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Supplemental Digital Content is Available in the Text. High-speed videography of hind paw withdrawal produced variable results across experimenters, did not consistently reflect intensity-dependent pain scores, and did not differentiate inflamed and naive animals. Few analgesics identified using preclinical models have successfully translated to clinical use. These translational limitations may be due to the unidimensional nature of behavioral response measures used to assess rodent nociception. Advances in high-speed videography for pain behavior allow for objective quantification of nuanced aspects of evoked paw withdrawal responses. However, whether videography-based assessments of mechanical hypersensitivity outperform traditional measurement reproducibility is unknown. First, we determined whether high-speed videography of paw withdrawal was reproducible across experimenters. Second, we examined whether this method distinguishes behavioral responses exhibited by naive mice and mice with complete Freund's adjuvant (CFA)-induced inflammation. Twelve experimenters stimulated naive C57BL/6 mice with varying mechanical stimuli. Paw withdrawal responses were recorded with high-speed videography and scored offline by one individual. Our group was unable to replicate the original findings produced by high-speed videography analysis. Surprisingly, ∼80% of variation was not accounted for by variables previously reported to distinguish between responses to innocuous and noxious stimuli (paw height, paw velocity, and pain score), or by additional variables (experimenter, time-of-day, and animal), but rather by unidentified factors. Similar high-speed videography assessments were performed in CFA- and vehicle-treated animals, and the cumulative data failed to reveal an effect of CFA injection on withdrawal as measured by high-speed videography. This study does not support using paw height, velocity, or pain score measurements from high-speed recordings to delineate behavioral responses to innocuous and noxious stimuli. Our group encourages the continued use of traditional mechanical withdrawal assessments until additional high-speed withdrawal measures are validated in established pain models. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the psychometric properties of the AL‐PROfile, a patient‐reported outcome measure combining the Patient‐Reported Outcomes Measurement Information System (PROMIS)‐29, two items from PROMIS Cognitive Function, and select Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO‐CTCAE) items. Methods: Content validity was assessed through cognitive debriefing interviews of 20 patients who completed the AL‐PROfile (Study 1). Study 2 involved 297 participants who completed the AL‐PROfile and Medical Outcomes Study 36‐item Short‐Form Health Survey (SF‐36). Reliability (internal consistency and test–retest reliability) and validity (convergent and discriminant validity, known groups validity by stage/organ involvement) were calculated. Results: Study 1 participants found the AL‐PROfile straightforward confirming the relevance of the included content. Some felt that certain questions were not related to their amyloidosis experience. Study 2 demonstrated acceptable internal consistency for all domains/items except PROMIS Cognitive Function and acceptable test–retest reliability for all except PROMIS Cognitive Function and PRO‐CTCAE nausea. Large correlations were seen for the same domain across measures while correlations for divergent domains within a measure and different domains across different measures were small. The PRO‐CTCAE items showed small to medium correlations with each other and with PROMIS and SF‐36 domains. Stage was associated with physical function, fatigue, social roles, swelling, and shortness of breath scores. Conclusion: The AL‐PROfile has acceptable reliability and validity for use in systemic light chain amyloidosis patients. [ABSTRACT FROM AUTHOR]

The semi‐parametric generalized linear model (SPGLM) proposed by Rathouz and Gao assumes that the response is from a general exponential family with unspecified reference distribution and can be applied to model the distribution of binomial event‐count data with a constant cluster size. We extend SPGLM to model response distributions of binomial data with varying cluster sizes by assuming marginal compatibility. The proposed model combines a non‐parametric reference describing the within‐cluster dependence structure with a parametric density ratio characterizing the between‐group effect. It avoids making parametric assumptions about higher order dependence and is more parsimonious than non‐parametric models. We fit the SPGLM with an expectation–maximization Newton–Raphson algorithm to the boron acid mouse data set and compare estimates with existing methods. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of organ involvement on patient‐reported outcomes (PROs) in light chain (AL) amyloidosis. Methods: PROs were evaluated using the KCCQ‐12, PROMIS‐29 + 2, and SF‐36 in individuals with AL amyloidosis. The 2004 Mayo system was used to stage disease and cardiac, neurologic, and renal involvement was considered. Global physical and mental health (MH) scores, physical function (PF), fatigue, social function (SF), pain, sleep, and MH domains were evaluated. Effect sizes between scores were measured using Cohen's d. Results: Of 297 respondents, the median age at diagnosis was 60 years with 58% cardiac, 58% renal, and 30% neurologic involvement. Fatigue, PF, SF, and global physical health with PROMIS and SF‐36 discriminated the most by stage. Significant discrimination in PROMIS and/or SF‐36 was seen in PF, fatigue, and global physical health with cardiac involvement. For neurologic involvement, PF, fatigue, SF, pain, sleep, global physical, and MH with PROMIS and role physical, vitality, pain, general health, and physical component summary with SF‐36 were discriminatory. For renal amyloid, pain by SF‐36 and PROMIS, and SF‐36 MH and role emotional subscales were significant. Conclusions: Fatigue, PF, SF, and global physical health can discriminate stage, cardiac and neurologic, but not renal, AL amyloidosis involvement. [ABSTRACT FROM AUTHOR]

Background: We conducted a cross-sectional study to characterize health-related quality of life and symptom burden in individuals living with light chain (AL) amyloidosis. Methods: Members of the Amyloidosis Support Groups, Inc. with AL amyloidosis who consented to this IRB-approved survey provided information on their amyloidosis diagnosis, treatment, symptoms, and functioning. HRQL was measured using PROMIS and PRO-CTCAE questionnaires. Results: Among 297 participants who responded, the median age at diagnosis was 60 years (23–82) with 52% female and 90% white race. There were 69% AL (lambda) and 39% reported 3 or more organs involved with amyloidosis (58% cardiac, 58% renal, 30% neurological AL). Time from diagnosis was less than 2 years in 64 (22%), 2–5 years in 105 (36%), > 5 years in 126 (43%), and unknown in 2 (< 1%) individuals. Therapy included prior chemotherapy in 88% and stem cell transplant in 52%. Fifty percent of the cohort was on active treatment. Multiple domains were impaired in AL amyloidosis compared to the general population, including physical function, fatigue, and social roles. While highest among those within 2 years of diagnosis, high symptom burden was also seen in long-term survivors. A trend to decreased severity and number of impaired symptoms was seen with longer treatment-free interval but many symptoms remained persistent. Conclusions: Significant and persistent symptom burden is seen in AL amyloidosis. Patient-reported outcomes should be routinely measured and used to provide best supportive care to all AL amyloidosis patients, including long-term survivors and those not on active therapy. [ABSTRACT FROM AUTHOR]

Little evidence exists about how mild traumatic brain injury (mTBI) is affected by commonly encountered exposures of sleep loss, sleep aids, and caffeine that might be potential therapeutic opportunities. In addition, while propofol sedation is administered in severe TBI, its potential utility in mild TBI is unclear. Each of these exposures is known to have pronounced effects on cerebral metabolism and blood flow and neurochemistry. We hypothesized that they each interact with cerebral metabolic dynamics post-injury and change the subclinical characteristics of mTBI. MTBI in rats was produced by head rotational acceleration injury that mimics the biomechanics of human mTBI. Three mTBIs spaced 48 h apart were used to increase the likelihood that vulnerabilities induced by repeated mTBI would be manifested without clinically relevant structural damage. After the third mTBI, rats were immediately sleep deprived or administered caffeine or suvorexant (an orexin antagonist and sleep aid) for the next 24 h or administered propofol for 5 h. Resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were performed 24 h after the third mTBI and again after 30 days to determine changes to the brain mTBI phenotype. Multi-modal analyses on brain regions of interest included measures of functional connectivity and regional homogeneity from rs-fMRI, and mean diffusivity (MD) and fractional anisotropy (FA) from DTI. Each intervention changed the mTBI profile of subclinical effects that presumably underlie healing, compensation, damage, and plasticity. Sleep loss during the acute post-injury period resulted in dramatic changes to functional connectivity. Caffeine, propofol sedation and suvorexant were especially noteworthy for differential effects on microstructure in gray and white matter regions after mTBI. The present results indicate that commonplace exposures and short-term sedation alter the subclinical manifestations of repeated mTBI and therefore likely play roles in symptomatology and vulnerability to damage by repeated mTBI. • Subclinical manifestations of mTBI both persist and emerge over time. • Commonplace experiences modify the subclinical manifestations of mTBI. • Sleep loss results in unique brain functional hyperconnectivity in mTBI. • Caffeine-treated mTBI results in some effects more abnormal than mTBI alone. • Suvorexant and sedatives resulted in unique mTBI phenotypes revealed by DTI. [ABSTRACT FROM AUTHOR]

Background: The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B‐cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. Methods: In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. Results: Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P =.73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety‐two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P =.09). Conclusions: Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL. Blinatumomab and inotuzumab ozogamicin have comparable efficacy as a first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia. The sequencing of these novel agents should be tailored according to individual patient needs. [ABSTRACT FROM AUTHOR]

• Long-term survival is feasible in high-risk patients with multiple myeloma (MM) who relapse after allogeneic hematopoietic cell transplantation (alloHCT). This is best achieved using combination treatment and donor lymphocyte infusion (DLI). DLI can be incorporated without a significantly increased risk of graft-versus-host disease (GVHD). • Cytogenetic risk, time to relapse after alloHCT, development of acute GVHD before relapse impact survival after relapse in allogeneic transplant recipients. There is a continued need to improve GVHD prophylaxis and treatment strategies. • The risk of GVHD after MM relapse post-alloHCT is associated with the use of immunomodulatory drugs and checkpoint inhibitors. There are limited data to support the use of checkpoint inhibitors in this population. Many patients with multiple myeloma (MM) eventually relapse even after allogeneic hematopoietic cell transplantation (alloHCT) for curative intent. Over the past decade, outcomes for patients with MM have improved significantly with the availability of new therapies, including next-generation proteasome inhibitors, immunomodulatory agents, and, more recently, monoclonal antibodies. Although several published studies have evaluated the outcomes of alloHCT for MM, the data on survival outcomes in patients with MM experiencing disease relapse following alloHCT are limited. In addition, the predictors for postrelapse survival in these patients are not known. In this study, we examined the outcomes of a single-center cohort of 60 patients with MM who experienced relapse or progression after alloHCT. In addition, we evaluated the use of salvage regimens for treatment of relapsed MM and analyzed the predictors for improved postrelapse survival. After a median follow-up of 2.2 years from the time of relapse, the median duration of postrelapse survival was 1.8 years (95% confidence interval [CI], 1.2 to 5.0 years). Patients received a median of 3 lines of therapy (range, 0 to 10) for treatment of MM beyond the post-alloHCT relapse/progression. Multivariate analysis identified cytogenetic risk (standard risk versus high risk; hazard ratio [HR],.34; P =.01), time to relapse after alloHCT (>12 months versus ≤12 months: HR,.41; P =.04), and occurrence of acute graft-versus-host disease (GVHD) before relapse (GVHD versus no GVHD: HR, 2.89; P =.01) significantly affected postrelapse survival. These data illustrate that long-term myeloma control and survival is attainable in those relapsing/progressing after alloHCT and suggest that the synergism between novel therapies and the allogeneic immune platform is the key to improved survival in this high-risk patient population. [ABSTRACT FROM AUTHOR]

A subset of AML with myelodysplastic syndrome (MDS)-related changes (MRCs) occurs without a documented MDS phase. We studied genomic profile of 646 patients: 310 with MDS, 167 with AML without (w/o) MRC, 99 with primary (p) AML-MRC, and 70 with secondary (s) AML-MRC and sought to find differences in mutational patterns. Among the 32-myeloid associated genes studied, SF3B1 (p ≤.001) was significantly mutated in higher proportion of patients with MDS, compared to other categories. NPM1 (p <.001), FLT3 ITD (p =.08), and NRAS (p =.02) mutations showed trend toward significance for AML w/o MRC, compared to other categories. In pAML-MRC, TP53 (p <.001) was significantly mutated in higher proportion of patients. Similarly, SETBP1 (p =.001), RUNX1 (p =.004), and SRSF2 (p =.04) mutations were more commonly seen in sAML-MRC. While these signatures may not be diagnostically discriminatory, they may help in disease categorization when other data are absent or in challenging cases. [ABSTRACT FROM AUTHOR]

There is no established procedure for testing for trend with nominal outcomes that would provide both a global hypothesis test and outcome-specific inference. We derive a simple formula for such a test using a weighted sum of Cochran–Armitage test statistics evaluating the trend in each outcome separately. The test is shown to be equivalent to the score test for multinomial logistic regression, however, the new formulation enables the derivation of a sample size formula and multiplicity-adjusted inference for individual outcomes. The proposed methods are implemented in the R package multiCA. [ABSTRACT FROM AUTHOR]

• Haploidentical related donor transplantation was associated lower graft acquisition cost compared with double umbilical cord blood transplantation. • Although early direct hospital related charges up to day +100 were similar in both groups, it favored haploidentical tranplant when restricted to patients surviving beyond 100 days post-transplantation. Alternative donor allogeneic hematopoietic cell transplants (HCTs), such as double umbilical cord blood transplants (dUCBT) and haploidentical related donor transplants (haplo-HCT), have been shown to be safe and effective in adult patients who do not have an HLA-identical sibling or unrelated donor available. Most transplant centers have committed to 1 of the 2 alternative donor sources, even with a lack of published randomized data directly comparing outcomes and comparative data on the cost-effectiveness of dUCBT versus haplo-HCT. We conducted a retrospective study to evaluate and compare the early costs and charges of haplo-HCT and dUCBT in the first 100 days at 2 US transplant centers. Forty-nine recipients of haplo-HCT (at 1 center) and 37 with dUCBT (at another center) were included in the analysis. We compared graft acquisition, inpatient/outpatient, and total charges in the first 100 days. The results of the analysis showed a significantly lower cost of graft acquisition and lower total charges (for 100-day HCT survivors) in favor of haplo-HCT. Importantly, to control for the obvious shortcomings of comparing costs at 2 different transplant centers, adjustments were made based on the current (2018) local wage index and inflation rate. In the absence of further guidance from a prospective study, the cost analysis in this study suggests that haplo-HCT may result in early cost savings over dUCBT and may be preferred by transplant centers and for patients with more limited resources. [ABSTRACT FROM AUTHOR]

Highlights • Body mass index (BMI) ≥30 was associated with increased risk of readmission after allogeneic hematopoietic stem cell transplantation (allo-HCT). • There was no difference in overall survival between allo-HCT recipients with BMI ≥30 or >35 and those with BMI <30. • In patients age ≥60 years, elevated BMI should not impact consideration for allo-HCT. ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) is a high-risk treatment option for patients with hematologic malignancies. Advanced age and obesity can impact outcomes after allo-HCT. Previous registry studies of all age groups found that obesity does not affect outcomes. However, obesity can accelerate age-related decline in physical function and exacerbate comorbid conditions in older patients. Studies evaluating the effect of obesity on elderly patients undergoing allo-HCT are lacking. We performed a retrospective analysis of 86 nonobese (body mass index [BMI] <30) and obese (BMI ≥30) patients age ≥60 years who underwent allo-HCT for myeloid malignancies between January 2010 and June 2015. We found no significant between-group differences in mean age, sex, comorbid conditions, cytogenetic risk, disease indication for transplantation, or donor type. The median overall survival (OS) was 36 months for the BMI <30 group and 24 months for the BMI ≥30 group (P =.55). The median progression-free survival (PFS) was 10.1 months in the BMI <30 group and 13.6 months in the BMI ≥30 group (P =.93). There were no significant between-group differences in acute graft-versus-host disease (GVHD) and cumulative incidence of chronic GVHD at 1 year post-transplantation. Among patients admitted for transplantation, the mean length of stay was 25 days in the BMI <30 group and 26 days in the BMI ≥30 group (P =.64). The rate of readmission within 30 days of discharge was significantly higher in the BMI ≥30 group (34% versus 16%; P =.045). Our data reveal that in these elderly patients with myeloid malignancies undergoing allo-HCT, clinical outcomes, including OS, PFS, and GVHD, were not affected by obesity. Thus, in elderly patients, obesity should not preclude consideration for curative allo-HCT and does not portend worse outcomes after allo-HCT. [ABSTRACT FROM AUTHOR]

Chronic diseases—including cancer, cardiovascular diseases, and metabolic conditions such as diabetes and obesity—account for over 60% of overall global mortality. Sedentary time increases the risk for chronic disease incidence and mortality, while moderate to vigorous physical activity is known to decrease risk. Most Americans spend at least half of their time sedentary, with a trend toward increasingly sedentary lifestyles, and few Americans achieve recommended levels of physical activity. Time spent outdoors has been associated with reduced sedentary time and increased physical activity among children/youth and the elderly, but few population-based studies have examined this relationship among working age adults who may face greater constraints on active, outdoor time. This study examines the relationship between time spent outdoors, activity levels, and several chronic health conditions among a population-based sample of working age American adults in the National Health and Nutrition Examination Survey (NHANES) for 2009-2012. Findings provide evidence that time spent outdoors, on both work days and non-work days, is associated with less time spent sedentary and more time spent in moderate to vigorous physical activity. Further, findings indicate that time spent outdoors is associated with lower chronic disease risk; while these associations are partially explained by activity levels, controlling for activity levels does not fully attenuate the relationship between time outdoors and chronic disease risk. While cross-sectional, study findings support the notion that increasing time spent outdoors could result in more active lifestyles and lower chronic disease risk. Future work should examine this relationship longitudinally to determine a causal direction. Additional work is also needed to identify mechanisms beyond physical activity, such as psychosocial stress, that could contribute to explaining the relationship between time spent outdoors and chronic disease risk. [ABSTRACT FROM AUTHOR]

This meta-analysis examines the impact of age on the efficacy and safety of chimeric antigen receptor (CAR)-T therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The study found that children had a higher complete remission or complete remission with incomplete hematological recovery (CR/CRi) rate compared to adults. Older patients also had lower CR/CRi rates, overall response rates, and 1-year overall survival and progression-free survival rates. The results suggest that CAR-T therapy is more beneficial for children with B-cell ALL, highlighting the need for age-adapted utilization of this therapy. [Extracted from the article]

Summary: Primary mediastinal (thymic) large B‐cell lymphoma (PMBCL) is an uncommon subtype of non‐Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose‐adjusted (DA) R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R‐CHOP versus DA‐R‐EPOCH. 132 patients were identified from 11 contributing centres (56 R‐CHOP and 76 DA‐R‐EPOCH). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, complete response (CR) rate, and rates of treatment‐related complications. Demographic characteristics were similar in both groups. DA‐R‐EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA‐R‐EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA‐R‐EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment‐related toxicities. At 2 years, 89% of R‐CHOP patients and 91% of DA‐R‐EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R‐CHOP to DA‐R‐EPOCH for PMBCL. [ABSTRACT FROM AUTHOR]

Efficient adjuvants have the potential to trigger both innate and adaptive immune responses simultaneously. Flagellin is a unique pathogen-derived protein, which is recognized by pattern recognition receptors (PRRs) as well as by B-cell and T cell receptors thus providing an important link between innate and adaptive immunity. The aforementioned properties define flagellin as an optimal adjuvant. The induction of immunogenic cell death could be an additional expectation for adjuvants in the context of cancer immunotherapy due to their ability to activate dendritic cells (DC) to present tumor antigens through the engulfment of dying cells. The immunostimulatory potential of flagellin in the course of DC and lymphocyte activation is well documented, however the exact mechanism is not fully explored. Based on this limitation we sought to investigate the potential modulatory effects of flagellin on various cell death processes knowing that it plays detrimental roles in regulating the final outcome of various types of immune responses. Here we provide evidence that the pre-treatment of Jurkat T-cells with recombinant flagellin is able to increase the degree of cell death provoked by FasL or TNF-α, and concomitantly increases the cytotoxic potential of phytohemagglutinin activated T-lymphocytes in a TLR5 dependent way. In contrast to these flagellin-mediated effects on the death receptor-induced signaling events, the mitochondrial apoptotic pathway remained unaffected. Furthermore, the cell culture supernatant of wild type Salmonella enteritidis bacteria, but not their flagellin deficient variant, was able to enhance the Fas-induced cell death process. To define the molecular mechanisms of flagellin-mediated elevated levels of cell death we were able to detect the upregulation of RIP1-dependent signaling events. These findings demonstrate that the cooperative actions of pattern recognition and different death receptors are able to initiate the cell death process with the mobilization of RIP-dependent cell death modalities. This finding highlights the capability of flagellin to act as a potential adjuvant which is relevant for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Environmental health literacy (EHL) is a promising and evolving field of research that could benefit from youth engagement. Yet studies focused on youths' environmental health awareness and concerns are limited. For example, although lead exposure remains a threat to youth development in urban environments, no published studies have measured urban youth's knowledge of lead poisoning. A CBPR partnership established a youth advisory council (YAC) who helped to design, interpret and disseminate a mixed methods study exploring environmental health perceptions among urban youths ages 10-18. Surveys assessed awareness, attitudes, and knowledge regarding lead poisoning and five environmental health issues determined by the YAC. Focus group questions further contextualized youths' lead knowledge and understanding of youths' environmental health concerns. A majority of youth could identify specific sources of lead exposure but had minimal knowledge of prevention strategies, and focus group data revealed misinformation regarding lead sources and consequences. Survey and focus group respondents' level of awareness and concern regarding YAC-selected EH issues was high in comparison to lead poisoning. In particular, job opportunities and police brutality were endorsed as both neighborhood concerns and priorities. Awareness and knowledge of environmental health issues among urban youth have not been well described. These findings reinforce the importance of addressing problems of local relevance. Moving forward, lead poisoning prevention education for youth and youth EHL partnerships may benefit from incorporating an ecological approach wherein connections to the social and economic context are made explicit. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming. We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements. We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (−7.0 ± 7.9) compared to SOC (−2.7 ± 6.9, p = 0.01) at six months. MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy. • This study is the first to evaluate model-based DBS programming in a randomized controlled clinical trial. • This study shows the utility of the MAP DBS platform with multiple anatomical targets, DBS systems, and clinical workflows. • The results suggest the utility of MAP DBS in the programming process, and will be further explored to develop new clinical practices that reduce the burden of therapy optimization. [ABSTRACT FROM AUTHOR]

Background: Nutrition screening is recommended to identify children at risk for malnutrition. A unique screening tool was developed based on American Society for Parenteral and Enteral Nutrition (ASPEN) recommendations and embedded in the electronic medical record to assess for nutrition risk. Methods: The components of the tool included the Paediatric Nutrition Screening Tool (PNST) and other elements recommended by ASPEN. To evaluate the screening tool, retrospective data were analysed on all patients admitted to acute care units of Children's Wisconsin in 2019. Data collected included nutrition screen results, diagnosis and nutrition status. All patients who received at least one full nutrition assessment by a registered dietitian (RD) were included in analysis. Results: One thousand five hundred seventy‐five patients were included in analysis. The following screen elements were significantly associated with a diagnosis of malnutrition: any positive screen (p < 0.001), >2 food allergies (p = 0.009), intubation (p < 0.001), parenteral nutrition (p = 0.005), RD‐identified risk (p < 0.001), positive risk per the PNST (p < 0.001), BMI‐for‐age or weight‐for‐length z‐score (p < 0.001), intake <50% for 3 days (p = 0.012) and NPO > 3 days (p = 0.009). The current screen had a sensitivity of 93.9%, specificity of 20.3%, positive predictive value (PPV) of 30.9% and negative predictive value (NPV) of 89.8%. This is compared with the PNST which had a sensitivity of 32%, specificity of 94.2%, PPV of 71% and NPV of 75.8% in this study population. Conclusion: This unique screening tool is useful for predicting nutrition risk and has a greater sensitivity than the PNST alone. Key points: A nutrition screening tool embedded in the electronic medical record is feasible for children's hospitals.The tool, which also incorporates the Paediatric Nutrition Screening Tool (PNST), has greater sensitivity than the PNST alone. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have explored neighborhood environmental correlates of mental illnesses, presuming that the time individuals spend in their environment can confer benefit or harm based on environmental characteristics. However, few population-based studies have directly examined the relationship between time spent outdoors and mental health, and little work has been done to explore how experiences differ by race and ethnicity. Though some have proposed "doses of outdoor time" to improve health, the absence of information about the benefits conferred by particular "doses," and expected baseline levels of outdoor time, are needed to inform the development of recommendations and interventions.Methods: This study examined the relationship between time spent outdoors and depression among a population-based sample of American adults, characterized current levels of time spent outdoors by race and ethnicity, and examined how the relationship between time spent outdoors and depression varies by race and ethnicity. Descriptive statistics and survey regression models were used to examine data from the National Health and Nutrition Examination Survey for 2009-2012.Results: Findings provide evidence that time spent outdoors is associated with fewer depressive symptoms, but this benefit may not be equally distributed by race and ethnicity. Descriptive analyses also reveal differences in time spent outdoors among different racial and ethnic groups.Conclusions: Study findings support the notion that increasing time spent outdoors may result in mental health benefits. However, this study questions whether that benefit is experienced equally among different groups, particularly given differences in occupational experiences and environmental characteristics of neighborhoods. [ABSTRACT FROM AUTHOR]

Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Renal transplantation is the best treatment for end-stage renal disease. However, limited availability of donor organs is a problem. We analyzed the changing trends of transplantation and mortality in subjects listed for deceased donor renal transplantation over successive years. Methods: By using US Renal Data System data, we identified Medicare patients receiving dialysis who were listed for their first deceased donor renal transplant between January 1996 and December 2005. Subjects were followed to the first occurrence of transplant, death, or September 30, 2007. The effect of the year of listing was analyzed adjusting for age, sex, race, vintage, panel reactive antibody, and cause of end-stage renal disease. Results: There were 70,891 subjects (mean age 50.1±14.3 years, 59.9% were men, 54% were white, average duration of dialysis 2±2.2 years). Multivariate analysis revealed that compared with patients listed in 1996, for patients listed in subsequent years the cumulative incidence of death remained within a narrow boundary and the cumulative incidence of transplant progressively declined. For example, for subjects listed in 1998, 2000, 2002, and 2004, the cumulative incidence of death relative to 1996 was 1.02 (95% confidence interval [CI], 1.01-1.03), 1.02 (CI, 1.01-1.03), 0.99 (CI, 0.98-0.99), and 0.94 (CI, 0.93-0.94), respectively, 12 months after listing. However, correspondingly for these subjects at the 12-month follow-up time point, the cumulative incidence of transplant relative to 1996 was 0.85 (CI, 0.84-0.86), 0.73 (CI, 0.71-0.74), 0.63 (CI, 0.62-0.64), and 0.58 (CI, 0.57-0.59), respectively. Conclusion: There is a progressive unfavorable pattern of declining transplantation rates with each successive year of listing in patients listed for deceased donor renal transplantation. [Copyright &y& Elsevier]

Summary We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intraarterially as rapid treatment for acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Chronic sleep disruption in laboratory rats leads to increased energy expenditure, connective tissue abnormalities, and increased weights of major organs relative to body weight. Here we report on expanded findings and the extent to which abnormalities become long-lasting, potentially permanent changes to health status after apparent recuperation from chronic sleep disruption. Rats were exposed 6 times to long periods of disrupted sleep or control conditions during 10 weeks to produce adaptations and then were permitted nearly 4 months of undisturbed sleep. Measurements were made in tissues from these groups and in preserved tissue from the experimental and control groups of an antecedent study that lacked a lengthy recuperation period. Cycles of sleep restriction resulted in energy deficiency marked by a progressive course of hyperphagia and major (15%) weight loss. Analyses of tissue composition in chronically sleep-restricted rats indicated that protein and lipid amounts in internal organs were largely spared, while adipose tissue depots appeared depleted. This suggests high metabolic demands may have preserved the size of the vital organs relative to expectations of severe energy deficiency alone. Low plasma corticosterone and leptin concentrations appear to reflect low substrate availability and diminished adiposity. After nearly 4 months of recuperation, sleep-restricted rats were consuming 20% more food and 35% more water than did comparison control rats, despite normalized weight, normalized adipocytes, and elevated plasma leptin concentrations. Plasma cholesterol levels in recuperated sleep-restricted rats were diminished relative to those of controls. The chronically increased intake of nutriments and water, along with altered negative feedback regulation and substrate use, indicate that internal processes are modified long after a severe period of prolonged and insufficient sleep has ended. [ABSTRACT FROM AUTHOR]

We introduce the use of stochastic ordering for defining treatment-related trend in clustered exchangeable binary data for both when cluster sizes are fixed and when they vary randomly. In the latter case, there is a well-documented tendency for such data to be sparse, a problem we address by making an assumption of interpretability or, equivalently, marginal compatibility. Our procedures are based on a representation of the joint distribution of binary exchangeable random variables by a saturated model, and may hence be considered nonparametric. The definition of trend by stochastic ordering is proposed to ensure a flexibility that allows for various forms of monotone increases in response to the cluster as a whole to be included in the evaluation of the trend. We obtain maximum likelihood estimates of probability functions under stochastic ordering using mixture-likelihood-based algorithms. Since the data are sparse, we avoid the use of asymptotic results and obtain p-values of the likelihood ratio procedures by permutation resampling. We demonstrate how the proposed framework can be used in risk assessment, and provide comparisons with existing procedures. [ABSTRACT FROM PUBLISHER]

Chronic restriction of a basic biological need induces adaptations to help meet requisites for survival. The adaptations to chronic restriction of sleep are unknown. A single episode of 10 days of partial sleep loss in rats previously was shown to be tolerated and to result in increased food intake and loss of body weight as principal signs. The purpose of the present experiment was to investigate the extent to which adaptation to chronic sleep restriction would ameliorate short-term effects and result in a changed internal phenotype. Rats were studied during 10 wk of multiple periods of restricted and unrestricted sleep to allow adaptive changes to develop. Control rats received the same ambulatory requirements only consolidated into periods that lessened interruptions of their sleep. The results indicate a latent period of relatively stable food and water intake without weight gain, followed by a dynamic phase marked by enormous increases in food and water intake and progressive loss of body weight, without malabsorption of calories. Severe consequences ensued, marked especially by changes to the connective tissues, and became fatal for two individuals. The most striking changes to internal organs in sleep-restricted rats included lengthening of the small intestine, decreased size of adipocytes, and increased incidence of multilocular adipocytes. Major organs accounted for an increased proportion of total body mass. These changes to internal tissues appear adaptive in response to high energy production, decomposition of lipids, and increased need to absorb nutrients, but ultimately insufficient to compensate for inadequate sleep. [ABSTRACT FROM AUTHOR]

Background. In 2004, the State of Wisconsin introduced a change to their Medicaid Policy allowing medical care providers to be reimbursed for fluoride varnish treatment provided to Medicaid enrolled children. Objective. To determine the extent by which a state-level policy change impacted access to fluoride varnish treatment (FVT) for Medicaid enrolled children. Data Source. The Electronic Data Systems of Medicaid Evaluation and Decision Support database for Wisconsin from 2002 to 2006. Study Design. We analyzed Wisconsin Medicaid claims for FVT for children between the ages of 1 and 6 years, comparing rates in the prepolicy period (2002–2003) to the period (2004–2006) following the policy change. Principal Findings. Medicaid claims for FVT in 2002–2003 totaled 3,631. Following the policy change, claims for FVT increased to 28,303, with 38.0 percent submitted by medical care providers. FVT rates increased for children of both sexes and all ages, rising from 1.4 per 1,000 person-years of enrollment in 2002–2003 to 6.6 per 1,000 person-years in 2004–2006. Overall, 48.6 percent of the increase in FVT was attributable to medical care providers. The largest increase was seen in children 1–2 years of age, among whom medical care providers were responsible for 83.5 percent of the increase. Conclusions. A state-level Medicaid policy change was followed by both a significant involvement of medical care providers and an overall increase in FVT. Children between the ages of 1 and 2 years appear to benefit the most from the involvement of medical care providers. [ABSTRACT FROM AUTHOR]

The article discusses a study on descriptive nomograms of adjuvant radiotherapy (RT) use and patterns of care analysis for stage I and II of endometrial adenocarcinoma. It found that higher tumor grade and stage led to greater use of RT. It notes that geographic location had a significant effect on overall RT use and therapy choice. It also mentions the absence of a national consensus on adjuvant treatment for early-stage disease.

The article presents a medical study to evaluate the frequency and effect of adjuvant radiation therapy among women with stage one endometrial adenocarcinoma. Endometrial cancer is the most common gynecological malignancy in the United States. The benefit of adjuvant radiation therapy in stage one endometrial adenocarcinoma remains controversial despite clinical trials. This medical study reveals a statistically significant association between improved survival and adjuvant radiation therapy.

In this paper we discuss some natural limitations in quantitative inference about the frequency, correlation and ordering of genetic events occurring in the course of tumor development. We consider a simple, yet frequently used experimental design, under which independent tumors are examined once for the presence/absence of specific mutations of interest. The most typical factors that affect the inference on the chronological order of genetic events are: a possible dependence of mutation rates, the sampling bias that arises from the observation process and small sample sizes. Our results clearly indicate that just these three factors alone may dramatically distort the outcome of data analysis, thereby leading to estimates of limited utility as an underpinning for mechanistic models of carcinogenesis. [ABSTRACT FROM AUTHOR]

Patient engagement, adaptation and self-management play a critical role in improving Health Related Quality of Life (HRQOL) and reducing health care utilization in chronic disorders. There is no data on the level of patient engagement in patients with cyclic vomiting syndrome (CVS); we thus sought to determine their level of engagement and its association with clinical covariates. The Patient Activation Measure (PAM-13), a validated tool that measures the degree of patient engagement in their health was administered prospectively to patients with CVS. Data on demographics, health care utilization, and HRQOL (using the NIH PROMIS 10) were obtained. Patients were stratified into low engagement (PAM 1 & 2) and high engagement (PAM 3 & 4). The Fisher's exact test and Wilcoxon rank-sum tests were used to identifying significant differences between the groups. Of 96 patients, 45% of patients had low levels of patient engagement. On multivariate analysis, low patient engagement was significantly associated with an increased number of CVS hospitalizations in the past year (aOR 1.26 [1.07, 1.54] p =.010), lower mental HRQOL scores (aOR 0.88 [0.78, 0.97] p =.022), current tobacco use (aOR 4.85 [1.24, 22.74] p =.031), and patients who were newly established in a specialized CVS clinic (aOR 44.40 [5.38, 70.02] p =.002). Almost half of CVS patients demonstrate poor patient engagement, which is associated with poor outcomes. Identifying these patients and treatment in a specialized CVS center can potentially improve HRQOL, reduce health care utilization and improve overall healthcare outcomes. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

BACKGROUND: As the COVID-19 pandemic shifts to an endemic phase, an increasing proportion of patients with cancer and a preoperative history of COVID-19 will require surgery. This study aimed to assess the influence of preoperative COVID-19 on postoperative risk for major adverse cardiovascular and cerebrovascular events (MACEs) among those undergoing surgical cancer resection. Secondary objectives included determining optimal time-to-surgery guidelines based on COVID-19 severity and discerning the influence of vaccination status on MACE risk. STUDY DESIGN: National COVID Cohort Collaborative Data Enclave, a large multi-institutional dataset, was used to identify patients that underwent surgical cancer resection between January 2020 and February 2023. Multivariate regression analysis adjusting for demographics, comorbidities, and risk of surgery was performed to evaluate risk for 30-day postoperative MACE. RESULTS: Of 204,371 included patients, 21,313 (10.4%) patients had a history of preoperative COVID-19. History of COVID-19 was associated with an increased risk for postoperative composite MACE as well as 30-day mortality. Among patients with mild disease who did not require hospitalization, MACE risk was elevated for up to 4 weeks after infection. Postoperative MACE risk remained elevated more than 8 weeks after infection in those with moderate disease. Vaccination did not reduce risk for postoperative MACE. CONCLUSIONS: Together, these data highlight that assessment of the severity of preoperative COVID-19 infection should be a routine component of both preoperative patient screening as well as surgical risk stratification. In addition, strategies beyond vaccination that increase patients' cardiovascular fitness and prevent COVID-19 infection are needed. [ABSTRACT FROM AUTHOR]

Background: Neck pain in a concussion population is an emerging area of study that has been shown to have a negative influence on recovery. This effect has not yet been studied in collegiate athletes. Hypothesis: New or worsened neck pain is common after a concussion (>30%), negatively influences recovery, and is associated with patient sex and level of contact in sport. Study Design: Cohort study; Level of evidence, 2. Methods: Varsity-level athletes from 29 National Collegiate Athletic Association member institutions as well as nonvarsity sport athletes at military service academies were eligible for enrollment. Participants completed a preseason baseline assessment and follow-up assessments at 6 and 24 to 48 hours after a concussion, when they were symptom-free, and when they returned to unrestricted play. Data collection occurred between January 2014 and September 2018. Results: A total of 2163 injuries were studied. New or worsened neck pain was reported with 47.0% of injuries. New or worsened neck pain was associated with patient sex (higher in female athletes), an altered mental status after the injury, the mechanism of injury, and what the athlete collided with. The presence of new/worsened neck pain was associated with delayed recovery. Those with new or worsened neck pain had 11.1 days of symptoms versus 8.8 days in those without (P <.001). They were also less likely to have a resolution of self-reported symptoms in ≤7 days (P <.001). However, the mean duration of the return-to-play protocol was not significantly different for those with new or worsened neck pain (7.5 ± 7.7 days) than those without (7.4 ± 8.3 days) (P =.592). Conclusion: This novel study shows that neck pain was common in collegiate athletes sustaining a concussion, was influenced by many factors, and negatively affected recovery. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T (n = 24) or BsAb (n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT. [ABSTRACT FROM AUTHOR]

Introduction. Bariatric surgery performed at high volume centers decreases length of stay, cost, and morbidity and mortality. The effect of a high volume of bariatric surgery procedures on outcomes may extend not just to bariatric surgery but to any general surgical procedure in morbidly obese patients. We hypothesized that patients with morbid obesity (body mass index >40 kg/m2) undergoing common, nonbariatric general surgery would have decreased morbidity and mortality at centers performing high volumes of bariatric surgery. Methods. The 2016 National Inpatient Sample (NIS) was used to identify the number of laparoscopic gastric bypass and sleeve gastrectomy performed at each hospital. Hospitals were classified as high volume bariatric hospitals (HVBH) ≥10 reported cases (50 actual)/year or low volume bariatric hospitals (LVBH) <10 reported cases (50 actual)/year, as NIS reports a 20% sample of actual cases. Patients with morbid obesity undergoing laparoscopic or open appendectomy, cholecystectomy, or ventral hernia repair were included for analysis. Propensity scores were developed based on available demographics, comorbidities, and hospital procedure volume. Postoperative complications during the index hospital admission, determined by ICD-10 code, were compared using inverse propensity weights. Differences were considered significant with a p value of <0.05. Results. The total number of general surgery patient cases analyzed was 14,028 from 2,482 hospitals, representing 70,140 admissions. The cohort of patients undergoing operations treated at HVBH were younger (p = 0.03) with higher rates of COPD (p = 0.04). Patients at LVBH had higher rates of nicotine dependence (p = 0.0001) and obstructive sleep apnea (p < 0.001). On propensity-weighted analysis adjusting for preoperative comorbidities and hospital procedure volume, there were significantly higher rates of multiple postprocedure complications at LVBH, specifically, postprocedure respiratory failure for patients undergoing elective laparoscopic cholecystectomy, elective ventral hernia repair with mesh and appendectomy. Conclusion. Patients with morbid obesity may have an advantage in having general surgery procedures at HVBH. HVBH may have a volume-outcomes relationship where the hospital and staff familiarity with the management principles required to minimize the postoperative risk associated with morbid obesity and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Opioid receptors are present in the esophagus, and chronic opioid therapy may be associated with esophageal dysfunction. Given the current opioid epidemic in the United States, the potential contribution of opioids to esophageal dysmotility is important from both public health and patient care perspectives. Therefore our aim is to investigate the potential contribution of opioids to dysphagia and the prevalence of major motor disorders in patients undergoing manometric evaluation. Methods: The anonymized electronic medical records of patients linked to their de‐identified high‐resolution manometry (HRM) studies were reviewed. The patients were grouped based on their opioid exposure history at the time of HRM: opioid‐naïve and chronic daily users. The oral morphine milligram equivalent daily dose (MMED) of opioids was computed. Key Results: 10% of patients referred for esophageal HRM were taking opioid analgesics on a chronic daily basis, and they had a significantly higher prevalence of dysphagia than their opioid‐naïve counterparts. The chronic daily opioid users displayed a significantly higher prevalence of achalasia type 3 (ACH3) and esophagogastric junction outflow obstruction (EGJOO) motility phenotypes. The MMED of opioids was a significant predictor of esophageal pressure metrics and motility diagnoses (P < 0.0001). Conclusions: Chronic daily opioid intake is associated with impaired deglutitive LES relaxation and disorganized peristaltic sequence. While a minority of patients on chronic daily opioid therapy present with major esophageal motor disorders, they comprise nearly half of ACH3 and a third of EGJOO motility phenotypes. [ABSTRACT FROM AUTHOR]

Background HaploHCT is a common alternative donor graft source for patients with hematological malignancies. A sepsis-like hyper-cytokine state referred to as cytokine release syndrome (CRS) has been described following haploHCT. Given the distinctive biology of CRS in haploHCT, understanding the infectious complications as a function of severity of CRS is critical. Methods We evaluated 78 consecutive adult haploHCT patients (pts) at our center for development of CRS (graded as per criteria by Lee et al. Blood 2014) and examined the incidence of infectious complications in correlation with CRS severity. All pts received haploHCT for malignancies between 04/2012-04/2018, using post-transplant cyclophosphamide (PTCY) and tacrolimus/mycophenolate mofetil for graft-versus-host disease prophylaxis. The incidence of infections was examined in two time periods in relation to day of stem cell infusion (day 0): day 0-100 (early) and day 101-180 (late). Results Among the 78 pts, 41 (53%) developed grade 0-1 CRS and 37 (47%) had grade 2-5 CRS. Overall, 61 patients (78%) experienced early infections whereas 19 (27%, n=70) experienced late infections. 44% of those with CRS grade 0-1 had early infections and 37% had late infections. In contrast, early and late infections occurred in 56% and 63% CRS grade 2-5 pts (p=.002 and p=.31). In CRS 0-1 cohort, blood-stream infections (BSI) were seen in 10% pts in first 180 days; the corresponding number was 46% in CRS 2-5 cohort (P<.001). There was evidence for increased viral infections in pts with CRS 2-5 (81% vs 61% in CRS 0-1; p=0.05). This was driven by increased frequency of BK viruria in CRS grade 2-5 (46% vs. 24%, p=.046). There was no significant difference in incidence of fungal infections with CRS severity. Conclusion Infections are common post-transplant complications in first 6 months. The severity of CRS developing after haploHCT using PTCY-platform is associated with increased frequency of BSI. Viral and fungal infections do not have a higher risk post-haploHCT based on CRS severity. [ABSTRACT FROM AUTHOR]

• Rats self-administered oxycodone, then underwent sleep restriction or control procedures, then were tested for drug seeking. • Sleep restriction did not affect oxycodone seeking in male or female rats. • In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. • In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking. During opioid use and abstinence, sleep disturbances are common and are thought to exacerbate drug craving. In this study, we tested the hypothesis that sleep restriction during abstinence from oxycodone self-administration would increase drug seeking during extinction and footshock reinstatement tests. We also performed behavioral phenotyping to determine if individual variation in responses to stressors and/or pain are associated with oxycodone seeking during abstinence, as stress, pain and sleep disturbance are often co-occurring phenomena. Sleep restriction during abstinence did not have selective effects on oxycodone seeking for either sex in extinction and footshock reinstatement tests. Some phenotypes were associated with drug seeking; these associations differed by sex and type of drug seeking assessment. In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking, although this effect was lost when correcting for oxycodone intake. Adrenal sensitivity prior to oxycodone exposure was positively associated with footshock reinstatement in females. This work identifies sex-dependent relationships between HPA axis function and opioid seeking, indicating that HPA axis function could be a therapeutic target for the treatment of opioid use disorder, with tailored approaches based on sex. Sleep disturbance during abstinence did not appear to be a major contributing factor to opioid seeking. [ABSTRACT FROM AUTHOR]

The robotic platform is increasingly used in colorectal surgery. Recent upgrades in the robotic platform and introduction of proctectomy-specific reports from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) warrant updated evaluation of minimally invasive proctectomy outcomes. The aim of this study was to compare outcomes in robotic versus laparoscopic proctectomy using ACS-NSQIP data. The ACS-NSQIP data set was used to identify adult patients undergoing elective robotic and laparoscopic proctectomy in 2016 and 2017. Demographics, preoperative and intraoperative data, and postoperative outcomes were collected. Propensity-weighted analysis was used to estimate the effect of robotic versus laparoscopic surgery on outcomes. Of 3845 patients meeting inclusion criteria, 2681 (70%) underwent a laparoscopic approach and 1164 (30%) underwent a robotic approach. Patients undergoing a robotic procedure were more likely to be older, have higher American Society of Anesthesiologists scores, low rectal tumors, and have undergone chemotherapy or radiation before surgery. After propensity adjustment, a robotic approach was associated with a decrease in conversion to open operation (estimated mean difference, −6.7%; P < 0.01), length of stay (−0.6 d; P = 0.01), occurrence of postoperative ileus (−3.7%; P = 0.01), and an increase in operative time (20.3 min; P < 0.01). Using data from a national cohort, we found that compared with laparoscopy, robotic proctectomy is associated with decreased conversion to open operation, longer operation time, decreased length of stay, and decreased postoperative ileus. Our study identified several advantages to a robotic approach; however, further work is needed to assess cost-effectiveness in conjunction with clinical outcomes. [ABSTRACT FROM AUTHOR]

• In the majority of patients with multiple myeloma, hematopoietic progenitor cells (HPCs) collected at the time of first autologous hematopoietic cell transplantation (autoHCT) are not used for a future salvage autoHCT or stem cell boost. • The evidence supporting continued collection HPCs for later use in patients age ≥70 years is weak. • A small proportion of the cost incurred during upfront HPC collection before first autoHCT and intended for later use is actually utilized for salvage autoHCT and/or stem cell boost. Autologous hematopoietic cell transplantation (autoHCT) is a standard initial treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient hematopoietic progenitor cells (HPCs) for 2 autoHCTs in all eligible patients. Despite a lack of published data on the utilization of HPCs stored for future use, it is common practice across transplantation programs to collect enough HPCs for 2 autoHCTs in MM patients. In this single-center retrospective study, we analyzed the utilization of HPCs collected and stored at the time of first autoHCT in patients with MM, along with the cost implications of HPC collection targets sufficient for 2 transplantations. In a cohort of 400 patients (median age, 63 years; range, 22 to 79 years), after a median follow-up of 50.4 months, 197 patients had relapsed and 36 had received HPC infusion as salvage autoHCT (n = 29) and/or HPC boost (n = 8). In this cohort, a median CD34+ cell dose of 4.3 × 106/kg (range, 1.1 to 12.94.3 × 106/kg) was used for first autoHCT, and a median of 4.4 × 106/kg (range, 1.0 to 20.2× 106/kg) CD34+ cells were stored for future use. At 6 years after the first autoHCT, the estimated cumulative incidence of salvage autoHCT was 12.0% without HPC boost and 13.9% with HPC boost. HPC utilization was significantly higher in the 60- to 64-year age group, whereas no patients who were age ≥70 years at the time of first autoHCT received salvage autoHCT. Using the CD34+ cell dose infused during the first autoHCT as the cutoff for individual patients, the estimated mean additional cost of HPC collection intended for subsequent use (over and above the HPCs used for first autoHCT) was $10,795 ($4.32 million for the entire cohort), an estimated 14% of which (ie, $583,600) was actually used up in salvage autoHCT by 6 years from first autoHCT. In conclusion, our results suggest the need for reappraisal of HPC collection targets for salvage autoHCT and argue against HPC collection and storage for salvage autoHCT in patients age ≥70 years at the time of first autoHCT. [ABSTRACT FROM AUTHOR]

• The severity of cytokine release syndrome (CRS) developing after T cell-replete haploidentical hematopoietic cell transplantation is associated with an increased risk of bacterial and viral infections. • Severe CRS significantly and independently increases the risk of viral infections but mediates the risk of bacterial infections through an effect on neutrophil recovery. • CRS grade is also a significant predictor for infection density (overall, bacterial, and viral) after adjusting for other predictors, including time to neutrophil engraftment. An increased risk of infections has been described after T cell-replete haploidentical cell transplantation (haploHCT). Cytokine release syndrome (CRS) after haploHCT is a known phenomenon, but the impact of CRS severity on the risk of infections remains unexplored. We retrospectively evaluated 78 consecutive adult haploHCT recipients from 2012 to 2018 for the development of CRS (graded based on the criteria of Lee et al) and examined the incidence and mortality due to infections in correlation with CRS severity. In our study cohort, which was stratified into 3 groups by severity of CRS, 80% of the patients developed infections within 180 days of HCT. Significantly higher proportions of patients with CRS grade 2 (89%) and grade ≥3 (90%) than patients with CRS grade 0-1 (68%) had at least 1 infection in the first 100 days (P =.04). Bloodstream infections (BSIs) were seen more frequently in patients with CRS grade 2 and grade ≥3 in the first 6 months. Multivariable analysis for time to infection showed that CRS grade ≥3 was independently associated with an elevated risk of any infection compared with CRS grade 0-1 (hazard ratio [HR], 3.05; P =.007). CRS grade ≥3 was also associated with a higher hazard of viral (HR, 3.42; P =.04) and bacterial infections (HR, 2.83; P =.03) compared with CRS grade 0-1. After adjusting for time to neutrophil engraftment as a time-dependent covariate, CRS grade ≥3 still had a significant effect on viral infections (HR, 2.49; P =.03), but not on bacterial infections (HR, 1.32; P =.57). CRS grade was also a significant predictor for infection density (overall, bacterial, and viral). The incidence of infection-related mortality by day +100 was higher in patients with severe CRS. Severe CRS developing after post-transplantation cyclophosphamide-based haploHCT is independently associated with viral infections and an increased risk of bacterial infections, likely through delayed neutrophil engraftment. [ABSTRACT FROM AUTHOR]

Background: There is evidence that palliative care and floating (inpatient) hospice can improve end-of-life experiences for patients and their families in the intensive care unit (ICU). However, both palliative care and hospice remain underutilized in the ICU setting. Objectives: This study examined palliative consultations and floating hospice referrals for ICU patients during a phased launch of floating hospice, 2 palliative order sets, and general education to support implementation of palliative care guidelines. Methods: This descriptive, retrospective study was conducted at a level I trauma and academic medical center. Electronic medical records of 400 ICU patients who died in the hospital were randomly selected. These electronic medical records were reviewed to determine if patients received a palliative consult and/or a floating hospice referral, as well as whether the new palliative support tools were used during the course of care. The numbers of floating hospice referrals and palliative consults were measured over time. Results: Although not significant, palliative consults increased over time (P = .055). After the initial introduction of floating hospice, 27% of the patients received referrals; however, referrals did not significantly increase over time (P = .807). Of the 68 patients who received a floating hospice referral (24%), only 38 were discharged to floating hospice. There was a trend toward earlier palliative care consults, although this was not statistically significant (P = .285). Conclusion: This study provided the organization with vital information about their initiative to expand end-of-life resources. Utilization and timing of palliative consults and floating hospice referrals were lower and later than expected, highlighting the importance of developing purposeful strategies beyond education to address ICU cultural and structural barriers. [ABSTRACT FROM AUTHOR]

Purpose: Defined animal models are needed to pursue the FDA Animal Rule for approval of medical countermeasure for radiation injuries. This study compares WAG/RijCmcr rat and nonhuman primate (NHP) models for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). Materials and methods: Irradiation models include total body irradiation, partial body irradiation with bone marrow sparing and whole thorax lung irradiations. Organ-specific sequelae of radiation injuries were compared using dose-response relationships. Results and conclusions: Rats and NHP manifest similar organ dysfunctions after radiation, starting with acute gastrointestinal (GI-ARS) and hematopoietic (H-ARS) syndromes followed by lung, heart and kidney toxicities. Humans also manifest these sequelae. Latencies for injury were earlier in rats than in NHP. After whole thorax lung irradiations (WTLI) up to 13Gy, there was recovery of lung function from pneumonitis in rats. This has not been evaluated in NHP. The latency, incidence, severity and progression of radiation pneumonitis was not influenced by early multi-organ injury from ARS in rats or NHP. Rats developed more severe radiation nephropathy than NHP, and also progressed more rapidly. Dosimetry, anesthesia, environment, supportive care, euthanasia criteria etc., may account for the alterations in radiation sensitivity observed between species. [ABSTRACT FROM AUTHOR]

Engraftment syndrome (ES), a complication of autologous hematopoietic cell transplantation (auto-HCT), can occur around the time of neutrophil recovery. We sought to identify the incidence of ES in light chain (AL) amyloidosis patients undergoing auto-HCT at our centre by evaluating 72 consecutive amyloidosis patients transplanted between 1999 and 2017. To assess trends in ES over time, patients were divided into two Eras (Era 1 = 1999–2008 and Era 2 = 2009–2017) based on year of auto-HCT. Twenty-two (31%) patients developed ES; three (16%) and 19 (36%) in Era 1 and 2, respectively (p =.1). Three (16%) and 51 (96%) patients in Era 1 and 2 received chemotherapy before auto-HCT (p = <.001). The most common symptoms observed with ES in addition to fever was diarrhoea (73%), rash (68%), weight gain (56%) and non-cardiogenic pulmonary oedema (23%). Day 100 post-auto-HCT haematological response (19.5% vs. 14%, p =.7) or post-transplant best organ response (23% vs. 36%, p =.2) were not significantly different in patients who did not or did develop ES, respectively. In this single centre series, we define the incidence and characteristics of ES in AL amyloidosis patients undergoing auto-HCT. [ABSTRACT FROM AUTHOR]