Loaded forced-marching shifts mechanical contributions proximally and disrupts stride-to-stride joint work modulation in recruit aged women.

BACKGROUND: Military personnel in combat roles often perform gait tasks with additional load, which can affect the contributions of joint mechanical work (positive and negative). Furthermore, different locomotion patterns can also affect joint specific work contributions. While mean behavior of joint work is important to understanding gait, changes in joint kinetic modulation, or the regulation/control of stride-to-stride joint work variability is necessary to elucidate locomotor system function. Suboptimal modulation exhibited as a stochastic time-series (large fluctuation followed by an opposite smaller fluctuation) could potentially affect locomotion efficiency and portend injury risk. It remains unclear how the locomotor system responds to a combination of load perturbations and varying locomotion patterns. RESEARCH QUESTION: What are the interactive effects of load magnitude and locomotion pattern on joint positive/negative work and joint work modulation in healthy, active, recruit-aged women? METHODS: Eleven healthy, active, recruit-aged (18-33 years) women ran and forced-marched (walking at a velocity an individual would typically jog) in bodyweight (BW), an additional 25 % of BW (+25 %BW) and an additional 45 % of BW (+45 %BW) conditions at a velocity above their gait transition velocity. Joint work was calculated as the time integral of joint power. Joint work modulation was assessed with detrended fluctuation analysis (DFA) on consecutive joint work time-series. RESULTS: Joint work contributions shifted proximally for forced-marching demonstrated by lesser (p < .001) positive/negative ankle work but greater (p = .001) positive hip work contributions compared to running. Running exhibited optimal positive ankle work modulation compared to forced-marching (p = .040). Knee and ankle negative joint work modulation was adversely impacted compared to the hip during forced-marching (p < .001). SIGNIFICANCE: Employing forced-marching gait while under loads of 25 and 45 % of BW reduces the ability of the plantar-flexors and knee extensors to optimally contribute to energy absorption and propulsion in recruit-aged women, potentially reducing metabolic efficiency and increasing injury risk.

Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018.

BACKGROUND: The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. METHODS: Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. RESULTS: In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. CONCLUSION: This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. IMPLICATIONS FOR PRACTICE: The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.

Clinical Outcomes of Patients with Metastatic Cancer Receiving Immune Checkpoint Inhibitors in the Inpatient Setting.

BACKGROUND: As indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials. MATERIAL AND METHODS: We conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality. RESULTS: During the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy. CONCLUSION: The poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality. IMPLICATIONS FOR PRACTICE: Immunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.

Factors that enable effective One Health collaborations - A scoping review of the literature.

Advocates for a One Health approach recognize that global health challenges require multidisciplinary collaborative efforts. While past publications have looked at interdisciplinary competency training for collaboration, few have identified the factors and conditions that enable operational One Health. Through a scoping review of the literature, a multidisciplinary team of researchers analyzed peer-reviewed publications describing multisectoral collaborations around infectious disease-related health events. The review identified 12 factors that support successful One Health collaborations and a coordinated response to health events across three levels: two individual factors (education & training and prior experience & existing relationships), four organizational factors (organizational structures, culture, human resources and, communication), and six network factors (network structures, relationships, leadership, management, available & accessible resources, political environment). The researchers also identified the stage of collaboration during which these factors were most critical, further organizing into starting condition or process-based factors. The research found that publications on multisectoral collaboration for health events do not uniformly report on successes or challenges of collaboration and rarely identify outputs or outcomes of the collaborative process. This paper proposes a common language and framework to enable more uniform reporting, implementation, and evaluation of future One Health collaborations.

Colitis after checkpoint blockade: A retrospective cohort study of melanoma patients requiring admission for symptom control.

BACKGROUND: Immune checkpoint inhibitors (CPIs) have revolutionized oncologic therapy but can lead to immune-related adverse events (irAEs). Corticosteroids are first-line treatment with escalation to biologic immunosuppression in refractory cases. CPI-related gastroenterocolitis (GEC) affects 20%-50% of patients receiving CPIs and can carry significant morbidity and mortality. Severe CPI-related GEC is not well-described. We present the clinical characterization of all CPI-related GEC requiring admission at a single institution. METHODS: Clinical, laboratory, radiographic, and endoscopic data were extracted from charts of all melanoma patients ≥18 years of age admitted to one institution for CPI-related GEC, from February 5, 2011 to December 13, 2016. Patients were followed until December 31, 2017 for further admissions. Survival, outcomes, and pharmaceutical-use analyses were performed. RESULTS: Median time-to-admission from initial CPI exposure was 73.5 days. Median length of stay was 4.5 days. About 50.0% required second-line immunosuppression. Readmission for recrudescence occurred in 33.3%. Common Terminology Criteria for Adverse Events (CTCAE) grade was not significantly associated with outcomes. Hypoalbuminemia (P = 0.005), relative lymphopenia (P = 0.027), and decreased lactate dehydrogenase (P = 0.026) were associated with second-line immunosuppression. There was no difference in progression-free survival (PFS) or OS (P = 0.367, 0.400) for second-line immunosuppression. Subgroup analysis showed that early corticosteroid administration (P = 0.045) was associated with decreased PFS. CONCLUSIONS: Severe CPI-related GEC typically manifests within 3 months of immunotherapy exposure. Rates of second-line immunosuppression and readmission for recrudescence were high. CTCAE grade did not capture the degree of severity in our cohort. Second-line immunosuppression was not associated with poorer oncologic outcomes; however, early corticosteroid exposure was associated with decreased PFS. Further investigation is warranted.

Cancer screening rates in individuals with different life expectancies.

IMPORTANCE: Routine cancer screening has unproven net benefit for patients with limited life expectancy. OBJECTIVE: To examine the patterns of prostate, breast, cervical, and colorectal cancer screening in the United States in individuals with different life expectancies. DESIGN, SETTING, AND PARTICIPANTS: Data from the population-based National Health Interview Survey (NHIS) from 2000 through 2010 were used and included 27 404 participants aged 65 years or older. Using a validated mortality index specific for NHIS, participants were grouped into those with low (<25%), intermediate (25%-49%), high (50%-74%), and very high (≥75%) risks of 9-year mortality. MAIN OUTCOMES AND MEASURES: Rates of prostate, breast, cervical, and colorectal cancer screening. RESULTS: In participants with very high mortality risk, 31% to 55% received recent cancer screening, with prostate cancer screening being most common (55%). For women who had a hysterectomy for benign reasons, 34% to 56% had a Papanicolaou test within the past 3 years. On multivariate analysis, very high vs low mortality risk was associated with less screening for prostate (odds ratio [OR], 0.65 [95% CI, 0.50-0.85]), breast (OR, 0.43 [95% CI, 0.35-0.53]), and cervical (OR, 0.50 [95% CI, 0.36-0.70]) cancers. There was less screening for prostate and cervical cancers in more recent years compared with 2000, and there was no significant interaction between calendar year and mortality risk for any cancer screening (P > .05 for all cancers). Our sensitivity analysis showed that screening was also common in individuals with less than 5-year life expectancy. CONCLUSIONS AND RELEVANCE: A substantial proportion of the US population with limited life expectancy received prostate, breast, cervical, and colorectal cancer screening that is unlikely to provide net benefit. These results suggest that overscreening is common in both men and women, which not only increases health care expenditure but can lead to net patient harm.

Vitamin C supplementation in pregnancy--does it decrease rates of preterm birth? A systematic review.

OBJECTIVE: To assess the evidence available on the use of vitamin C supplementation greater than recommended dietary intake to reduce preterm birth rates. STUDY DESIGN: Systematic review of randomized controlled trials using vitamin C alone or with one other supplement other than iron. Trials must report preterm birth rates but can have other primary outcomes. Preterm birth is defined as birth at less than 37 weeks' gestational age for this review. Review focused on studies with populations representative of Organization for Economic Co-operation and Development countries. RESULTS: Inadequate level of evidence on the use of vitamin C alone to prevent preterm birth rates in low-risk populations based on one study. Three studies provided convincing evidence of no benefit in low-risk groups of use of vitamins C and E combined. Three studies provided adequate evidence of no benefit in high-risk groups of use of vitamins C and E combined. CONCLUSION: The available evidence supports no benefit gained from using vitamin C to prevent preterm birth. Evidence does not support limiting use of vitamin C supplementation for other indications.

Trends in the use of postprostatectomy therapies for patients with prostate cancer: a surveillance, epidemiology, and end results Medicare analysis.

BACKGROUND: For patients with adverse pathologic factors (positive surgical margins, extracapsular extension, or seminal vesicle invasion) on prostatectomy pathology, the use and timing of postsurgical treatments are controversial. The goal of the current study was to examine patterns of care in patients with a pathologic indication for postprostatectomy radiotherapy (RT) using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. METHODS: A total of 3460 men treated with radical prostatectomy for localized prostate cancer between 2000 and 2006 with at least 1 adverse pathologic factor and at least 3 years of claims data after surgery were included. Medicare claims through December 31, 2009 were examined. Rates of postprostatectomy hormonal therapy, RT, or both were examined. Logistic regression analysis examined potential factors associated with the receipt and timing of RT. RESULTS: Within 3 years after surgery, 1076 patients (31%) received some form of further therapy, including 850 (25%) who received RT. Receipt of RT was < 35% in all subgroups including every year of study. Fewer than one-half of patients who received RT (43%) did so within 6 months of surgery. On multivariate analysis, pathologic T classification and tumor grade were associated with receipt of RT within 6 months or 3 years of surgery, as were younger age, geographic region, and population density. CONCLUSIONS: Rates of postprostatectomy RT remain low and the timing of RT has not appreciably changed since the publication of the randomized trials supporting the use of adjuvant RT. The use of hormone therapy is almost as common as RT, despite a relative lack of evidence supporting its use in this setting.

Racial differences in time from prostate cancer diagnosis to treatment initiation: a population-based study.

BACKGROUND: Timely delivery of care has been identified by the Institute of Medicine as an indicator for quality health care, and treatment delay is a potentially modifiable obstacle that can contribute to the disparities among African American (AA) and Caucasian patients in prostate cancer recurrence and mortality. Using the Surveillance, Epidemiologic and End Results (SEER)-Medicare linked database, we compared time from diagnosis to treatment in AA and Caucasian prostate cancer patients. METHODS: A total of 2506 AA and 21,454 Caucasian patients diagnosed with localized prostate cancer from 2004 through 2007 and treated within 12 months were included. Linear regression was used to assess potential differences in time to treatment between AA and Caucasian patients, after adjusting for sociodemographic and clinical covariates. RESULTS: Time from diagnosis to definitive (prostatectomy and radiation) treatment was longer for AA patients in all risk groups, and most pronounced in high-risk cancer (96 versus 105 days, P < .001). On multivariate analysis, racial differences to any and definitive treatment persisted (ß = 7.3 and 7.6, respectively, for AA patients). Delay to definitive treatment was longer in high-risk (versus low-risk) disease and in more recent years. CONCLUSIONS: AA patients with prostate cancer experienced longer time from diagnosis to treatment than Caucasian patients with prostate cancer. AA patients appear to experience disparities across all aspects of this disease process, and together these factors in receipt of care plausibly contribute to the observed differences in rates of recurrence and mortality among AA and Caucasian patients with prostate cancer.

Analysis of the soluble matrix of vaterite otoliths of juvenile herring (Clupea harengus): do crystalline otoliths have less protein?

Otoliths are calcium carbonate concretions laid down in the inner ear of fish and used in fish age estimation. Otoliths precipitate in the form of aragonite but aberrant precipitation may result in vaterite formation instead of aragonite. Vaterite otoliths are more translucent than aragonite. The quantity of HCl-soluble proteins (SP) was measured in the vaterite otoliths and their aragonite pairs of one year old reared herring Clupea harengus to assess the changes induced by the precipitation of vaterite in the amount of soluble proteins in the otolith. Results showed that vaterite otoliths had as much soluble proteins as their aragonite pairs (p>0.05). Due to the lower density of the vaterite, vaterite otoliths were lighter than their aragonite pairs (p<0.05) which explained that protein concentrations were significantly higher (p<0.05) than in aragonite otoliths. These results indicate that the precipitation of vaterite in otoliths did not affect the inclusion of soluble proteins. Furthermore, they suggest that soluble proteins do not affect the translucent or opaque appearance of otoliths. Differences in translucency may instead be caused by the amounts of insoluble proteins or by differences in the physical properties of proteins. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of the otolith proteins revealed two bands at 50 and 62 kDa in both aragonite and vaterite otoliths suggesting that the precipitation of vaterite in the otolith is not controlled by either of these two proteins present in the otolith.