Digital Phenotypes of Instability and Fatigue Derived From Daily Standing Transitions in Persons With Multiple Sclerosis.

Impairment in persons with multiple sclerosis (PwMS) can often be attributed to symptoms of motor instability and fatigue. Symptom monitoring and queued interventions often target these symptoms. Clinical metrics are currently limited to objective physician assessments or subjective patient reported measures. Recent research has turned to wearables for improving the objectivity and temporal resolution of assessment. Our group has previously observed wearable assessment of supervised and unsupervised standing transitions to be predictive of fall-risk in PwMS. Here we extend the application of standing transition quantification to longitudinal home monitoring of symptoms. Subjects (N=23) with varying degrees of MS impairment were recruited and monitored with accelerometry for a total of  âˆ¼  6 weeks each. These data were processed using a preexisting framework, applying a deep learning activity classifier to isolate periods of standing transition from which descriptive features were extracted for analysis. Participants completed daily and biweekly assessments describing their symptoms. From these data, Canonical Correlation Analysis was used to derive digital phenotypes of MS instability and fatigue. We find these phenotypes capable of distinguishing fallers from non-fallers, and further that they demonstrate a capacity to characterize symptoms at both daily and sub-daily resolutions. These results represent promising support for future applications of wearables, which may soon augment or replace current metrics in longitudinal monitoring of PwMS.

Fire as a driver of fungal diversity - A synthesis of current knowledge.

Fires occur in most terrestrial ecosystems where they drive changes in the traits, composition, and diversity of fungal communities. Fires range from rare, stand-replacing wildfires to frequent, prescribed fires used to mimic natural fire regimes. Fire regime factors, including burn severity, fire intensity, and timing, vary widely and likely determine how fungi respond to fires. Despite the importance of fungi to post-fire plant communities and ecosystem functioning, attempts to identify common fungal responses and their major drivers are lacking. This synthesis addresses this knowledge gap and ranges from fire adaptations of specific fungi to succession and assembly fungal communities as they respond to spatially heterogenous burning within the landscape. Fires impact fungi directly and indirectly through their effects on fungal survival, substrate and habitat modifications, changes in environmental conditions, and/or physiological responses of the hosts with which fungi interact. Some specific pyrophilous, or "fire-loving," fungi often appear after fire. Our synthesis explores whether such taxa can be considered cosmopolitan, and whether they are truly fire-adapted or simply opportunists adapted to rapidly occupy substrates and habitats made available by fires. We also discuss the possible inoculum sources of post-fire fungi and explore existing conceptual models and ecological frameworks that may be useful in generalizing fungal fire responses. We conclude with identifying research gaps and areas that may best transform the current knowledge and understanding of fungal responses to fire.

Watershed and fire severity are stronger determinants of soil chemistry and microbiomes than within-watershed woody encroachment in a tallgrass prairie system.

Fire can impact terrestrial ecosystems by changing abiotic and biotic conditions. Short fire intervals maintain grasslands and communities adapted to frequent, low-severity fires. Shrub encroachment that follows longer fire intervals accumulates fuel and can increase fire severity. This patchily distributed biomass creates mosaics of burn severities in the landscape-pyrodiversity. Afforded by a scheduled burn of a watershed protected from fires for 27 years, we investigated effects of woody encroachment and burn severity on soil chemistry and soil-inhabiting bacteria and fungi. We compared soils before and after fire within the fire-protected, shrub-encroached watershed and soils in an adjacent, annually burned and non-encroached watershed. Organic matter and nutrients accumulated in the fire-protected watershed but responded less to woody encroachment within the encroached watershed. Bioavailable nitrogen and phosphorus and fungal and bacterial communities responded to high-severity burn regardless of encroachment. Low-severity fire effects on soil nutrients differed, increased bacterial but decreased fungal diversity and effects of woody encroachment within the encroached watershed were minimal. High-severity burns in the fire-protected watershed led to a novel soil system state distinct from non-encroached and encroached soil systems. We conclude that severe fires may open grassland restoration opportunities to manipulate soil chemistry and microbial communities in shrub-encroached habitats.

Lung Cancer Strategist Program: A novel care delivery model to improve timeliness of diagnosis and treatment in high-risk patients.

INTRODUCTION: The diagnosis and treatment of lung cancer is challenged by complex diagnostic pathways and fragmented care that can lead to care disparities for vulnerable patients. METHODS: A multi-institutional, multidisciplinary conference was convened to address the complexity of lung cancer care particularly in patients at high-risk for treatment delay. The resulting care delivery model, called the Lung Cancer Strategist Program (LCSP), was led by a thoracic-trained advanced practice provider (APP) with emphasis on expedited surgery and early oncologic consultation in the assessment of a newly diagnosed suspicious lung nodule. We performed a retrospective review to evaluate care efficiency and oncologic outcomes in the first 100 LCSP patients compared to 100 concurrent patients managed via routine surgical referral. RESULTS: In the 78 LCSP and 41 routine referral patients managed via nodule surveillance, LCSP patients had a shorter time from suspicious finding to work-up (3 vs. 26 days, p < 0.001) and to surveillance decision (12.5 vs. 39 days, p < 0.001). In the 22 LCSP and 59 routine referral patients treated for intrathoracic malignancy, LCSP patients had fewer hospital visits (4 vs 6, p < 0.001), clinicians seen (1.5 vs. 2, p = 0.08), and diagnostic studies (4 vs 5, p = 0.01) with a shorter time to diagnosis (30.5 vs. 48 days, p = 0.02) and treatment (40.5 vs. 68.5 days, p = 0.02). CONCLUSIONS: Patient triage through a thoracic-trained APP in consultation with surgical, medical, and radiation oncology facilitates rapid assessment of benign versus malignant lesions with reduced time to diagnosis and treatment, even among patients at high-risk for treatment delay.

Opportunities for quality improvement in the morbidity pattern of older adults undergoing pulmonary lobectomy for cancer.

BACKGROUND: There is limited information on the frequency of complications among older adults after oncological thoracic surgery in the modern era. We hypothesized that morbidity and mortality in older adults with lung cancer undergoing lobectomy is low and different than that of younger patients undergoing thoracic surgery. METHODS: All patients undergoing lobectomy at a large volume academic center between May 2016 and May 2019 were included. Patients were prospectively monitored to grade postoperative morbidity by organ system, based on the Clavien-Dindo classification. Patients were divided into two groups: Group 1 included patients 65-91 years of age, and Group 2 included those <65 years. RESULTS: Of 680 lobectomies in 673 patients, 414(61%) were older than 65 years of age (group 1). Median age at surgery was 68 years (20-91). Median hospital stay was 4 days (1-38) and longer in older adults. Older adults experienced higher rates of grade II and IV complications, mostly driven by an increased incidence of delirium, atrial fibrillation, prolonged air leak, respiratory failure and urinary retention. In this modern cohort, there was only 1 stroke (0.1%), and delirium was reduced to 7%. Patients undergoing minimally invasive (MI) surgery had a lower rate of Grade IV life-threatening complications. Older adults were more likely to be discharged to a rehabilitation facility, however this difference also disappeared with MI surgical procedures. CONCLUSIONS: Current morbidity of older adults undergoing lobectomy for cancer is low and is different than that of younger patients. Thoracotomy may be associated with postoperative complications in these patients. Our findings suggest the need to consider MI approaches and broad-based, geriatric-focused perioperative management of older adults undergoing lobectomy.

Impact of Neoadjuvant Chemoradiation on Adverse Events After Bronchial Sleeve Resection.

BACKGROUND: We analyzed the association between neoadjuvant chemoradiation in patients undergoing bronchial sleeve resection with the incidence of postoperative pulmonary and airway complications. METHODS: After instructional review board approval we performed a retrospective review of a prospectively maintained database of 136 patients who underwent sleeve resection in our institution between January 1998 and December 2016. Administration of neoadjuvant chemoradiation treatment was the studied exposure. Outcomes of interest were rates of postoperative pulmonary and airway complications. Nonparametric testing of demographic, surgical, and pathologic characteristics and morbidity was performed. Logistic regression models evaluated postoperative pulmonary complications and airway complications. Analysis was performed using Stata/IC 15. RESULTS: We analyzed 136 patients (18 underwent neoadjuvant chemoradiation), 77 (57%) of whom had non-small cell lung cancer. Postoperative pulmonary complications were observed in 44 of 136 patients (32%). Incidences of pulmonary complications were higher in the neoadjuvant chemoradiation group compared with the non-neoadjuvant radiation group (15/18 patients [83%] vs 29/118 patients [25%], respectively; P < .001). Likewise, rates of pneumonia, atelectasis, respiratory insufficiency, bronchial stenosis, prolonged air leak, bronchopleural fistula, and completion pneumonectomy (2/18 [11%]) were higher in the neoadjuvant chemoradiation group, reaching statistical significance in all cases except bronchial stenosis and prolonged air leak. Only neoadjuvant chemoradiation therapy remained significant for postoperative pulmonary and airway complications on logistic regression (both P < .05) CONCLUSIONS: Patients who undergo neoadjuvant chemoradiation before sleeve resection are at an increased risk of pulmonary and airway complications.

Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

Routine surveillance for diagnosis of venous thromboembolism after pleurectomy for malignant pleural mesothelioma.

OBJECTIVE: The purpose of this study was to determine the incidence of venous thromboembolism and utility of a routine surveillance program in patients undergoing surgery for mesothelioma. METHODS: Patients undergoing pleurectomy from May 2016 to August 2018 were included. A standardized surveillance program to look for venous thromboembolism in this group included noninvasive studies every 7 days postoperatively or earlier if symptomatic. All patients received external pneumatic compression sleeves in addition to prophylactic heparin. If deep vein thrombosis or pulmonary embolus was discovered, heparin drip was initiated until conversion to therapeutic anticoagulation. RESULTS: A total of 100 patients underwent pleurectomy for mesothelioma. Seven patients were found to have preoperative deep vein thrombosis, and as such only 93 patients were included for analysis. The median age of patients at surgery was 71 years (30-85 years). During the study, 30 patients (32%) developed evidence of thrombosis; 20 patients (22%) developed only deep vein thrombosis without embolism, 3 patients (3%) developed only pulmonary embolism, and 7 patients (7%) developed both deep vein thrombosis and pulmonary embolus. Of the 27 patients who developed deep vein thrombosis, 9 (33%) were asymptomatic at the time of diagnosis, and none of these developed a pulmonary embolus or other bleeding complications. There were 2 (2%) events of major postoperative bleeding related to therapeutic anticoagulation. CONCLUSIONS: The incidence of venous thromboembolism is high (32%) among patients undergoing surveillance after pleurectomy for mesothelioma. Up to 33% of patients with deep vein thrombosis are asymptomatic at the time of diagnosis, and the incidence of complications related to anticoagulation is low. Routine surveillance may be useful to diagnose and treat deep vein thrombosis before it progresses to symptomatic or fatal pulmonary embolus.

Risk of Urinary Recatheterization for Thoracic Surgical Patients with Epidural Anesthesia.

BACKGROUND: Current quality guidelines recommend the removal of urinary catheters on or before postoperative day two, to prevent catheter-associated urinary tract infections (CAUTI). The goal of this study was to evaluate the impact urinary catheter removal on the need for urinary recatheterization (UR) of patients with epidural anesthesia undergoing thoracic surgery. MATERIALS AND METHODS: All patients undergoing thoracic surgery between November 4th, 2017 and January 9th, 2018 who had a urinary catheter placed at the time of intervention were prospectively evaluated. Patient characteristics including: history of benign prostatic hyperplasia (BPH), catheter related variables and rates of UR were collected through chart review and daily visits to the wards. BPH was defined as history of transurethral resection of the prostate or treatment with selective α1-adrenergic receptor antagonists. RESULTS: Over a two-month period 267 patients were included, 124 (46%) were male. Epidural catheters were placed in 88 (33%) patients. Median duration of urinary catheters for the cohort was 1 day (0 days - 18 days), and it was significantly higher in patients with epidural anesthesia (Table 1). Overall 20 (7%) patients required UR. On initial analysis, there was no statistical difference in the rate of UR among patients with and without epidural catheters [9/88 (10%) vs 11/179 (6%), p=0.23). The rate of UR was higher in males than in females (14/124 (11%) vs 6/143 (4%), p=0.03). Fifteen (12%) patients had a diagnosis of BPH. The rate of UR was three-times higher in this group than in those without BPH [4/15 (27%) vs 10/109 (9%) p=0.05]. Four (1%) patients developed a CAUTI during follow-up, and the rate of CAUTI was not different between those with and without epidural catheters. CONCLUSION: Urinary catheters in patients with thoracic epidural anesthesia can be safely removed, as evidenced by low reinsertion and infection rates. Removal of urinary catheters in patients with a history of BPH should be carefully evaluated, as over 1/4 will require urinary recatheterization in this subgroup. Further study of this group is needed to avoid unnecessary patient discomfort associated with recatheterization.

Cumulative nonsmoking risk factors increase the probability of developing lung cancer.

BACKGROUND: It is estimated that 20% of lung cancer cases in the United States are among never smokers, yet current screening recommendations only include a small subset of high-risk patients. In this study, 2 models were used to predict the risk of developing lung cancer in subgroups of never smoking patients with additional risk variables. METHODS: The Liverpool Lung Project (LLP) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were 2 models used to calculate risk of developing lung cancer. Risk was calculated as a function of age for developing lung cancer within the next 5 to 10 years. RESULTS: PLCO estimated a peak risk of 16.20% at age 75 for 30-pack-year smokers with a first-degree relative with lung cancer. LLP estimated a peak risk of 7.3% over the next 5 years at age 79 for men with 30-pack-year and a first-degree relative with early-onset lung cancer (<60 years). Female never smokers with cumulative variables other than smoking had a peak risk of 3.40% for age 74 to 75 years. In contrast, women with only 30-pack-year smoking history and no other variable had a peak risk of 2.20% at age 74 to 75 years. CONCLUSIONS: Models such as LLP and PLCO might be used to identify risk for patients who would otherwise not receive lung cancer screening. These individual risk assessments can be used by patients and providers to assess if one is at substantial risk for developing lung cancer.

Sensitivity to stress-induced reproductive dysfunction linked to activity of the serotonin system.

OBJECTIVE: To use a nonhuman primate model and determine whether individuals sensitive to stress-induced reproductive dysfunction have lower activity of central serotonergic neurons under nonstressed conditions. DESIGN: The activity of the central serotonergic system was assessed by measuring responsiveness to a fenfluramine challenge (5 mg/kg, IV) in sedated monkeys previously categorized as highly stress resistant (HSR; n = 4; normal menstrual cyclicity through two stress cycles), medium stress resistant (MSR; n = 5; ovulatory in the first stress cycle but anovulatory in the second stress cycle), or low stress resistant (i.e., stress sensitive, SS; n = 4; anovulatory as soon as stress is initiated). To control for differences in pituitary stores of prolactin or ACTH, the animals were subsequently administered a bolus of thyrotropin-releasing hormone (3 microg/kg) plus corticotropin releasing factor (CRF), (3 microg/kg). SETTING: Oregon National Primate Research Center, Animal Services Building. PATIENT(S): Female cynomolgus macaques exhibiting normal menstrual cycles. INTERVENTION(S): Administration of fenfluramine, a serotonin-releasing drug. MAIN OUTCOMES MEASURE(S): Serum concentrations of prolactin (PRL) and cortisol (F). RESULT(S): Prolactin release in response to fenfluramine was significantly greater in the HSR group compared with the MSR or SS groups. In contrast, cortisol was higher in the SS group compared with the other two groups. Similar responses were not evident after thyrotropin-releasing hormone + CRF stimulation. CONCLUSION(S): The lower PRL response to fenfluramine in the stress-sensitive animals suggests that stress-sensitive individuals have decreased activity in central serotonergic neurons. However, the F data suggest that the hypothalamic-pituitary-adrenal axis in stress-sensitive individuals is highly responsive to even small increases in serotonin.