Safety and Efficacy of Ketamine Without Intubation in the Management of Refractory Seizures: A Case Series.

BACKGROUND: Continuous infusion ketamine has demonstrated efficacy in the management of refractory seizures yet does not suppress respiratory drive like other continuous infusion anesthetics (CIAs) used for this indication. The aim of this study is to describe the safety and efficacy of ketamine infusions in patients with refractory seizure without intubation. METHODS: We analyzed a retrospective cohort of adult patients who were not intubated at the time of initiation of a ketamine infusion for refractory seizures. Seizure onset was determined to be the first clinical seizure or nonconvulsive seizure reported on electroencephalography (EEG) or the start time of EEG for patients with seizures at EEG initiation. Responders were defined as patients with resolution of seizures within 24 h of initiation without the need for intubation or an additional CIA. RESULTS: A total of 28 patients were analyzed (median age 62 years, 64.3% female, 82.1% African American, 82.1% with structural seizure etiology, and 85.7% focal seizures). Of patients, 78.5% received an initial bolus averaging 0.9 mg/kg, and the majority (89.3%) were initiated on an infusion at 10 µg/kg/minute; median duration was 39.8 h. Maximum infusion rates were 10 µg/kg/minute in 16 patients, 20 µg/kg/minute in seven patients, and 30 µg/kg/minute in five patients. Of patients, 71.4% were assessed to be ketamine responders; six of the eight nonresponders required intubation and an additional CIA. Responders were 80% more likely to have received ketamine 5 or more hours earlier than nonresponders. Hypotension (systolic blood pressure < 90 mmHg) occurred in 31.8% of patients receiving only ketamine, which did not correlate with duration or maximum dose of ketamine; hypertension (systolic blood pressure > 180 mmHg) occurred in 39.3%. CONCLUSIONS: Ketamine represents a safe and effective treatment option for refractory seizures and has potential to reduce morbidity associated with intubation in a carefully selected patient population. Early initiation may increase the likelihood of success.

Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Tofacitinib inhibits inflammatory cytokines from ulcerative colitis and healthy mucosal explants and is associated with pSTAT1/3 reduction in T-cells.

Poor translatability of animal disease models has hampered the development of new inflammatory bowel disorder (IBD) therapeutics. We describe a preclinical, ex vivo system using freshly obtained and well-characterized human colorectal tissue from patients with ulcerative colitis (UC) and healthy control (HC) participants to test potential therapeutics for efficacy and target engagement, using the JAK/STAT inhibitor tofacitinib (TOFA) as a model therapeutic. Colorectal biopsies from HC participants and patients with UC were cultured and stimulated with multiple mitogens ± TOFA. Soluble biomarkers were detected using a 29-analyte multiplex ELISA. Target engagement in CD3+CD4+ and CD3+CD8+ T-cells was determined by flow cytometry in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMCs) following the activation of STAT1/3 phosphorylation. Data were analyzed using linear mixed-effects modeling, t test, and analysis of variance. Biomarker selection was performed using penalized and Bayesian logistic regression modeling, with results visualized using uniform manifold approximation and projection. Under baseline conditions, 27 of 29 biomarkers from patients with UC were increased versus HC participants. Explant stimulation increased biomarker release magnitude, expanding the dynamic range for efficacy and target engagement studies. Logistic regression analyses identified the most representative UC baseline and stimulated biomarkers. TOFA inhibited biomarkers dependent on JAK/STAT signaling. STAT1/3 phosphorylation in T-cells revealed compartmental differences between PBMCs and MMCs. Immunogen stimulation increases biomarker release in similar patterns for HC participants and patients with UC, while enhancing the dynamic range for pharmacological effects. This work demonstrates the power of ex vivo human colorectal tissue as preclinical tools for evaluating target engagement and downstream effects of new IBD therapeutic agents.NEW & NOTEWORTHY Using colorectal biopsy material from healthy volunteers and patients with clinically defined IBD supports translational research by informing the evaluation of therapeutic efficacy and target engagement for the development of new therapeutic entities. Combining experimental readouts from intact and dissociated tissue enhances our understanding of the tissue-resident immune system that contribute to disease pathology. Bayesian logistic regression modeling is an effective tool for predicting ex vivo explant biomarker release patterns.

Pulse oximeter plethysmograph waveform and automated oscillometric sphygmomanometer for ankle-brachial index measurement.

OBJECTIVES: There are limited non-invasive methods to assess lower extremity arterial injuries in the emergency department (ED) and pre-hospital setting. The ankle-brachial index (ABI) requires careful auscultation by Doppler, an approach made difficult in noisy environments. We sought to determine the agreement of the ABI measured using the pulse oximeter plethysmograph waveform (Pleth) with auscultation by Doppler in a controlled setting. A secondary outcome sought to examine the agreement of ABI by automated oscillometric sphygmomanometer (AOS) with Doppler. METHODS: We measured blood pressure in the right upper and lower extremities of healthy volunteers using: (1) Doppler and manual sphygmomanometer; (2) Pleth and manual sphygmomanometer; and (3) AOS. The Bland-Altman approach to assessing agreement between methods was used comparing mean differences between ABI pairs to their means for Doppler versus Pleth and Doppler versus AOS. The intraclass correlation coefficient (ICC) from mixed effects models examined intra- and inter-rater reliability. RESULTS: Among 100 participants with normal ABI the mean ABI (95%CI) were Doppler 1.11 (0.90-1.33), Pleth 1.10 (0.91-1.30), and AOS 1.10 (0.90-1.30). The ABI difference (95% CI for limits of agreement) were 0.01 (-0.20,0.18) for Doppler-Pleth and 0.02 (-0.26, 0.22) for Doppler-AOS. The ICC for the Doppler-Pleth comparison (ICC = 0.56, 95% CI 0.47-0.63) was greater than for the Doppler-AOS (ICC = 0.32, 95% CI 0.19-0.43). CONCLUSIONS: The ABI measured using the Pleth has a high level of agreement with measurement by Doppler. The AOS and Doppler have good agreement with greater measurement variability. Pleth and AOS may be reasonable alternatives to Doppler for ABI.

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Predictors for Tracheostomy with External Validation of the Stroke-Related Early Tracheostomy Score (SETscore).

BACKGROUND AND PURPOSE: Ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) patients often require endotracheal intubation (EI) and mechanical ventilation (MV). Predicting the need for prolonged EI and timing of tracheostomy (TR) is challenging. While TR is performed for about 10-15% of patients in the general intensive care unit (ICU), the rate in the neurological ICU and for stroke patients ranges between 15 and 35%. Thus, we performed an external validation of the recently published SETscore. METHODS: This is a retrospective review for all patients with IS, non-traumatic ICH, and SAH who required intubation within 48 h of admission to the neurological ICU. We compared the SETscore between tracheostomized versus successfully extubated patients, and early TR (within 7 days) versus late TR (after 7 days). RESULTS: Out of 511 intubated patients, 140 tracheostomized and 105 extubated were included. The sensitivity for a SETscore > 10 to predict the need for TR was 81% (95% CI 74-87%) with a specificity of 57% (95% CI 48-67%). The score had moderate accuracy in correctly identifying those requiring TR and those successfully extubated: 71% (95% CI 65-76%). The AUC of the score was 0.74 (95% CI 0.68-0.81). Multivariable logistic regression models were used to identify other independent predictors of TR. After including body mass index (BMI), African American (AA) race, ICH and a positive sputum culture in the SETscore, sensitivity, specificity, overall accuracy, and AUC improved to 90%, 78%, 85%, and 0.89 (95% CI 0.85-0.93), respectively. In our cohort, performing early TR was associated with improvement in the ICU median length of stay (LOS) (15 vs 20.5 days; p = 0.002) and mean ventilator duration (VD) (13.4 vs 18.2 days; p = 0.005) in comparison to late TR. CONCLUSIONS: SETscore is a simple score with a moderate accuracy and with a fair AUC used to predict the need for TR after MV for IS, ICH, and SAH patients. Our study also demonstrates that early TR was associated with a lower ICU LOS and VD in our cohort. The utility of this score may be improved when including additional variables such as BMI, AA race, ICH, and positive sputum cultures.

Health-related quality of life in active duty military: A secondary data analysis of two randomized controlled trials.

BACKGROUND: Military service members with lower extremity injuries are at risk for compromised health-related quality of life during rehabilitation. PURPOSE: The purpose of this secondary data analysis was to examine changes in self-perceived physical and mental health in two clinical trials of military service members during rehabilitation for a lower extremity injury. METHODS: This study is a secondary analysis of existing data from two cohorts of active duty military service members with lower extremity injuries as they participated in separate randomized controlled trials. DISCUSSION: A similar pattern for both physical and mental health was observed in both groups of participants. Perceptions of physical health improved significantly in both studies, whereas mental health perceptions may or may not have declined. CONCLUSION: Increased attention to mental health may be important during rehabilitation after major and minor lower extremity injuries. Although perceptions of physical health improve, corresponding changes may not occur in mental health perceptions.

FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department.

BACKGROUND AND PURPOSE: A large number of patients with symptoms of acute cerebral ischemia are stroke mimics (SMs). In this study, we sought to develop a scoring system (FABS) for screening and stratifying SM from acute cerebral ischemia and to identify patients who may require magnetic resonance imaging to confirm or refute a diagnosis of stroke in the emergency setting. METHODS: We designed a scoring system: FABS (6 variables with 1 point for each variable present): absence of Facial droop, negative history of Atrial fibrillation, Age <50 years, systolic Blood pressure <150 mm Hg at presentation, history of Seizures, and isolated Sensory symptoms without weakness at presentation. We evaluated consecutive patients with symptoms of acute cerebral ischemia and a negative head computed tomography for any acute finding within 4.5 hours after symptom onset in 2 tertiary care stroke centers for validation of FABS. RESULTS: A total of 784 patients (41% SMs) were evaluated. Receiver operating characteristic curve (C statistic, 0.95; 95% confidence interval [CI], 0.93-0.98) indicated that FABS≥3 could identify patients with SM with 90% sensitivity (95% CI, 86%-93%) and 91% specificity (95% CI, 88%-93%). The negative predictive value and positive predictive value were 93% (95% CI, 90%-95%) and 87% (95% CI, 83%-91%), respectively. CONCLUSIONS: FABS seems to be reliable in stratifying SM from acute cerebral ischemia cases among patients in whom the head computed tomography was negative for any acute findings. It can help clinicians consider advanced imaging for further diagnosis.

Changes in blood lymphocyte numbers with age in vivo and their association with the levels of cytokines/cytokine receptors.

BACKGROUND: Alterations in the number and composition of lymphocytes and their subsets in blood are considered a hallmark of immune system aging. However, it is unknown whether the rates of change of lymphocytes are stable or change with age, or whether the inter-individual variations of lymphocyte composition are stable over time or undergo different rates of change at different ages. Here, we report a longitudinal analysis of T- and B-cells and their subsets, and NK cells in the blood of 165 subjects aged from 24 to 90 years, with each subject assessed at baseline and an average of 5.6 years follow-up. RESULTS: The rates of change of T-(CD4(+) and CD8(+)) and B-cells, and NK cells were relative stable throughout the adult life. A great degree of individual variations in numbers of lymphocytes and their subsets and in the rates of their changes with age was observed. Among them, CD4(+) T cells exhibited the highest degree of individual variation followed by NK cells, CD8(+) T cells, and B cells. Different types of lymphocytes had distinct trends in their rates of change which did not appear to be influenced by CMV infection. Finally, the rates of CD4(+), CD8(+) T cells, naive CD4(+) and naïve CD8(+) T cells were closely positively correlated. CONCLUSION: Our findings provide evidence that the age-associated changes in circulating lymphocytes were at relative stable rates in vivo in a highly individualized manner and the levels of selected cytokines/cytokine receptors in serum might influence these age-associated changes of lymphocytes in circulation.

Replication study of the vitamin D receptor (VDR) genotype association with skeletal muscle traits and sarcopenia.

Polymorphisms in the vitamin D receptor (VDR) gene are some of the most studied in relation to skeletal muscle traits and significant associations have been observed by multiple groups. One such paper by our group provided the first evidence of a genetic association with sarcopenia in men, but that finding has yet to be replicated in an independent cohort. In the present study, we examined multiple VDR polymorphisms in relation to skeletal muscle traits and sarcopenia in 864 men and women across the adult age span. In addition to VDR genotypes and haplotypes, measurements of skeletal muscle strength and fat-free mass (FFM) were determined in all subjects and a measure of sarcopenia was calculated. We observed significant associations between Fok1 and Bsm1 genotypes and skeletal muscle strength in men and women, though these associations were modest and no significant associations were observed for these polymorphisms and muscle mass traits nor for Bsm1-Taq1 haplotype with muscle strength. Fok1 FF genotype was associated with an increased the risk of sarcopenia in older women compared to f-allele carriers (1.3-fold higher risk). These results support previous findings that VDR genetic variation appears to impact skeletal muscle strength and risk for sarcopenia but the influence is modest.

Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults.

BACKGROUND: Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown. METHODS: We selected 22 HLA-A2-positive healthy older adults who have relatively short or long telomere lengths to compare their antibody response against the influenza vaccine, and their CD8(+) T-cell response against an influenza antigen. RESULTS: B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte-derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8(+) T cells. Vaccination did not increase M1-specific CD8(+) T cells in blood, but M1-specific CD8(+) T cells from the long telomere group exhibited significantly greater expansion in vitro than those from the short telomere group. Finally, M1-specific CD8(+) T cells that underwent more expansions had significantly longer telomeres than cells with fewer divisions. CONCLUSIONS: Telomere length is positively associated with a robust lymphocyte response, and telomere attrition may contribute to the age-associated decline of adaptive immunity.

Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions.

Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes and monocytes of 216 human subjects aged from 20-90 years assessed at 0-, 5- and 12-year follow-up. For the 5- and 12-year follow-up, telomere length in the PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47% and increased in 10% and 7% of the subjects respectively. The rate of telomere change was distinct for T-cells, B-cells and monocytes for any given subject. Telomerase activity declined with age in the resting T-cells and B-cells and the activated T-cells. Finally, a significant portion of telomere attrition in T-cells with age was explained by a decline in the telomerase activity, decreased naïve cells and the change in physiological conditions such as elevated blood glucose and interleukin (IL)-6 levels. These findings show that changes in the telomere length of the PBMCs with age in vivo occur at different rates in different individuals and cell types and reveal that changes in the telomere length in the T-cells with age is influenced by the telomerase activity, naïve T-cell percentage and changes in health conditions.

Time Thresholds for Using Pressure Reactivity Index in Neuroprognostication for Patients With Severe Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Severe traumatic brain injury (sTBI) represents a diffuse, heterogeneous disease where therapeutic targets for optimizing clinical outcome remain unclear. Mean pressure reactivity index (PRx) values have demonstrated associations with clinical outcome in sTBI. However, the retrospective derivation of a mean value diminishes its bedside significance. We evaluated PRx temporal profiles for patients with sTBI and identified time thresholds suggesting optimal neuroprognostication. METHODS: Patients with sTBI and continuous bolt intracranial pressure monitoring were identified. Outcomes were dichotomized by disposition status ("good outcome" was denoted by home and acute rehabilitation). PRx values were obtained every minute by taking moving correlation coefficients of intracranial pressures and mean arterial pressures. Average PRx trajectories for good and poor outcome groups were calculated by extending the last daily averaged PRx value to day 18. Each patient also had smoothed PRx trajectories that were used to generate "candidate features." These "candidate features" included daily average PRx's, cumulative first-order changes in PRx and cumulative second-order changes in PRx. Changes in sensitivity over time for predicting poor outcome was then evaluated by generating penalized logistic regression models that were derived from the "candidate features" and maximized specificity. RESULTS: Among 33 patients with sTBI, 18 patients achieved good outcome and 15 patients had poor outcome. Average PRx trajectories for the good and poor outcome groups started on day 6 and consistently diverged at day 9. When targeting a specificity >83.3%, an 85% maximum sensitivity for determining poor outcome was achieved at hospital day 6. Subsequent days of PRx monitoring showed diminishing sensitivities. CONCLUSION: Our findings suggest that in a population of sTBI, PRx sensitivities for predicting poor outcome was maximized at hospital day 6. Additional study is warranted to validate this model in larger populations.

Nonpharmacological Therapies for Musculoskeletal Injury in Military Personnel: A Systematic Review/Meta-Analysis.

INTRODUCTION: Musculoskeletal (MSK) injury is an inherent risk for military personnel that can potentially impact job performance, productivity, and military readiness. Evidence is needed to show the efficacy of nonpharmacological, self-managed therapies to reduce MSK symptoms at common injury sites that are feasible for use during expeditionary operations and home stations. This systematic review and meta-analysis identified, summarized, and synthesized available evidence from randomized and non-randomized trials on the effectiveness of self-managed, home-use therapies to improve pain, muscle strength, and physical performance in military personnel with MSK injuries, when compared to controls. METHODS: The electronic databases of MEDLINE ALL Ovid, Embase.com, Cochrane Library, Scopus, Clinicaltrial.gov, and CINAHL Complete via EBSCO were systematically searched for relevant reports published in English. Utilizing the Covidence platform and consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, multiple reviewers, using pre-determined data fields, screened for eligibility, assessed risk of bias (RoB), and performed data extraction. Evaluation of treatment effectiveness was determined using multilevel mixed-effects meta-analysis. RESULTS: The database and register search yielded 1,643 reports that were screened for eligibility. After screening of titles/abstracts and full texts, 21 reports were identified for evidence synthesis. Of these, two reports were excluded and two described the same study, resulting in a final list of 18 studies (19 reports). For quality assessment, the overall RoB for the 18 studies was categorized as 33.3% low risk, 55.6% with some concerns, and 11.1% high risk. Across the five domains of bias, 70% of the reports were classified as low risk. This systematic review found that the differences in interventions, outcome measures, and design between the studies were associated with a substantial degree of heterogeneity (I2 = 60.74%), with a small overall improvement in outcomes of the interventions relative to their specific control (standard mean difference 0.28; 95% CI, 0.12 to 0.45). There were varying degrees of heterogeneity for individual body regions. This was due, in part, to a small number of studies per bodily location and differences in the study designs. For the neck/shoulder, heterogeneity was moderate, with the clearest positive effect being for physical performance outcomes via other medical devices. For the back, there was substantial heterogeneity between studies, with modest evidence that pain was favorably improved by other medical devices and exercise interventions. For the leg, one study showed a clear large effect for other medical devices (shockwave treatment) on pain with substantial heterogeneity. The best evidence for positive effects was for the knee, with mainly negligible heterogeneity and some benefits from bracing, electrotherapy, and exercise. CONCLUSION: Evidence showed small beneficial effects in pain, strength, and physical performance by individual body regions for some interventions, compared to controls. The best evidence for a positive effect was for the knee. The findings suggest that some benefit may be obtained by including several treatments during deployment in austere environments and prolonged casualty care scenarios of military personnel with MSK injuries. Further research is warranted to better assess the potential benefits of using these treatments during deployments in austere environments as part of an individualized, multimodal approach for MSK injuries.

Predicting 3-year incident mobility disability in middle-aged and older adults using physical performance tests.

OBJECTIVE: To identify a standard physical performance test, which can predict 3-year incident mobility disability independent of demographics. DESIGN: Longitudinal cohort study. SETTING: Population-based middle-aged and older adult cohort assessment performed at a local geriatric clinical center. PARTICIPANTS: Community-living middle-aged and older persons (age, 50-85y) without baseline mobility disability (N=622). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mobility disability was ascertained at baseline and at 3-year follow-up using an established self-report method: self-reported inability to walk a quarter mile without resting or inability to walk up a flight of stairs unsupported. Physical performance tests included self-selected usual gait speed, time required to complete 5 times sit-to-stand (5TSTS), and 400-m brisk walking. Demographic variables age, sex, height, and weight were recorded. RESULTS: Overall, 13.5% participants reported 3-year incident mobility disability. Usual gait speed <1.2m/s, requiring >13.6 seconds to complete 5TSTS, and completing 400m at <1.19m/s walking speed were highly predictive of future mobility disability independent of demographics. CONCLUSIONS: Inability to complete 5TSTS in <13.7 seconds can be a clinically convenient guideline for monitoring and for further assessment of middle-aged and older persons, in order to prevent or delay future mobility disability.

Electromyostimulation With Blood Flow Restriction for Patellofemoral Pain Syndrome in Active Duty Military Personnel: A Randomized Controlled Trial.

INTRODUCTION: The high prevalence of patellofemoral pain in military service members results in strength loss, pain, and functional limitations during required physical performance tasks. Knee pain is often the limiting factor during high-intensity exercise for strengthening and functional improvement, thus limiting certain therapies. Blood flow restriction (BFR) improves muscle strength when combined with resistance or aerobic exercise and may serve as a possible alternative to high-intensity training during recovery. In our previous work, we showed that Neuromuscular electrical stimulation (NMES) improves pain, strength, and function in patellofemoral pain syndrome (PFPS), which led us to ask whether the addition of BFR to NMES would result in further improvements. This randomized controlled trial compared knee and hip muscle strength, pain, and physical performance of service members with PFPS who received BFR-NMES (80% limb occlusion pressure [LOP]) or BFR-NMES set at 20 mmHg (active control/sham) over 9 weeks. METHODS: This randomized controlled trial randomly assigned 84 service members with PFPS to one of the two intervention groups. In-clinic BFR-NMES was performed two times per week, while at-home NMES with exercise and at-home exercise alone were performed on alternating days and omitted on in-clinic days. The outcome measures included strength testing of knee extensor/flexor and hip posterolateral stabilizers, 30-second chair stand, forward step-down, timed stair climb, and 6-minute walk. RESULTS: Improvement was observed in knee extensor (treated limb, P < .001) and hip strength (treated hip, P = .007) but not flexor over 9 weeks of treatment; however, there was no difference between high BFR (80% LOP) and BFR-sham. Physical performance and pain measures showed similar improvements over time with no differences between groups. In analyzing the relationship between the number of BFR-NMES sessions and the primary outcomes, we found significant relationships with improvements in treated knee extensor strength (0.87 kg/session, P < .0001), treated hip strength (0.23 kg/session, P = .04), and pain (-0.11/session, P < .0001). A similar set of relationships was observed for the time of NMES usage for treated knee extensor strength (0.02/min, P < .0001) and pain (-0.002/min, P = .002). CONCLUSION: NMES strength training offers moderate improvements in strength, pain, and performance; however, BFR did not provide an additive effect to NMES plus exercise. Improvements were positively related to the number of BFR-NMES treatments and NMES usage.

Non-pharmacological Home Therapies for Subacute Low Back Pain in Active Duty Military Personnel: A Randomized Controlled Trial.

INTRODUCTION: Low back pain (LBP) is a major cause of visits to ambulatory care, missed duty time, and disability discharge. The subacute phase of LBP presents an opportune time to prevent chronicity and lessen recurrence. The goal of this randomized controlled trial (RCT) was to determine the relative effectiveness of neuromuscular electrical stimulation (NMES) training and a progressive exercise program (PEP) on improving physical performance, pain, and torso strength in U.S. service members with subacute LBP, compared to standard primary care management (PCM) alone. METHODS: This is an Institutional Review Board-approved protocol for an RCT conducted with active duty military personnel (n = 128) at Fort Campbell, Kentucky, between April 2018 and March 2020. Participants were randomized to receive NMES (n = 43), PEP (n = 42), or PCM (n = 43) for 9 weeks. Outcome measures of physical performance (sit-ups, push-ups, walking, and torso endurance), torso muscle strength (flexion and extension), and pain were assessed at baseline and after 3, 6, and 9 weeks. Analysis was intent-to-treat using linear mixed effects models. A sensitivity analysis was performed to address the protocol deviations that occurred in response to coronavirus disease 2019 pandemic, which required rescheduling 17 in-person study visits to home assessments at 9-week testing. RESULTS: Evidence was found for group differences in physical performance for sit-ups and push-ups, with NMES showing greater improvement than PCM. The two groups showed similar improvements in torso muscle strength, although the NMES groups may show better improvement during early treatment. No group differences in pain levels were observed during the intervention, and all groups improved during the course of the study period. The amount of NMES muscle stimulation was directly related to the level of improvement, which was not the case for the hours reported for PEP exercise. CONCLUSION: In an active duty population with subacute LBP, integrating NMES strength training into the rehabilitation therapy may offer a modest benefit for increasing sit-ups and push-ups and improving torso strength.

rxCOV is a quantitative metric for assessing immunoassay analyte fidelity.

Immunoassay based bioanalytical measurements are widely used in a variety of biomedical research and clinical settings. In these settings they are assumed to faithfully represent the experimental conditions being tested and the sample groups being compared. Although significant technical advances have been made in improving sensitivity and quality of the measurements, currently no metrics exist that objectively quantify the fidelity of the measured analytes with respect to noise associated with the specific assay. Here we introduce ratio of cross-coefficient-of-variation (rxCOV), a fidelity metric for objectively assessing immunoassay analyte measurement quality when comparing its differential expression between different sample groups or experimental conditions. We derive the metric from first principles and establish its feasibility and applicability using simulated and experimental data. We show that rxCOV assesses fidelity independent of statistical significance, and importantly, identifies when latter is meaningful. We also discuss its importance in the context of averaging experimental replicates for increasing signal to noise ratio. Finally, we demonstrate its application in a Lynch Syndrome case study. We conclude by discussing its applicability to multiplexed immunoassays, other biosensing assays, and to paired and unpaired data. We anticipate rxCOV to be adopted as a simple and easy-to-use fidelity metric for performing robust and reproducible biomedical research.

Pressure reactivity index for early neuroprognostication in poor-grade subarachnoid hemorrhage.

BACKGROUND: Pressure reactivity index (PRx) utilizes moving correlation coefficients from intracranial pressure (ICP) and mean arterial pressures to evaluate cerebral autoregulation. We evaluated patients with poor-grade subarachnoid hemorrhage (SAH), identified their PRx trajectories over time, and identified threshold time points where PRx could be used for neuroprognostication. METHODS: Patients with poor-grade SAH were identified and received continuous bolt ICP measurements. Dichotomized outcomes were based on ninety-day modified Rankin scores and disposition. Smoothed PRx trajectories for each patient were created to generate "candidate features" that looked at daily average PRx, cumulative first-order changes in PRx, and cumulative second-order changes in PRx. "Candidate features" were then used to perform penalized logistic regression analysis using poor outcome as the dependent variable. Penalized logistic regression models that maximized specificity for poor outcome were generated over several time periods and evaluated how sensitivities changed over time. RESULTS: 16 patients with poor-grade SAH were evaluated. Average PRx trajectories for the good (PRx < 0.25) and poor outcome groups (PRx > 0.5) started diverging at post-ictus day 8. When targeting specificities ≥88% for poor outcome, sensitivities for poor outcome consistently increased to >70% starting at post-ictus days 12-14 with a maximum sensitivity of 75% occurring at day 18. CONCLUSIONS: Our results suggest that by using PRx trends, early neuroprognostication in patients with SAH and poor clinical exams may start becoming apparent at post-ictus day 8 and reach adequate sensitivities by post-ictus days 12-14. Further study is required to validate this in larger poor-grade SAH populations.

Advancing Readiness Through Military Programs: An Evidence-Based Practice Perspective.

INTRODUCTION: Military nurses comprise the largest percentage of military health care providers. In the current military health care system, they have two roles: (1) Patient care in military treatment facilities (MTFs) and (2) patient care during combat operations. Although in MTFs, the military nurse's roles are similar to those of their civilian counterpart, their roles are unique and varied in the combat operational environment. These combined roles lead to questions regarding readiness training to ensure that nurses are proficient in both MTFs and combat operational settings where treatment requirements may differ. The purpose of this paper is to (1) present the current state of educational readiness programs to maintain a ready medical force that entail formal teaching programs, military-civilian partnerships, and joint exercises of combat simulations, and (2) identify gaps as presented in an evidence-based practice educational panel. METHODS: On March 11, 2022, TriService Nursing Research Program hosted the virtual First Military Evidence-Based Practice Summit from the Uniformed Services University of the Health Sciences in Bethesda, MD. As part of the summit, an evidence-based practice education panel discussed the availability of current evidence-driven military medical readiness programs and identified gaps in the integration of military readiness for nursing personnel into the Defense Health Agency and Armed Services. RESULTS: The panel participants discussed the separate requirements for training within the MTFs and in combat operational settings. The available training programs identified by the panel were primarily those developed in local MTF settings to meet local needs. Although these programs support the MTFs' peacetime mission, competing roles, limited time, and limited funds contributed to limited preparation of nursing personnel in skills associated with combat-related injuries and illnesses. Prolonged casualty care has become an important focus for the Department of Defense as greater considerations are directed to wartime operations in austere expeditionary environments. Although there is some training available that is specific for prolonged casualty care, the focus has been the adaptation of combat casualty care during contingency operations. A keynote here was the concept that combat casualty care training must include both development of individual skills and integration of the team since maximal care can be achieved only when the individual and the team operate as a unit. A key point was the utility of central repositories for storing information related to training a ready medical force at individual and unit levels and that these repositories could also be used to collect and facilitate the accession of current evidence-based information. DISCUSSION: Optimal patient care at all levels of the military health system requires training that maximizes individual and unit skills specific to the environment at an MTF or in a combat operational setting. Training must be designed to incorporate evidence-driven knowledge in all military settings with guidance that is specific to the environment. CONCLUSION: Enhanced communication of evidence-based training and knowledge is an important component of maintaining a ready medical force for broader medical support of combat contingency operations.