared with group I. The single most frequent cause of donor deferral was low antibody index ( P  = 0·0001). The total donor adverse event rate in CCP donation was significantly lower compared with routine plateletpheresis procedures. The donor's compliance to blood centre's protocol was satisfactory in both the groups., Conclusion: Recruitment of patients in the post-COVID-19 follow-up in the clinic was more effective than the general recruitment through mass and electronic media for convalescence plasma donation in a resource-constrained blood centre., Competing Interests: The authors declare no conflict of interests., (© 2021 International Society of Blood Transfusion.)

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sarif, Raychaudhuri, D’Rozario, Bandopadhyay, Singh, Mehta, Hoque, Sinha, Kushwaha, Sahni, Devi, Chattopadhyay, Paul, Ray, Chaudhuri, Banerjee, Majumdar, Saha, Sarkar, Bhattacharya, Chatterjee, Paul, Ghosh, Pandey, Sengupta and Ganguly.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has led to significant morbidity and mortality. While most suffer from mild symptoms, some patients progress to severe disease with acute respiratory distress syndrome (ARDS) and associated systemic hyperinflammation., Methods: First, to characterize key cytokines and their dynamics in this hyperinflammatory condition, we assessed abundance and correlative expression of a panel of 48 cytokines in patients progressing to ARDS as compared to patients with mild disease. Then, in an ongoing randomized controlled trial of convalescent plasma therapy (CPT), we analyzed rapid effects of CPT on the systemic cytokine dynamics as a correlate for the level of hypoxia experienced by the patients., Results: We identified an anti-inflammatory role of CPT independent of its neutralizing antibody content., Conclusions: Neutralizing antibodies, as well as reductions in circulating interleukin-6 and interferon-γ-inducible protein 10, contributed to marked rapid reductions in hypoxia in response to CPT., Clinical Trial Registry of India: CTRI/2020/05/025209. http://www.ctri.nic.in/., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To assess the diagnostic accuracy of antigen compared with reverse transcriptase (RT)-PCR testing in an asymptomatic athlete screening programme and to monitor infection in college athletes., Methods: Quidel Sofia-2 SARS-CoV-2 Antigen Tests were performed daily before sports participation for football, basketball, wrestling and water polo from 29 September 2020 to 28 February 2021. Paired RT-PCR and antigen tests were performed at least once a week. Positive antigen tests were confirmed with RT-PCR., Results: 81 175 antigen and 42 187 RT-PCR tests were performed, including 23 462 weekly paired antigen/RT-PCR screening tests in 1931 athletes. One hundred and seventy-two athletes had a positive screening RT-PCR (0.4%), of which 83 (48%) occurred on paired testing days. The sensitivity of antigen tests varied with the frequency of RT-PCR testing and prevalence of COVID-19. The sensitivity of antigen testing was 35.7% (95% CI: 17% to 60%) and specificity 99.8% (95% CI: 99.7% to 99.9%) with once-a-week RT-PCR testing after adjusting for school prevalence. Daily antigen testing was similar to RT-PCR testing two to three times a week in identifying infection. Antigen testing identified infection before the next scheduled PCR on 89 occasions and resulted in 234 days where potentially infectious athletes were isolated before they would have been isolated with RT-PCR testing alone. Two athletic-related outbreaks occurred; 86% of total infections were community acquired., Conclusion: Antigen testing has high specificity with a short turnaround time but is not as sensitive as RT-PCR. Daily antigen testing or RT-PCR testing two to three times a week is similar. There are benefits and drawbacks to each testing approach., Competing Interests: Competing interests: KH has stock options in 98point6 which are not relevant to this paper., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Morphological variability in the shoulder influences the joint biomechanics and is an important consideration in arthroplasty and implant design. The objectives of this study were to quantify cortical and cancellous proximal humeral morphology and to assess whether shape variation was influenced by gender and ethnicity, with the overarching goal of informing implant design and treatment. A statistical shape model of the proximal humeral cortical and cancellous regions was developed for a training set of 84 subjects of both genders and different ethnicities. Cortical and cancellous bone geometries were reconstructed from CT scans, meshed with triangular elements, and registered to a template. Principal component analysis was applied to quantify modes of variation. Anatomical measurements were computed on the registered geometries to assess correlation with modes of variation. Parallel analysis identified six significant modes of variation, which accounted for 93% of variation in the training set and described scaling (Mode 1), inclination of the head (Modes 2 and 5), and shape of the greater tuberosity and neck region (Modes 3, 4, and 6). Size differences as described by Mode 1 were statistically significant for gender and ethnicity, where female and Asian subjects were smaller than male and Caucasian subjects, respectively; however, differences in other modes were not significant. Cortical thickness of the shaft after normalization by outer diameter was significantly larger for Asian subjects compared to Caucasian subjects. The statistical shape model quantified cortical and cancellous humeral morphology considering gender and ethnicity, providing descriptive data to support surgical planning, and implant design. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3043-3052, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Mass cytometry enables highly multiplexed profiling of cellular immune responses in limited-volume samples, advancing prospects of a new era of systems immunology. The capabilities of mass cytometry offer expanded potential for deciphering immune responses to infectious diseases and to vaccines. Several studies have used mass cytometry to profile protective immune responses, both postinfection and postvaccination, although no vaccine-development program has yet systematically employed the technology from the outset to inform both candidate design and clinical evaluation. In this article, we review published mass cytometry studies relevant to vaccine development, briefly compare immune profiling by mass cytometry to other systems-level technologies, and discuss some general considerations for deploying mass cytometry in the context of vaccine development.-Reeves, P. M., Sluder, A. E., Raju Paul, S., Scholzen, A., Kashiwagi, S., Poznansky, M. C. Application and utility of mass cytometry in vaccine development., (© FASEB.)

Development of vaccines that are both safe and effective remains a costly and time-consuming challenge. To accelerate the pace of development and improve the efficacy and safety of candidate vaccines for both existing and emerging infectious agents, we have used a distributed development approach. This features the managed integration of individual expert groups having the requisite vaccine platforms, pre-clinical models, assays, skills and knowledge pertinent to a specific pathogen into a single, end-to-end development team capable of producing a new vaccine tailored to that particular agent. Distributed development focuses on integrating existing effort across multiple institutions rather than developing new capabilities or consolidating resources within an individual organization. Previously we have used the distributed development strategy to generate vaccine candidates for emerging viral diseases. Coxiella burnetii is a highly infectious and resilient bacterium and the causative agent of Q fever. Treatment for Q fever can require months of antibiotics. The current vaccine for Q-fever is only approved in Australia and requires prescreening due to the potential for severe reactogenicity in previously exposed individuals. Here we discuss Q-VaxCelerate, a distributed development consortium for the development of a new vaccine to prevent Q fever.

The interests of the public and both the medical and legal professions are best served when scientifically sound and unbiased expert witness testimony is readily available in civil and criminal proceedings. As members of the medical community, patient advocates, and private citizens, pediatricians have ethical and professional obligations to assist in the civil and criminal judicial processes. This policy statement offers recommendations on advocacy, education, research, qualifications, standards, and ethical business practices all aimed at improving expert testimony., (Copyright © 2017 by the American Academy of Pediatrics.)

The interests of the public and both the medical and legal professions are best served when scientifically sound and unbiased expert witness testimony is readily available in civil and criminal proceedings. As members of the medical community, patient advocates, and private citizens, pediatricians have ethical and professional obligations to assist in the civil and criminal judicial processes. This technical report explains how the role of the expert witness differs in civil and criminal proceedings, legal and ethical standards for expert witnesses, and strategies that have been employed to deter unscientific and irresponsible testimony. A companion policy statement offers recommendations on advocacy, education, research, qualifications, standards, and ethical business practices all aimed at improving expert testimony., (Copyright © 2017 by the American Academy of Pediatrics.)

DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Objective: Documenting the implementation of a public health programme as per its design is critical to interpretation of results from survey-led outcome and impact evaluation activities, the authors describe the scale-up and coverage of large-scale HIV-prevention services provided to female sex workers (FSWs) and high-risk men who have sex with men (HR-MSM) during the first 5 years of the Avahan programme in India., Methods: Implementing NGO partner-generated denominator estimates from 70 districts were used to estimate the programme's intended coverage. Routine programme-monitoring data until December 2008 were used to describe the service and commodity availability, service utilisation to generate internal estimates of coverage. Coverage was validated in few districts using data from a cross-sectional survey., Results: In December 2008, the estimated denominators for intended services were about 217,000 FSWs and 80,000 HR-MSM. By January 2007, 79% of eventual total clinics and 75% drop-in centres were established, and 83% of eventual peer educators were active. By month 48, sufficient condoms to cover all estimated FSW commercial sex acts were distributed free. By month 60, 75% of the estimated denominator intended to be covered was met monthly. 86% of FSWs and 67% of HR-MSM ever contacted had used sexually transmitted infections services at least once. Cross-sectional survey generated coverage results suggest that programme-monitoring data provide a proxy to coverage of services., Conclusion: Avahan's monitoring data show that Avahan achieved infrastructure scale by year 3 and high contact coverage through peers and with commodities by year 5 of implementation as per the design.

Risk difference (RD) is an important measure in epidemiological studies where the probability of developing a disease for individuals in an exposed group, for example, is compared with that in a control group. There are varying cluster sizes in each group and the binary responses within each cluster cannot be assumed independent. Under the cluster sampling scenario, Lui (Statistical Estimation of Epidemiological Risk. Wiley: CA, 2004; 7-27) discusses four methods for the construction of a confidence interval for the RD. In this paper we introduce two very simple methods. One method is based on an estimator of the variance of a ratio estimator (Sampling Techniques (3rd edn). Wiley: New York, 1977; 30-67) and the other method is based on a sandwich estimator of the variance of the regression estimator using the generalized estimating equations approach of Zeger and Liang (Biometrics 1986; 42:121-130). These two methods are then compared, by simulation, in terms of maintaining nominal coverage probability and average coverage length, with the four methods discussed by Lui (Statistical Estimation of Epidemiological Risk. Wiley: CA, 2004; 7-27). Simulations show at least as good properties of these two methods as those of the others. The method based on an estimate of the variance of a ratio estimator performs best overall. It involves a very simple variance expression and can be implemented with a very few computer codes. Therefore, it can be considered as an easily implementable alternative.

A popular model to analyse over/under-dispersed proportions is to assume the extended beta-binomial model with dispersion (intraclass correlation) parameter phi and then to estimate this parameter by maximum likelihood. However, it is well known that maximum likelihood estimate (MLE) may be biased when the sample size n or the total Fisher information is small. In this paper we obtain a bias-corrected maximum likelihood (BCML) estimator of the intraclass correlation parameter and compare it, by simulation, in terms of bias and efficiency, with the MLE, an estimator Q(2) based on optimal quadratic estimating equations of Crowder and recommended by Paul et al. and a double extended quasi-likelihood (DEQL) estimator proposed by Lee. The BCML estimator has superior bias and efficiency properties in most instances. Analyses of a set of toxicological data from Paul and a set of medical data pertaining to chromosomal abnormalities among survivors of the atomic bomb in Hiroshima from Otake and Prentice show, in general, much improvement in standard errors of the BCML estimates over the other three estimates., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

In this paper we derive explicit expressions for the elements of the exact Fisher information matrix of the Dirichlet-multinomial distribution. We show that exact calculation is based on the beta-binomial probability function rather than that of the Dirichlet-multinomial and this makes the exact calculation quite easy. The exact results are expected to be useful for the calculation of standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters for data that arise in practice in toxicology and other similar fields. Standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters, based on the exact and the asymptotic Fisher information matrix based on the Dirichlet distribution, are obtained for a set of data from Haseman and Soares (1976), a dataset from Mosimann (1962) and a more recent dataset from Chen, Kodell, Howe and Gaylor (1991). There is substantial difference between the standard errors of the estimates based on the exact Fisher information matrix and those based on the asymptotic Fisher information matrix.

A procedure for testing for treatment effect in data similar to the data on premature ventricular contractions (PVC) is presented. We consider a zero-inflated beta-binomial model. Based on this model, we develop score tests to test for treatment effect in the data in which observations in the form of counts are recorded before and after applying a therapy. Results of a small simulation experiment, to study small sample behaviour of a score test and a likelihood ratio test, are reported and the PVC data are analysed. Both the score and the likelihood ratio tests show good level properties. Either the score tests or the likelihood ratio tests can be used for testing the presence of treatment effect. The score tests, however, may be preferable because they use estimates of the parameters only under the null hypothesis and in the important range pi<0.5 power of the score test statistic S1 is slightly better than the likelihood ratio statistic LR1., (Copyright 2004 John Wiley & Sons, Ltd.)

Purpose: Vigabatrin (VGB) has been shown to cause visual field constriction and other forms of mild visual dysfunction. We determined the safety of continuing VGB therapy in patients who had received prolonged treatment (>2 years) with the drug by serially monitoring changes in visual function over a 1-year period of continued therapy. We also followed up patients who discontinued VGB to see whether alternative therapies are effective., Methods: Fifteen of 17 patients who continued VGB therapy had visual-function testing (visual acuity, color vision, kinetic and static perimetry) every 3 months for 1 year. Eighteen patients who discontinued VGB were given alternative antiepileptic drugs (AEDs); their seizure responses were measured after > or =3 months of treatment., Results: Patients continuing VGB showed no worsening of visual acuity, color vision, or visual-field constriction beyond that measured in the initial test. Many patients who discontinued VGB had good seizure control with either newer or previously unsuccessful AEDs., Conclusions: For patients who have an excellent response to VGB and only mild visual changes, continued therapy may be safe with close visual monitoring. Patients who do not have a significant reduction in seizures or who experience considerable visual dysfunction with VGB may respond well to alternative therapies.