Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding.

Introduction: Mouse models of radiation injury are critical to the development of medical countermeasures (MCMs) against radiation. Now that MCMs against hematopoietic acute radiation syndrome (H-ARS) have achieved regulatory approval, attention is shifting to develop MCMs against the adverse effects of gastrointestinal acute radiation syndrome (GI-ARS) and delayed effects of acute radiation exposure (DEARE). The C57L/J mouse model of partial body irradiation (PBI) with 2.5% bone marrow shielding (BM2.5) is being leveraged to examine both GI-ARS and DEARE effects. Within days of PBI, mice may develop H- and GI-ARS followed several months later by DEARE as a multi-organ injury, which typically involves the lung and kidney (L- and K-DEARE, respectively). The objective of this manuscript is to describe the dose response relationship and progression of radiation injury in the C57L/J mouse and to evaluate its suitability for use in DEARE MCM testing. Materials and methods: In two separate studies conducted over 2 years, male and female C57L/J mice were exposed to PBI BM2.5 with one hindlimb shielded from radiation, representing ~2.5% bone marrow shielding/sparing. Mice were X-ray irradiated at doses ranging from 9 to 13 Gy at 10 to 12 weeks of age for the purposes of assessing ARS survival at 30 days and DEARE survival at 182 days post-irradiation. Clinical indicators of ARS and DEARE were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging (MRI) of lung, and histopathology of selected tissues. Results: C57L/J mice developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in dose dependent mortality at doses ≥11 Gy between 1- and 15-days post-irradiation. In animals that survived ARS, DEARE associated mortality occurred in dose dependent fashion at ≥9 Gy for both sexes between 60- and 159-days post-irradiation with histopathology examinations indicating lung injury as the primary cause of death in moribund animals. Conclusion: The PBI BM2.5 C57L/J mouse model reliably produced known H- and GI-ARS effects at doses greater than those resulting in DEARE effects. Because of this, the C57L/J mouse can be used to test MCMs against L-DEARE injury, while avoiding ARS associated mortality.

An initial set of reference values for the Balance Tracking System (BTrackS) Limits of Stability protocol.

BACKGROUND: The Balance Tracking System (BTrackS) Limits of Stability (LOS) protocol is a relatively new means of evaluating unconstrained dynamic postural control ability. While the reliability of this protocol has previously been established, reference data is currently unavailable to assist in the interpretation of results. RESEARCH QUESTION: What are typical reference values for the BTrackS LOS protocol with respect to sex, height, and BMI? METHODS: A cross= -section of 800 healthy, young adults (aged 18-29 years; 368 men, 432 women) were administered the BTrackS LOS protocol. Sex, height and weight variables were also captured for the participants. RESULTS: Results of a stepwise linear regression showed that the outcome measure for BTrackS LOS testing (i.e. LOS Area) was larger in taller individuals and in men. Based on these findings, four percentile ranking categories were established and associated look-up tables created. SIGNIFICANCE: The reference values provided by this study offer much needed guidance to clinicians and researchers for the determination of dynamic balance abnormalities based on BTrackS LOS testing.

Potential Factors Associated with Healthcare Utilization for Balance Problems in Community-Dwelling Adults within the United States: A Narrative Review.

Falls are the leading cause of mortality and chronic disability in elderly adults. There are effective fall prevention interventions available. But only a fraction of the individuals with balance/dizziness problems are seeking timely help from the healthcare system. Current literature confirms the underutilization of healthcare services for the management of balance problems in adults, especially older adults. This review article explores factors associated with healthcare utilization as guided by the Andersen Healthcare Utilization Model, a framework frequently used to explore the factors leading to the use of health services. Age, sex, race/ethnicity, BMI, and comorbidities have been identified as some of the potential predisposing factors; socioeconomic status, health insurance, and access to primary care are the enabling and disabling factors; and severity of balance problem, perceived illness, and its impact on daily activities are the factors affecting need for care associated with healthcare utilization for balance or dizziness problems. Knowledge about these barriers can help direct efforts towards improved screening of vulnerable individuals, better access to care, and education regarding effective fall prevention interventions for those who are at risk for underutilization. This can aid in timely identification and management of balance problems, thereby reducing the incidence of falls.

The progression of radiation injury in a Wistar rat model of partial body irradiation with ∼5% bone marrow shielding.

PURPOSE: To describe the dose response relationship and natural history of radiation injury in the Wistar rat and its suitability for use in medical countermeasures (MCM) testing. MATERIALS & METHODS: In two separate studies, male and female rats were exposed to partial body irradiation (PBI) with 5% bone marrow sparing. Animals were X-ray irradiated from 7 to 12 Gy at 7-10 weeks of age. Acute radiation syndrome (ARS) survival at 30 days and delayed effects of acute radiation exposure (DEARE) survival at 182 days were assessed. Radiation effects were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging of lung, whole-body plethysmography, and histopathology. RESULTS: Rats developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in mortality at doses ≥8Gy in males and ≥8.5 Gy in females. DEARE mortality occurred at doses ≥8Gy for both sexes. Findings indicate lung, kidney, and/or liver injury, and persistent hematological dysregulation, revealing multi-organ injury as a DEARE. CONCLUSION: The Wistar rat PBI model is suitable for testing MCMs against hematopoietic and gastrointestinal ARS. DEARE multi-organ injury occurred in both sexes irradiated with 8-9Gy, also suggesting suitability for polypharmacy studies addressing the combination of ARS and DEARE injury.

Need for inpatient rehabilitation and skilled nursing services in COVID-19 patients post hospitalization: a retrospective cohort study.

BACKGROUND: The need for rehabilitation and skilled nursing services for coronavirus disease 2019 (COVID-19) survivors has been speculated from the beginning of the pandemic. However, real-world data describing utilization of these services post COVID-19 hospitalization and the factors associated with the same is limited. This retrospective cohort study on COVID-19 patients aims to identify the patients discharged to inpatient rehabilitation or nursing facilities post-hospitalization and the factors associated with the same. METHODS: A retrospective cohort study on COVID-19 patients during second wave of the pandemic in the state of Michigan. Primary outcome was discharge disposition. Binary logistic regression was conducted to identify the factors associated with discharge to a facility. RESULTS: A total of 559 COVID-19 patients [median age 64 years, interquartile range (IQR) 53-73 years, 48.5% males (n=271), 67.6% Blacks (n=378)] were included in the study. During hospitalization, 17.4% of the patients (n=97) died. Around 65% (n=365) patients were discharged home whereas 12.5% (n=70) were discharged to a facility for inpatient rehabilitation/nursing services. Older patients, males, those with longer hospital stay, and patients who needed new percutaneous endoscopic gastrostomy (PEG) tube, tracheostomy, initiation of hemodialysis or continuous renal replacement therapy (CRRT), or had an acute stroke during admission were more likely to be discharged to a facility post-hospitalization. CONCLUSIONS: About 12.5% of hospitalized COVID-19 patients needed discharge to a facility for inpatient rehabilitation/nursing services. Knowledge of the factors associated with discharge to a facility can optimize discharge planning, efficient resource allocation, and improve long-term COVID-19 care.

Statins and clinical outcomes in hospitalized COVID-19 patients with and without Diabetes Mellitus: a retrospective cohort study with propensity score matching.

BACKGROUND: The pleiotropic effects of statins may reduce the severity of COVID-19 disease. This study aims to determine the association between inpatient statin use and severe disease outcomes among hospitalized COVID-19 patients, especially those with Diabetes Mellitus (DM). RESEARCH DESIGN AND METHODS: A retrospective cohort study on hospitalized patients with confirmed COVID-19 diagnosis. The primary outcome was mortality during hospitalization. Patients were classified into statin and non-statin groups based on the administration of statins during hospitalization. Analysis included multivariable regression analysis adjusting for confounders and propensity score matching to achieve a 1:1 balanced cohort. Subgroup analyses based on presence of DM were conducted. RESULTS: In the cohort of 922 patients, 413 had a history of DM. About 27.1% patients (n = 250) in the total cohort (TC) and 32.9% patients (n = 136) in DM cohort received inpatient statins. Atorvastatin (n = 205, 82%) was the most commonly prescribed statin medication in TC. On multivariable analysis in TC, inpatient statin group had reduced mortality compared to the non-statin group (OR, 0.61; 95% CI, 0.42-0.90; p = 0.01). DM modified this association between inpatient statins and mortality. Patients with DM who received inpatient statins had reduced mortality (OR, 0.35; 95% CI, 0.21-0.61; p < 0.001). However, no such association was noted among patients without DM (OR, 1.21; 95% CI, 0.67-2.17; p = 0.52). These results were further validated using propensity score matching. CONCLUSIONS: Inpatient statin use was associated with significant reduction in mortality among COVID-19 patients especially those with DM. These findings support the pursuit of randomized clinical trials and inpatient statin use appears safe among COVID-19 patients.

Letter to the editor: Vitamin D levels in acute illness and clinical severity in COVID-19 patients.

We would like to comment on the recently published article titled: "Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients" by Ricci et al. The authors grouped the patients into two groups according to the vitamin D levels measured at the time of admission into the hospital and reported that lower vitamin D levels are associated with elevated D-dimer and IL-6 levels, low CD4/CD8 ratio and compromised clinical findings with elevated LIPI and SOFA scores. However, review of recent literature shows this association to be debatable. The 25-hydroxyvitamin D levels in the initial phase of critical illness have been reported to drop rapidly and hence consideration of the time of measurement from symptom onset would have enhanced the clinical relevance of these findings. Inferred association between vitamin D levels and disease severity based on SOFA score in COVID-19 patients, needs to be further explored in the light of the recent literature which casts doubt on using SOFA score at admission to predict mortality in COVID-19.

Association between antecedent statin use and severe disease outcomes in COVID-19: A retrospective study with propensity score matching.

BACKGROUND: Statins have been associated with a reduction in inflammatory markers and improved endothelial function. Whether statins offer any benefit in COVID-19 needs to be elucidated. OBJECTIVE: To determine the association between antecedent statin use and severe disease outcomes among COVID-19 patients. METHODS: A retrospective cohort study on 1014 patients with confirmed COVID-19 diagnosis. Outcomes were mortality, need for mechanical ventilation, and intensive care admission. Patients were classified into statin-users vs statin non-users based on antecedent use of statins. Multivariable regression analysis was performed adjusting for confounders such as age, sex, race, BMI, smoking, insurance, and comorbidities. Propensity score matching was performed to achieve a 1:1 balanced cohort. RESULTS: A total of 1014 patients (Median age 65 (IQR 53-73); 530 (52.3%) males; 753 (74.3%) African Americans; median BMI 29.4 (IQR 25.1-35.9); 615 (60.7%) with Medicare insurance) were included in the study. About 454 patients (44.77%) were using statins as home medication. Antecedent statin use was associated with significant decrease in mortality in the total cohort (OR, 0.66; 95% CI, 0.46 - 0.95; p = 0.03). Among the propensity score matched (PSM) cohort of 466 patients (233 statin users and 233 statin non-users), all the baseline characteristics had similar distribution among the two groups. Statin users had significant reduction in mortality in the PSM cohort as well (OR, 0.56; 95% CI, 0.37 - 0.83; p = 0.004). CONCLUSIONS: Statin use was associated with significant reduction in mortality among COVID-19 patients. These findings support the pursuit of randomized clinical trials to explore the possible benefits of statins in COVID-19.

Preexisting respiratory diseases and clinical outcomes in COVID-19: a multihospital cohort study on predominantly African American population.

BACKGROUND: Comorbidities play a key role in severe disease outcomes in COVID-19 patients. However, the literature on preexisting respiratory diseases and COVID-19, accounting for other possible confounders, is limited. The primary objective of this study was to determine the association between preexisting respiratory diseases and severe disease outcomes among COVID-19 patients. Secondary aim was to investigate any correlation between smoking and clinical outcomes in COVID-19 patients. METHODS:  This is a multihospital retrospective cohort study on 1871 adult patients between March 10, 2020, and June 30, 2020, with laboratory confirmed COVID-19 diagnosis. The main outcomes of the study were severe disease outcomes i.e. mortality, need for mechanical ventilation, and intensive care unit (ICU) admission. During statistical analysis, possible confounders such as age, sex, race, BMI, and comorbidities including, hypertension, coronary artery disease, congestive heart failure, diabetes, any history of cancer and prior liver disease, chronic kidney disease, end-stage renal disease on dialysis, hyperlipidemia and history of prior stroke, were accounted for. RESULTS:  A total of 1871 patients (mean (SD) age, 64.11 (16) years; 965(51.6%) males; 1494 (79.9%) African Americans; 809 (43.2%) with ≥ 3 comorbidities) were included in the study. During their stay at the hospital, 613 patients (32.8%) died, 489 (26.1%) needed mechanical ventilation, and 592 (31.6%) required ICU admission. In fully adjusted models, patients with preexisting respiratory diseases had significantly higher mortality (adjusted Odds ratio (aOR), 1.36; 95% CI, 1.08-1.72; p = 0.01), higher rate of ICU admission (aOR, 1.34; 95% CI, 1.07-1.68; p = 0.009) and increased need for mechanical ventilation (aOR, 1.36; 95% CI, 1.07-1.72; p = 0.01). Additionally, patients with a history of smoking had significantly higher need for ICU admission (aOR, 1.25; 95% CI, 1.01-1.55; p = 0.03) in fully adjusted models. CONCLUSION:  Preexisting respiratory diseases are an important predictor for mortality and severe disease outcomes, in COVID-19 patients. These results can help facilitate efficient resource allocation for critical care services.

Metabolic syndrome and clinical outcomes in patients infected with COVID-19: Does age, sex, and race of the patient with metabolic syndrome matter?

BACKGROUND: Metabolic syndrome (MetS) is highly prevalent worldwide, and its individual components obesity, diabetes, and hypertension have been identified as risk factors to develop severe coronavirus disease 2019 (COVID-19); however, data on MetS and clinical outcomes in COVID-19 are scarce. This study aims to determine association between MetS and severe disease outcomes, that is, mortality, need for mechanical ventilation, and intensive care unit (ICU) requirement among patients with COVID-19. METHODS: This is a retrospective multihospital cohort study on 1871 patients with confirmed COVID-19 diagnosis. Patient data including demographics, comorbidities, body mass index (BMI), smoking, laboratory data, and the clinical course of hospitalization were collected. Multivariable regression was performed adjusting for age, sex, race, insurance, smoking, and comorbidities. RESULTS: A total of 1871 patients (median age 66 [interquartile range, IQR 54-75]; 965 (51.6%) males; 1494 (80%) African Americans; median BMI 29.4 kg/m2 [IQR 25-35.8]; 573 (30.6%) patients with MetS) were included. Patients with MetS had increased mortality (odds ratio [OR], 1.40; 95% CI, 1.11-1.75; P = .004), higher ICU admission (OR, 1.68; 95% CI, 1.36-2.08; P < .001), and increased need for mechanical ventilation (OR, 1.90; 95% CI, 1.52-2.37; P < .001). Among individual comorbidities, diabetes had significant association with mortality (OR, 1.30; 95% CI, 1.05-1.63; P = 0.02), ICU admission (OR, 1.56; 95% CI, 1.27-1.93; P < .001), and need for mechanical ventilation (OR, 1.63; 95% CI, 1.30-2.03; P < .001). CONCLUSIONS: MetS is a better prognostic indicator for severe disease outcomes in patients with COVID-19 than its individual components. Patients with MetS had significantly higher mortality, increased ICU admissions, and need for mechanical ventilation.

Exploring the link between vitamin D and clinical outcomes in COVID-19.

The immunomodulating role of vitamin D might play a role in COVID-19 disease. We studied the association between vitamin D and clinical outcomes in COVID-19 patients. This is a retrospective cohort study on COVID-19 patients with documented vitamin D levels within the last year. Vitamin D levels were grouped as ≥ 20 ng/mL or < 20 ng/mL. Main outcomes were mortality, need for mechanical ventilation, new DVT or pulmonary embolism, and ICU admission. A total of 270 patients (mean ± SD) age, 63.81 (14.69) years); 117 (43.3%) males; 216 (80%) Blacks; 139 (51.5%) in 65 and older age group were included. Vitamin D levels were less than 20 ng/mL in 95 (35.2%) patients. During admission, 72 patients (26.7%) died, 59 (21.9%) needed mechanical ventilation, and 87 (32.2%) required ICU. Vitamin D levels showed no significant association with mortality (OR = 0.69; 95% CI, 0.39-1.24; P = 0.21), need for mechanical ventilation (OR = 1.23; 95% CI, 0.68-2.24; P = 0.49), new DVT or PE(OR= 0.92; 95% CI, 0.16-5.11; P = 1.00) or ICU admission (OR = 1.38; 95% CI, 0.81-2.34; P = 0.23). We did not find any significant association of vitamin D levels with mortality, the need for mechanical ventilation, ICU admission and the development of thromboembolism in COVID-19 patients.NEW & NOTEWORTHY Low vitamin D has been associated with increased frequency and severity of respiratory tract infections in the past. Current literature linking clinical outcomes in COVID-19 with low vitamin D is debatable. This study evaluated the role of vitamin D in severe disease outcomes among COVID-19 patients and found no association of vitamin D levels with mortality, the need for mechanical ventilation, ICU admission, and thromboembolism in COVID-19.

Age-related changes in the control of finger force vectors.

We explored changes in finger interaction in the process of healthy aging as a window into neural control strategies of natural movements. In particular, we quantified the amount of force produced by noninstructed fingers in different directions, the amount of force produced by the instructed finger orthogonally to the task direction, and the strength of multifinger synergies stabilizing the total force magnitude and direction during accurate force production. Healthy elderly participants performed accurate isometric force production tasks in five directions by individual fingers and by all four fingers acting together. Their data were compared with a dataset obtained in a similar earlier study of young subjects. Finger force vectors were measured using six-component force/torque sensors. Multifinger synergies were quantified using the framework of the uncontrolled manifold hypothesis. The elderly participants produced lower force magnitudes by noninstructed fingers and higher force magnitudes by instructed fingers in nontask directions. They showed strong synergies stabilizing the magnitude and direction of the total force vector. However, the synergy indexes were significantly lower than those observed in the earlier study of young subjects. The results are consistent with an earlier hypothesis of preferential weakening of intrinsic hand muscles with age. We interpret the findings as a shift in motor control from synergic to element-based, which may be causally linked to the documented progressive neuronal death at different levels of the neural axis.

Finger interaction in a three-dimensional pressing task.

Accurate control of forces produced by the fingers is essential for performing object manipulation. This study examines the indices of finger interaction when accurate time profiles of force are produced in different directions, while using one of the fingers or all four fingers of the hand. We hypothesized that patterns of unintended force production among shear force components may involve features not observed in the earlier studies of vertical force production. In particular, we expected to see unintended forces generated by non-task fingers not in the direction of the instructed force but in the opposite direction as well as substantial force production in directions orthogonal to the instructed direction. We also tested a hypothesis that multi-finger synergies, quantified using the framework of the uncontrolled manifold hypothesis, will help reduce across-trials variance of both total force magnitude and direction. Young, healthy subjects were required to produce accurate ramps of force in five different directions by pressing on force sensors with the fingers of the right (dominant) hand. The index finger induced the smallest unintended forces in non-task fingers. The little finger showed the smallest unintended forces when it was a non-task finger. Task fingers showed substantial force production in directions orthogonal to the intended force direction. During four-finger tasks, individual force vectors typically pointed off the task direction, with these deviations nearly perfectly matched to produce a resultant force in the task direction. Multi-finger synergy indices reflected strong co-variation in the space of finger modes (commands to fingers) that reduced variability of the total force magnitude and direction across trials. The synergy indices increased in magnitude over the first 30% of the trial time and then stayed at a nearly constant level. The synergy index for stabilization of total force magnitude was higher for shear force components when compared to the downward pressing force component. The results suggest complex interactions between enslaving and synergic force adjustments, possibly reflecting the experience with everyday prehensile tasks. For the first time, the data document multi-finger synergies stabilizing both shear force magnitude and force vector direction. These synergies may play a major role in stabilizing the hand action during object manipulation.