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Objectives This study aimed to evaluate the cost-effectiveness of the randomized clinical trial STEP-KOA (STepped Exercise Program for patients with Knee OsteoArthritis). Methods The trial included 230 intervention and 115 control participants from 2 Veterans Affairs (VA) medical centers. A decision tree simulated outcomes for cohorts of patients receiving arthritis education (control) or STEP-KOA (intervention), which consisted of an internet-based exercise training program (step 1), phone counseling (step 2), and physical therapy (step 3) according to patient’s response. Intervention costs were assessed from the VA perspective. Quality of life (QOL) was measured using 5-level EQ-5D US utility weights. Incremental cost-effectiveness ratios (ICERs) were calculated as the difference in costs divided by the difference in quality-adjusted life-years (QALYs) between arms at 9 months. A Monte Carlo probabilistic sensitivity analysis was used to generate a cost-effectiveness acceptability curve. Results The adjusted model found differential improvement in QOL utility weights of 0.042 (95% confidence interval 0.003-0.080; P=.03) for STEP-KOA versus control at 9 months. In the base case, STEP-KOA resulted in an incremental gain of 0.028 QALYs and an incremental cost of $279 per patient for an ICER of $10 076. One-way sensitivity analyses found the largest sources of variation in the ICER were the impact on QOL and the need for a VA-owned tablet. The probabilistic sensitivity analysis found a 98% probability of cost-effectiveness at $50 000 willingness-to-pay per QALY. Conclusions STEP-KOA improves QOL and has a high probability of cost-effectiveness. Resources needed to implement the program will decline as ownership of mobile health devices increases.

Pathological conditions in skeletal remains, such as cribra orbitalia and porotic hyperostosis, can be caused by etiologically different forms of anemia: hereditary hemolytic anemias, iron deficiency anemias, megaloblastic anemias, etc. Though not always simple to apply, differential diagnosis of cases of anemia found in the archaeological record is essential to correlate the pathology with the wider environmental and socio-cultural context. Anthropological analysis of the skeletal sample from the archaeological site of Vetricella showed a very high prevalence of cribra orbitalia and porotic hyperostosis. The differential diagnosis between acquired and congenital anemia is essential in the study of this condition, especially considering the presence of Plasmodium falciparum in this area and its role in the possible subsequent spread of the thalassaemia gene, which was widespread until a few decades ago. Carbon and nitrogen stable isotope analysis was carried out on a large subset of the skeletal sample, including both anemic and non-anemic individuals, to investigate the nutritional patterns of the Vetricella population in order to verify whether the widespread traces of anemia might be of dietary origin. Isotope results allowed for the exclusion of the hypothesis of nutritional-deficiency anemia and supported the hypothesis of congenital anemia.

Citrus black spot (CBS) is a disease caused by the ascomycetous fungus Phyllosticta (formerly Guignardia) citricarpa (Botryosphaeriales, Pezizomycotina) currently present in citrus groves in five counties in southwest Florida. Within Florida, P. citricarpa shows limited reproduction via asexual sporulation due to the presence of only one (MAT1-2-1) of the two required mating types for sexual reproduction. Here, we present two novel PCR assays standardized in quantitative PCR (qPCR) and digital PCR (dPCR) platforms to distinguish both mating types (MAT1-1-1 and MAT1-2-1) of P. citricarpa to monitor for the potential introduction of the MAT1-1-1 mating type into Florida and a novel protocol for DNA extraction from asymptomatic leaves. During citrus harvesting season 2018 − 19, fruit lesions as well as asymptomatic leaves adjacent to symptomatic fruit and asymptomatic trees in CBS-infected groves were surveyed for P. citricarpa presence and mating types. Results support the presence of only the MAT1-2-1 mating type in Florida, after surveying more than 1,145 citrus fruit lesions. We also confirmed the limited dispersal ability of the asexual state of P. citricarpa in Florida in 10 groves using the enhanced capabilities of the dPCR platform in the detection of P. citricarpa directly from asymptomatic leaves with low pathogen inoculum. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.

Clinical and pathological heterogeneity is common in patients with frontotemporal lobar degeneration (FTLD) pathology. This investigated clinical or imaging characteristics that differentiate FTLD-TDP from FTLD-tau, FTLD-TDP subtypes from each other, or pathological stages of FTLD-TDP. Initial clinical, neuropsychological and neuroimaging characteristics were compared between pathologically defined FTLD-tau and FTLD-TDP groups. Voxel-based morphometry analyses contrasted grey matter atrophy patterns. Twenty-six FTLD-TDP, 28 FTLD-tau and 78 controls were included. Amyotrophic lateral sclerosis features, when present, were highly specific FTLD-TDP, which displayed greater cortical and subcortical atrophy than FTLD-tau. FTLD-TDP-43 type B had significantly shorter survival than type A. Type A patients were more cognitively impaired than type B, and basal ganglia atrophy appeared to distinguish type A from type B. Age at onset and survival duration were comparable between stages II and IV. In conclusion, Amyotrophic lateral sclerosis features may be useful in distinguishing FTLD-TDP from FTLD-tau. TDP-43 type A and B appear to present with distinct profiles. The relationship between clinical features and pathological staging in FTLD-TDP-43 is complex, and TDP-43 subtyping may have more clinical utility.

OBJECTIVE: To investigate the effect of restriction measures implemented to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy duration and outcome. METHODS: A before-and-after study was conducted with cohort sampling in three maternity hospitals in Melbourne, Australia, including women who were pregnant when restriction measures were in place during the COVID-19 pandemic (estimated conception date between 1 November 2019 and 29 February 2020) and women who were pregnant before the restrictions (estimated conception date between 1 November 2018 and 28 February 2019). The primary outcome was delivery before 34 weeks' gestation or stillbirth. The main secondary outcome was a composite of adverse perinatal outcomes. Pregnancy outcomes were compared between women exposed to restriction measures and unexposed controls using the χ-square test and modified Poisson regression models, and duration of pregnancy was compared between the groups using survival analysis. RESULTS: In total, 3150 women who were exposed to restriction measures during pregnancy and 3175 unexposed controls were included. Preterm birth before 34 weeks or stillbirth occurred in 95 (3.0%) exposed pregnancies and in 130 (4.1%) controls (risk ratio (RR), 0.74 (95% CI, 0.57-0.96); P = 0.021). Preterm birth before 34 weeks occurred in 2.4% of women in the exposed group and in 3.4% of women in the control group (RR, 0.71 (95% CI, 0.53-0.95); P = 0.022), without evidence of an increase in the rate of stillbirth in the exposed group (0.7% vs 0.9%; RR, 0.83 (95% CI, 0.48-1.44); P = 0.515). Competing-risks regression analysis showed that the effect of the restriction measures on spontaneous preterm birth was stronger and started earlier (subdistribution hazard ratio (HR), 0.81 (95% CI, 0.64-1.03); P = 0.087) than the effect on medically indicated preterm birth (subdistribution HR, 0.89 (95% CI, 0.70-1.12); P = 0.305). The effect was stronger in women with a previous preterm birth (RR, 0.42 (95% CI, 0.21-0.82); P = 0.008) than in parous women without a previous preterm birth (RR, 0.93 (95% CI, 0.63-1.38); P = 0.714) (P for interaction = 0.044). Composite adverse perinatal outcome was less frequent in the exposed group than in controls (all women: 2.1% vs 2.9%; RR, 0.73 (95% CI, 0.54-0.99); P = 0.042); women with a previous preterm birth: 4.5% vs 8.4%; RR, 0.54 (95% CI, 0.25-1.18); P = 0.116). CONCLUSIONS: Restriction measures implemented to mitigate SARS-CoV-2 transmission during the COVID-19 pandemic were associated with a reduced rate of preterm birth before 34 weeks. This reduction was mainly due to a lower rate of spontaneous prematurity. The effect was more substantial in women with a previous preterm birth and was not associated with an increased stillbirth rate. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND Total pancreatectomy with islet autotransplantation (TPIAT) involves pancreatectomy, splenectomy, and reinjection of the patient's pancreatic islets into the portal vein. This process triggers a local inflammatory reaction and increase in portal pressure, threatening islet survival and potentially causing portal vein thrombosis. Recent research has highlighted a high frequency of extreme thrombocytosis (platelets ≥1000 × 109/L) after TPIAT, but its cause and association with thrombotic risk remain unclear. METHODS This retrospective single-site study of a contemporary cohort of 409 pediatric and adult patients analyzed the frequency of thrombocytosis, risk factors for thrombosis, and antiplatelet and anticoagulation strategies. RESULTS Of 409 patients, 67% developed extreme thrombocytosis, peaking around postoperative day 16. Extreme thrombocytosis was significantly associated with infused islet volumes. Thromboembolic events occurred in 12.2% of patients, with portal vein thromboses occurring significantly earlier than peripheral thromboses. Portal vein thromboses were associated with infused islet volumes and portal pressures but not platelet counts or other measures. Most thromboembolic events (82.7%) occurred before the postoperative day of maximum platelet count. Only 4 of 27 (14.8%) of portal vein thromboses occurred at platelet counts ≥500 × 109/L. Perioperative heparin was given to all patients. Treatment of reactive thrombocytosis using aspirin in adults and hydroxyurea in children was not associated with significantly decreased thromboembolic risk. CONCLUSIONS These results suggest that post-TPIAT thrombocytosis and portal vein thromboses may be linked to the islet infusion inflammation, not directly to each other, and further reducing this inflammation may reduce thrombosis and thrombocytosis frequencies simultaneously.

Cancer screening is an important approach to reducing disease burden. The rate of colorectal cancer (CRC) screening among immigrants in the U.S. is very low. Our study's aim was to examine correlates of experience with, and intention to, receive CRC screening among East African men who were up-to-date (UTD) with CRC screening (n = 64, mean age 65) and those who had never been screened or were overdue for one (NOD; n = 47, mean age 60), compared on demographic characteristics, attitudes toward cancer, psychosocial stress, and health behaviors. UTD men had significantly less emotional concerns about cancer screening and experienced significantly greater distress and lower resiliency than NOD men. However, these results were attenuated after controlling for demographic confounders. Perceived risk, trust in the medical system, and PTSD symptoms were significantly associated with an intention to undertake CRC screening in the next 12 months. These results should be used to guide efforts toward increasing CRC screening rates among immigrant communities.

During the COVID-19 outbreak, the Center for Disease Control (CDC) recommended that everyone 2 years and older wear a face mask while in a community setting. However, children with autism may be reluctant to wear a mask, particularly for extended durations. In the current study, we implemented a graduated exposure procedure to teach mask wearing for a minimum of 1 hour in an early intensive behavioral (EIBI) intervention clinic to three children diagnosed with autism. We subsequently probed mask wearing, and if necessary implemented the graduated exposure procedure, in each participant’s home and in a mock physician’s office. Finally, we collected probe data on mask wearing in another community setting and 1 month post-treatment maintenance data in the EIBI clinic. During baseline, participants wore masks for 0 second to 5 minutes. After treatment, all participants wore the mask for at least 1 hour in each setting, with maintenance probes indicating 4 to 5 hour mask tolerance.

OBJECTIVENontraumatic, primary intracerebral hemorrhage (ICH) accounts for 2 million strokes worldwide annually and has a 1-year survival rate of 50%. Recent studies examining functional outcomes from ICH evacuation have been performed, but limited work has been done quantifying the incidence of subsequent complications and their healthcare economic impact. The purpose of this study was to quantify the incidence and healthcare resource utilization (HCRU) for major complications that can arise from ICH.METHODSThe IBM MarketScan Research databases were used to retrospectively identify patients with ICH from 2010 to 2015. Complications examined included cerebral edema, hydrocephalus, venous thromboembolic events (VTEs), pneumonia, urinary tract infections (UTIs), and seizures. For each complication, inpatient mortality and HCRU were assessed.RESULTSOf 25,322 adult patients included, 10,619 (42%) developed complications during the initial admission of ICH: 22% had cerebral edema, 11% hydrocephalus, 10% pneumonia, 6% UTIs, 5% seizures, and 5% VTEs. The inpatient mortality rates at 7 and 30 days for each complication of ICH ranked from highest to lowest were hydrocephalus (24% and 32%), cerebral edema (15% and 20%), pneumonia (8% and 18%), seizure (7% and 13%), VTE (4% and 11%), and UTI (4% and 8%). Hydrocephalus had the highest total cost (median $92,776, IQR $39,308–$180,716) at 7 days post–ICH diagnosis and the highest cumulative total cost (median $170,839, IQR $91,462–$330,673) at 1 year post–ICH diagnosis.CONCLUSIONSThis study characterizes one of the largest cohorts of patients with nontraumatic ICH in the US. More than 42% of the patients with ICH developed complications during initial admission, which resulted in high inpatient mortality and considerable HCRU.

BACKGROUND AND OBJECTIVES The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection. METHODS Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT). RESULTS Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p

Environmental enteric dysfunction (EED) is a syndrome characterized by impairments of digestion and absorption and intestinal barrier failure in people living in insanitary or tropical environments. There is substantial evidence that it contributes to impaired linear growth of millions of children in low- and middle-income countries, to slowed neurocognitive development, and to diminished responses to oral vaccines. It represents the functional consequences of environmental enteropathy, an asymptomatic inflammatory disorder of the mucosa, and there is considerable overlap with the enteropathy observed in severe clinical malnutrition. The majority of studies of EED have employed functional tests based on lactulose permeation to define the presence of abnormal leak in the gut. However, where intestinal biopsies can safely be collected the opportunity then arises to study the underlying enteropathy in cellular and molecular detail, as well as to measure important functional elements such as enzyme expression. The purpose of this narrative review is to summarize the current understanding of environmental enteropathy obtained from small intestinal biopsies, and prospects for future work. We review histology, electron microscopy, transcription and protein expression, physiological measures, and the microbiome. We conclude that while noninvasive biomarkers of enteropathy and intestinal dysfunction permit large-scale studies of unquestionable value, intestinal biopsies are still required to investigate pathophysiology in depth.

OBJECTIVE Gastrointestinal bleeding (GIB) is an uncommon complication after abdominal surgery. Given the unique risks in the total pancreatectomy with islet autotransplant (TPIAT) population, we aimed to describe this population's incidence of postoperative GIB. METHODS Prospectively collected data on patients who underwent a TPIAT from 2001 to 2018 at the University of Minnesota were reviewed for postoperative GIB. Each GIB patient was matched to a control patient and compared for medical, medication, and social history and for clinical outcomes. RESULTS Sixty-eight patients developed a GIB (12.4%) at median time after surgery of 17 months. Etiologies included the following: anastomotic ulcer (35%), Clostridium difficile (4%), gastric or duodenal ulcers (9%), esophagitis/gastritis (10%), hemorrhoids (3%), inflammatory bowel disease (4%), Mallory-Weiss tears (1%), and unknown (29%). During diagnostic workup, 87% had an endoscopic procedure and 3% underwent imaging. Seven patients required an operation (10%), 1 required an open embolization (1%), and 13 required endoscopic treatments (19%). Patients with a GIB were more likely to die (15% vs 5%, P = 0.055). CONCLUSIONS Twelve percent of patients developed a GIB after TPIAT. One third of those had an undefined etiology despite endoscopy. The need for intervention was high (30%).

Summary Background Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care. Methods We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation). Findings Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (–0·68% change in incidence per week [95% CI −1·37 to −0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care. Interpretation Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models. Funding None.

Objective The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS‐FTD. Methods In a prospective case‐controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS‐Plus), ALS‐FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel‐based morphometry analyses determined atrophy patterns in patients experiencing psychosis‐like experiences and other perceptual abnormalities. Results The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS‐FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer‐based reports (18%) and self‐report measures of psychotic‐like experiences (21%). In an ENTER regression model, social anxiety and ACE‐III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis‐like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus. Interpretation The model for psychosis proneness in ALS‐FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.

Silicone is widely used in chronic implants and is generally perceived to be safe. However, textured breast implants have been associated with immune-related complications, including malignancies. Here, by examining for up to one year the foreign body response and capsular fibrosis triggered by miniaturized or full-scale clinically approved breast implants with different surface topography (average roughness, 0–90 μm) placed in the mammary fat pads of mice or rabbits, respectively, we show that surface topography mediates immune responses to the implants. We also show that the surface surrounding human breast implants collected during revision surgeries also differentially alters the individual’s immune responses to the implant. Moreover, miniaturized implants with an average roughness of 4 μm can largely suppress the foreign body response and fibrosis (but not in T-cell-deficient mice), and that tissue surrounding these implants displayed higher levels of immunosuppressive FOXP3+ regulatory T cells. Our findings suggest that, amongst the topographies investigated, implants with an average roughness of 4 μm provoke the least amount of inflammation and foreign body response. The surface topography of breast implants mediates the immune responses to them, and implants with an average roughness of 4 μm largely suppress foreign body response and fibrosis.

INTRODUCTION/AIMS Clinical trials addressing treatments for Duchenne muscular dystrophy (DMD) require reliable and valid measurement of muscle contractile function across all disease severity levels. In this work we aimed to evaluate a protocol combining voluntary and evoked contractions to measure strength and excitability of wrist extensor muscles for safety, feasibility, reliability, and discriminant validity between males with DMD and controls. METHODS Wrist extensor muscle strength and excitability were assessed in males with DMD (N = 10; mean ± standard deviation: 15.4 ± 5.9 years of age), using the Brooke Upper Extremity Rating Scale (scored 1-6), and age-matched healthy male controls (N = 15; 15.5 ± 5.0 years of age). Torque and electromyographic (EMG) measurements were analyzed under maximum voluntary and stimulated conditions at two visits. RESULTS A protocol of multiple maximal voluntary contractions (MVCs) and evoked twitch contractions was feasible and safe, with 96% of the participants completing the protocol and having a less than 7% strength decrement on either measure for both DMD patients and controls (P ≥ .074). Reliability was excellent for voluntary and evoked measurements of torque and EMG (intraclass correlation coefficient [ICC] over 0.90 and over 0.85 within and between visits, respectively). Torque, EMG, and timing of twitch-onset measurements discriminated between DMD and controls (P

Objective To evaluate the rate of subtalar arthrodesis based on a computed tomography (CT) scan after open reduction and primary subtalar arthrodesis for acute, displaced, intra-articular calcaneal fractures. Design Retrospective chart review. Setting Single tertiary care practice. Patients A retrospective chart review was performed to identify patients who sustained an acute, displaced, intra-articular calcaneal fracture and underwent open reduction and primary subtalar arthrodesis. Thirty-five patients participated in the study. Intervention Each patient included in the study was treated with open reduction and primary subtalar arthrodesis. Main outcome measures All patients were evaluated with CT for arthrodesis of the posterior facet of the subtalar joint, which was quantitated. Other outcome measures included radiographic parameters, the Veterans RAND Item Health Survey, and the Foot and Ankle Ability Measure. Results The median patient age was 47.8 years (range 21.5-79.5 years). The median patient follow-up was 34.4 months (range 4.6-104.1 months). The Sanders classification was as follows: 3% (1/35) type II, 40% (14/35) type III, and 57% (20/35) type IV. Based on a CT scan, primary subtalar union occurred in 94.3% (33/35) of patients. Conclusions Open reduction and primary subtalar arthrodesis for acute, displaced, intra-articular calcaneus fractures has a high rate of union and good pain and function outcomes. It should be strongly considered for patients with significant cartilage injury and comminution of the posterior facet. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Primary progressive aphasia (PPA) is characterised by predominant language and communication impairment. However, behavioural changes, such as apathy, are increasingly recognised. Apathy is defined as a reduction in motivation and goal-directed behaviour. Recent theoretical models have suggested that apathy can be delineated into multiple dimensions: executive apathy (i.e., deficits in maintaining goals and organisation), emotional apathy (i.e., emotional blunting and indifference) and initiation apathy (i.e., reduced self-initiation). Whether the nature of apathy differs between clinical variants of PPA, and across early and late disease stages, remains to be established. Here, carers/informants of 20 semantic variant PPA (svPPA), 15 non-fluent variant PPA (nfvPPA), 16 logopenic variant PPA (lvPPA) and 25 healthy older controls completed the Dimensional Apathy Scale to quantify executive, emotional and initiation apathy. Voxel-based morphometry was used to identify associations between dimensions of apathy and regions of grey matter intensity decrease. Our behavioural results showed greater executive and initiation apathy in late svPPA than in late nfvPPA patients, while late svPPA had greater emotional apathy than both late nfvPPA and late lvPPA groups. Executive and initiation apathy were significantly higher than premorbid levels in all PPA subtypes, while elevated emotional apathy was only seen in early and late svPPA. Distinct neural correlates were identified across apathy dimensions. Executive apathy correlated with grey matter intensity of the left dorsolateral prefrontal and inferior parietal cortices; emotional apathy with the left medial prefrontal, insular and cerebellar regions; and initiation apathy with right parietal areas. Our findings are the first to reveal evidence of the dimensional nature of apathy in PPA, with different clinical signatures observed for each subtype. From a clinical standpoint, these results will inform the development of targeted interventions for specific aspects of apathy which emerge in PPA.

Cell nuclear architecture has been explored in cancer and laminopathies but not in neurodegenerative disorders. Huntington’s disease (HD) is a neurodegenerative disorder that leads to neuronal death. Chromosome-wide changes in gene expression have been reported in HD, not only in the brain but also in peripheral blood cells, but whether this translates into nuclear and chromosome architecture alterations has not yet been studied. We investigate nuclear structure and chromosome organization in HD blood cells using fluorescence in situ hybridization in ultrathin cryosections (cryoFISH), coupled with machine learning image analysis to evaluate size, distribution, and morphology of nuclei and chromosomes. Four chromosomes were analyzed based on up- or downregulation of gene expression in HD. We show that blood cells from HD patients display increased nuclear size and filamentary shape, increased size of gene-rich chromosome 19, decreased filamentary shape of gene-rich chromosome 22, and a more radially centralized position for chromosome 19, whereas chromosomes 4 and 5 do not show detectable differences. We identify gross changes in nuclear architecture and chromosome organization associated with HD in blood. This adds a new layer of information onto disrupting mechanisms in HD and increases the potential of using blood to survey HD.

Leveraging recent advances in automated language analysis and anovel statistical approach utilizing an independent control group, we explored changes in lexical output across two published works of a man diagnosed with semantic dementia. We found significant increase in adverb usage and decline in familiarity, meaningfulness, age of acquisition and co-occurrence probability over 2 years. Collectively, these indices suggest that WR's narrative structure became progressively simpler, lexically less sophisticated, and that words commonly associated together no longer appeared in close proximity. Our study illustrates how degeneration of the semantic knowledge base impacts the production, content, and quality of literary works.

This study tested whether the longitudinal effects of mothers' and fathers' corporal punishment on children's aggression would vary depending on the context of the parent-child relationship (gender of the parent-child dyad, other parenting practices).Participants were 325 children (MWe found that the effects of both mothers' and fathers' corporal punishment on changes in children's aggressive behavior were conditional. In contexts that were characterized by a lack of parental warmth or overuse of behavioral control, corporal punishment was associated with increases in aggression; in parent-child relationships with high levels of parental affection or low levels of behavioral control, it was unrelated to, or associated with, decreases in aggression. Some of these conditional effects were specific to the gender of the parent and the child.Our findings suggest that we should try to better understand the complexities of different parent-child relationships that magnify vs. minimize the negative consequences of corporal punishment.

Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.

Background: Hematogenous osteomyelitis is commonly observed in the pediatric population across sub-Saharan Africa. This retrospective case series was designed to evaluate the complications and outcomes of treatment using a vascularized fibula flap (VFF) to fill segmental bone defects secondary to osteomyelitis in children in a low-resource setting in CoRSU Rehabilitation Hospital, Uganda. Methods: Clinical notes and radiographs of children with a diagnosis of osteomyelitis that subsequently underwent a VFF procedure between October 2013 and December 2017 were reviewed. All patients were clinically and radiographically evaluated in 2019. Results: Forty-four children, with an average bone defect of 10.5 cm, were included. Eighty-four percent of children had successful VFF limb reconstruction. Integration of the graft was radiologically sound in 20.8 weeks on average. The postoperative phase was uneventful in 29 % of patients. Complications were observed in the remaining patients, including flap failure (6), donor leg neurapraxia (3), cutaneous paddle necrosis (11), graft fracture (2), skin graft loss (6), fixator failure (1) and non-union (2). Functional outcomes were rated as excellent in 13 patients, good in 14, fair in 9 and poor in 8. There was no recurrence of the bone infection in any of the enrolled children. Conclusion: Despite being a complex and demanding procedure, VFF is a good option for reconstructing post-osteomyelitis bone defects, particularly when associated with loss of soft tissue envelope. Considering the more than satisfactory functional and clinical outcomes, this procedure should be kept in mind for these complex pediatric cases of bone and soft tissue loss, even in a low-resource setting.

BACKGROUND CONTEXT Effective alternatives to lumbar fusion for degenerative conditions have remained elusive. Anterior total disc replacement does not address facet pathology or central/recess stenosis, resulting in limited indications. A posterior-based motion-preserving option that allows for neural decompression, facetectomy, and reconstruction of the disc and facets may have a role. PURPOSE The purpose was to compare one-year patient-reported outcomes for a novel, all-posterior, lumbar total joint replacement (LTJR - replacing both the disc and facet joints) against transforaminal lumbar interbody fusion (TLIF) for degenerative lumbar conditions warranting fusion (degenerative spondylolisthesis, recurrent disc herniation, severe foraminal stenosis requiring facet removal, and adjacent segment degeneration). STUDY DESIGN/SETTING A retrospective analysis of prospectively collected data comparing outcomes for LTJR patients to TLIF patients at an academic teaching hospital. PATIENT SAMPLE Analysis was conducted on 156 adult TLIF patients who were propensity matched to the 52 LTJR patients for a total sample of 208. OUTCOME MEASURES Self-reported Oswestry Disability Index (ODI) and Numeric Rating Scale (NRS) for back and leg pain were compared preoperatively, 3 months and 1 year after surgery. METHODS The implant is a motion-preserving lumbar reconstruction that replaces the function of both the disc and facets and is implanted using a bilateral transforaminal approach with complete facetectomies. Adult patients with degenerative lumbar pathology undergoing either LTJR or open TLIF were analyzed. These degenerative conditions included: grade 1 degenerative spondylolisthesis, recurrent disc herniation, adjacent segment disease, disc degeneration with severe foraminal stenosis). Trauma, tumor, grade 2 or higher spondylolisthesis, spinal deformity, and infection cases were excluded. Propensity score matching was performed to ensure parity between the cohorts. Multivariable regression analyses were done to compare the 1-year results as measured by 3 different standards to assess procedure success. RESULTS At 3 months, both the LTJR and TLIF cohorts showed significant and similar improvements in ODI and NRS back and leg pain. At 1 year, the LTJR cohort showed continued improvement in ODI and NRS back pain, while the TLIF group showed a plateau for ODI, back and leg pain. In a series of three multivariable logistic regressions, LTJR was shown to provide 3.3 times greater odds of achieving the minimal clinical symptom state in disability and pain (ODI

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and aldehyde dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxicity of endogenous aldehydes. We show DNA hypermethylation and silencing of ALDH2 occur in a recurrent manner in human AML, which is sufficient to confer FA pathway dependency. Our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML. Significance: Aberrant gene silencing is an epigenetic hallmark of human cancer, but the functional consequences of this process are largely unknown. In this study, we show how an epigenetic alteration leads to an actionable dependency on a DNA repair pathway through the disabling of genetic redundancy. This article is highlighted in the In This Issue feature, p. 2113

BACKGROUND Traumatic spinal cord injury (SCI) is a serious public health problem. Outcomes are determined by severity of immediate injury, mitigation of secondary downstream effects, and rehabilitation. This study aimed to understand how the center type a patient presents to and whether they are transferred influence management and outcome. METHODS The National Trauma Data Bank was used to identify patients with SCI. The primary objective was to determine association between center type, transfer, and surgical intervention. A secondary objective was to determine association between center type, transfer, and surgical timing. Multivariable logistic regression models were fit on surgical intervention and timing of the surgery as binary variables, adjusting for relevant clinical and demographic variables. RESULTS There were 11,744 incidents of SCI identified. A total of 2,883 patients were transferred to a Level I center and 4,766 presented directly to a level I center. Level I center refers to level I trauma center. Those who were admitted directly to level I centers had a higher odd of receiving a surgery (odds ratio, 1.703; 95% confidence interval, 1.47-1.97; p < 0.001), but there was no significant difference in terms of timing of surgery. Patients transferred into a level I center were also more likely to undergo surgery than those at a level II/III/IV center, although this was not significant (odds ratio, 1.213; 95% confidence interval, 0.099-1.48; p = 0.059). CONCLUSION Patients with traumatic SCI admitted to level I trauma centers were more likely to have surgery, particularly if they were directly admitted to a level I center. This study provides insights into a large US sample and sheds light on opportunities for improving pre hospital care pathways for patients with traumatic SCI, to provide the timely and appropriate care and achieve the best possible outcomes. LEVEL OF EVIDENCE Care management, Level IV.

Objective: Ischemic heart disease accounts for over 20% of all deaths worldwide. As the global population faces a rising burden of chronic diseases, such as hypertension, hyperlipidemia, and diabetes, the prevalence of heart failure due to ischemic heart disease is estimated to increase. We sought to develop a model that may more accurately identify therapeutic targets to mitigate the development of heart failure following myocardial infarction (MI). Approach: Having utilized fetal large mammalian models of scarless wound healing, we proposed a fetal ovine model of myocardial regeneration after MI. Results: Use of this model has identified critical pathways in the mammalian response to MI, which are differentially activated in the regenerative, fetal mammalian response to MI when compared to the reparative, scar-forming, adult mammalian response to MI. Innovation: While the foundation of myocardial regeneration research has been built on zebrafish and rodent models, effective therapies derived from these disease models have been lacking; therefore, we sought to develop a more representative ovine model of myocardial regeneration after MI to improve the identification of therapeutic targets designed to mitigate the development of heart failure following MI. Conclusions: To develop therapies aimed at mitigating this rising burden of disease, it is critical that the animal models we utilize closely reflect the physiology and pathology we observe in human disease. We encourage use of this ovine large mammalian model to facilitate identification of therapies designed to mitigate the growing burden of heart failure.

There is evidence that diffusion-weighted imaging (DWI) is able to detect tissue alterations following mild traumatic brain injury (mTBI) that may not be observed on conventional neuroimaging; however, findings are often inconsistent between studies. This systematic review assesses patterns of differences in DWI metrics between those with and without a history of mTBI. A PubMed literature search was performed using relevant indexing terms for articles published prior to May 14, 2020. Findings were limited to human studies using DWI in mTBI. Articles were excluded if they were not full-length, did not contain original data, if they were case studies, pertained to military populations, had inadequate injury severity classification, or did not report post-injury interval. Findings were reported independently for four subgroups: acute/subacute pediatric mTBI, acute/subacute adult mTBI, chronic adult mTBI, and sport-related concussion, and all DWI acquisition and analysis methods used were included. Patterns of findings between studies were reported, along with strengths and weaknesses of the current state of the literature. Although heterogeneity of sample characteristics and study methods limited the consistency of findings, alterations in DWI metrics were most commonly reported in the corpus callosum, corona radiata, internal capsule, and long association pathways. Many acute/subacute pediatric studies reported higher FA and lower ADC or MD in various regions. In contrast, acute/subacute adult studies most commonly indicate lower FA within the context of higher MD and RD. In the chronic phase of recovery, FA may remain low, possibly indicating overall demyelination or Wallerian degeneration over time. Longitudinal studies, though limited, generally indicate at least a partial normalization of DWI metrics over time, which is often associated with functional improvement. We conclude that DWI is able to detect structural mTBI-related abnormalities that may persist over time, although future DWI research will benefit from larger samples, improved data analysis methods, standardized reporting, and increasing transparency.

Extratropical cyclones are a relevant feature in the climate at middle and high latitudes. Despite their relevance, most of studies typically focus on cyclones identified at a single atmospheric level and on events close to the surface. This paper provides a new perspective on the Southern Hemisphere cyclone events based on the multilevel cyclone tracking algorithm STACKER. The algorithm, using relative vorticity, detects the raw tracks at single levels and objectively combine them to provide the 3D events and their evolutionary timeline. As result, 3D cyclone climatology, based on ECMWF Reanalysis ERA-I data from 12 pressure levels in the troposphere and lowermost stratosphere is presented. To the best of our knowledge this is the first analysis carried out throughout the troposphere and the lowermost extratropical/subpolar stratosphere in order to give a comprehensive picture of the cyclone events as physical entities throughout their lifetime. Cyclone properties analysed are track densities, translational velocity, vorticity and lifetimes. For the subtropical and extrattropical SH, results support many previous ideas about cyclone characteristics, but new insights are also obtained. A total of 58231 multilevel cyclone events lasting at least 2 days were detected, with vertical structures spanning two or more levels. This means an average of 303 cyclone events of all types per month, between 2001 and 2017, disregarding seasonality. Results shows that the lowermost level of cyclones are most frequently detected at 925 and 700 hPa, Considering that cyclonic systems can be grouped into families, results per month on average, show that shallow systems are the most frequent events with approximately 248 systems detected, followed by 43 intermediates and 11 deep events. Shallow and deep systems have a large percentage of events with genesis at 925 and 700hPa. Density statistics show that shallow events are present at all latitude ranges mostly poleward 30oS with high and medium intensities, while intermediate ones are mostly restricted to mid-latitudes and deep events are mostly confined to sub-polar and polar latitudes. Cyclones over Antarctica seems to be mostly intermediates and deeps, with longer lifetimes and lower velocities.

Background Evidence-based models are needed to deliver exercise-related services for knee osteoarthritis efficiently and according to patient needs. Objective To examine a stepped exercise program for patients with knee osteoarthritis (STEP-KOA). Design Randomized controlled trial. (ClinicalTrials.gov: NCT02653768). Setting 2 U.S. Department of Veterans Affairs sites. Participants 345 patients (mean age, 60 years; 15% female; 67% people of color) with symptomatic knee osteoarthritis. Intervention Participants were randomly assigned in a 2:1 ratio to STEP-KOA or an arthritis education (AE) control group, respectively. The STEP-KOA intervention began with 3 months of an internet-based exercise program (step 1). Participants who did not meet response criteria for improvement in pain and function after step 1 progressed to step 2, which involved 3 months of biweekly physical activity coaching calls. Participants who did not meet response criteria after step 2 went on to in-person physical therapy visits (step 3). The AE group received educational materials via mail every 2 weeks. Measurements Primary outcome was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Scores for the STEP-KOA and AE groups at 9 months were compared by using linear mixed models. Results In the STEP-KOA group, 65% of participants (150 of 230) progressed to step 2 and 35% (81 of 230) to step 3. The estimated baseline WOMAC score for the full sample was 47.5 (95% CI, 45.7 to 49.2). At 9-month follow-up, the estimated mean WOMAC score was 6.8 points (CI, -10.5 to -3.2 points) lower in the STEP-KOA than the AE group, indicating greater improvement. Limitation Participants were mostly male veterans, and follow-up was limited. Conclusion Veterans in STEP-KOA reported modest improvements in knee osteoarthritis symptoms compared with the control group. The STEP-KOA strategy may be efficient for delivering exercise therapies for knee osteoarthritis. Primary funding source Department of Veterans Affairs, Health Services Research and Development Service.

Background Sudden cardiac death remains a leading cause of mortality in Canada, resulting in more than 35,000 deaths annually. Most cardiac arrest victims collapse in their own home (85% of the time) and 50% are witnessed by a family member or bystander. Survivors have a quality of life similar to the general population, but the overall survival rate for out-of-hospital cardiac arrest (OHCA) rarely exceeds 8%. Victims are almost four times more likely to survive when receiving bystander CPR, but bystander CPR rates have remained low in Canada over the past decade, not exceeding 15–25% until recently. Telecommunication-assisted CPR instructions have been shown to significantly increase bystander CPR rates, but agonal breathing may be misinterpreted as a sign of life by 9–1-1 callers and telecommunicators, and is responsible for as much as 50% of missed OHCA diagnoses. We sought to improve the ability and speed with which ambulance telecommunicators can recognize OHCA over the phone, initiate timely CPR instructions, and improve survival. Methods In this multi-center national study, we will implement and evaluate an educational program developed for ambulance telecommunicators using a multiple baseline interrupted time-series design. We will compare outcomes 12 months before and after the implementation of a 20-min theory-based educational video addressing barriers to recognition of OHCA while in the presence of agonal breathing. Participating Canadian sites demonstrated prior ability to collect standardized data on OHCA. Data will be collected from eligible 9–1-1 recordings, paramedic documentation and hospital medical records. Eligible cases will include suspected or confirmed OHCA of presumed cardiac origin in patients of any age with attempted resuscitation. Discussion The ability of telecommunication-assisted CPR instructions to improve bystander CPR and survival rates for OHCA victims is undeniable. The ability of telecommunicators to recognize OHCA over the phone is unequivocally impeded by relative lack of training on agonal breathing, and reluctance to initiate CPR instructions when in doubt. Our pilot data suggests the potential impact of this project will be to increase absolute OHCA recognition and bystander CPR rates by at least 10%, and absolute out-of-hospital cardiac arrest survival by 5% or more. Trial registration Prospectively registered on March 28, 2019 at ClinicalTrials.gov identifier: NCT03894059.

Objective Enhanced recovery after surgery (ERAS) with a pre-emptive pain management program has been shown to decrease opioid prescriptions after thoracic surgery. We sought to determine which patient or procedural factors were associated with the need for prescription opioid medications after thoracic surgical procedures. Methods We performed a retrospective analysis of a postoperative pain survey at the time of follow-up in combination with procedural and patient characteristic data. We then performed univariate and multivariate logistic regression to determine factors associated with prescription opioids use. Results Two hundred twenty-eight patients completed questionnaires at a median of 37 days after surgery. Most patients received minimally invasive surgery (n = 213, 93%) with the 2 most common types of operations being foregut (n = 92, 40%) and pulmonary resection (n = 80, 35%). Thirty-nine percent of patients (n = 89) were taking chronic pain medications preoperatively, with 15% on chronic opioids medication (n = 33). After surgery, 166 patients (72%) did not take opioids at home. Multivariate analysis showed any chronic opioid medications before surgery (odds ratio, 28.8; 95% confidence interval, 9.13-90.8, P Conclusions ERAS with pre-emptive pain management was associated with patients avoiding opioid prescriptions during recovery. The patient factor of preoperative opioid pain medication(s) and younger age is a significant factor for the patient needing opioids at home after surgery instead of procedural factors. Patient characteristics should be considered when tailoring the patient's pain management after thoracic surgical procedures.

Limited interventions exist that support student’s school participation. This paper describes a theoretical model of school participation and the iterative process that led to the development of an intervention that aims to improve the school participation of students on the autism spectrum and their typically developing peers. Literature on autism, school participation and intervention research were integrated to develop a theoretical model. Focus groups, a Delphi study, online surveys, and reference group consultation helped to develop and refine the intervention. A novel school-based intervention was developed. The impetus to develop interventions with a strong theoretical rationale is discussed.

Supplemental Digital Content is available in the text., OBJECTIVES: To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN: Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING: The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS: We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS: We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS: Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

To comprehensively examine the clinical presentation of patients diagnosed with frontotemporal dementia–motor neuron disease (FTD–MND) compared to FTD subtypes. To clarify the heterogeneity of behavioural and language deficits in FTD–MND using a data-driven approach. Patients with FTD–MND (n = 31), behavioural variant FTD (n = 119), non-fluent variant primary progressive aphasia (n = 47), semantic variant primary progressive aphasia (n = 42), and controls (n = 127) underwent comprehensive clinical, cognitive and behavioural assessments. Two-step cluster analysis examined patterns of behavioural and language impairment. Voxel-based morphometry and tract-based spatial statistics were used to investigate differences across the subgroups that emerged from cluster analysis. More than half of FTD–MND patients initially presented with variable combinations of deficits (e.g., mixed behaviour/cognitive, mixed behaviour/cognitive/motor deficits), with 74% of them meeting criteria for FTD–MND within 24 months with a median of 12 months. The frequency and severity of behavioural and language abnormalities in FTD–MND lie between that seen in the three FTD phenotypes. Cluster analysis identified three patterns of behavioural and language impairment in FTD–MND. The three FTD–MND subgroups demonstrated different profiles of white matter tract disruption, but did not differ in age at onset, disease duration or patterns of cortical atrophy. While highly heterogeneous, in terms of behavioural and language deficits, and disease severity, the presentation of FTD–MND may be distinct to that of FTD. Distinct white matter degeneration patterns may underpin heterogeneous clinical profiles in FTD–MND. FTD presenting with mixed behavioural-language disturbances should be monitored closely for at least 12–24 months for the emergence of MND symptoms/signs.

Background Superior mesenteric artery aneurysms (SMAAs) are a rare clinical problem that can be associated with significant morbidity and mortality. The optimal surgical approach for both mycotic and degenerative SMAAs remains poorly defined. The study was designed to review our institutional experience and develop a treatment algorithm. Methods A single-institution, retrospective review was performed to document presentation, treatment, and outcomes of patients undergoing surgical repair of SMAAs from 2003 to 2020. The primary end-point was 30-day mortality, and secondary end-points included complications, patency, freedom from reinfection, freedom from reintervention, and survival. Results Eighteen patients (mean age: 46 ± 16 yrs; 50% male; mean diameter 2.4 ± 2.0 cm) underwent treatment of mycotic (50%) or degenerative (50%) SMAAs. Abdominal pain (66%) was the most common presenting symptom, and the diagnosis was confirmed with CT arteriography. Endocarditis secondary to intravenous drug abuse was responsible for most (88%) of the mycotic SMAAs, with a majority (66%) having positive cultures and Streptococcus being the most common organism. The majority (61%) of patients underwent urgent or emergent repair with aneurysmectomy and interposition saphenous vein bypass being the most common treatment of mycotic SMAAs while aneurysmectomy and prosthetic bypass were used most frequently for degenerative aneurysms. The operative mortality rate was 6% with a major complication rate of 17% (n = 3 patients: respiratory failure/reintubation-1, pulmonary embolism-1, necrotizing pancreatitis/graft disruption and death-1). The single death occurred in a patient with a degenerative aneurysm that developed postoperative pancreatitis and multiple organ dysfunction. The mean clinical follow-up time was 25 ± 48 (95% CI 1–48) months. The estimated primary patency, freedom from reinfection, and freedom from reintervention were 93 ± 7 %, 94 ± 5%, and 94 ± 5%, respectively, at 1 year. The overall mean survival was 55 ± 51 (95% CI 30–80) months with an estimated survival at 3 years of 77 ± 10%. Conclusions SMAAs associated with both degenerative and mycotic etiologies can be treated using a variety of surgical approaches with acceptable morbidity and mortality. Mycotic SMAAs should likely be repaired, regardless of size, while the indications for asymptomatic, degenerative aneurysms remain to be defined by further natural history studies.

Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (

Retrograde false lumen (FL) perfusion after thoracic endovascular aortic repair (TEVAR) for chronic dissection is a mode of treatment failure. Thrombosis of the FL is associated with favorable reverse remodeling. Objectives are to describe FL embolization (FLE) strategy and assess aortic remodeling and survival.From January 2009 to December 2017, 51 patients with chronic dissection underwent FLE, most after previous TEVAR. Devices included a combination of iliac plug (29 patients), coils (19 patients), or nitinol plug (3 patients). Computed tomography was performed before discharge, at 3 months, and annually (median follow-up 2 years [range, 1 month to 7 years]).After FLE, mean maximum aortic diameter decreased (64.2 ± 12 mm to 61.0 ± 13 mm; P = .03), true lumen diameter increased (24.7 ± 10 mm to 33.7 ± 8 mm; P.001), and FL diameter decreased (36.7 ± 12 mm to 25.6 ± 15 mm, P.001). For reverse remodeling, FL thrombosis with ≥10% decrease in diameter and ≥10% increase in true lumen diameter was achieved in 20 (39.2%; 16 primarily, 4 secondarily). Nine patients progressed after the first FLE: persistent FL flow with increase in aortic diameter and underwent repeat FLE with complete thrombosis (n = 4) or open thoracoabdominal completion (n = 5). A total of 26 patients had indeterminate response (FL thrombosis without change in maximum diameter), and none have required reoperation. Six patients had complete obliteration of the entire FL. At last follow-up, 42 (82%) patients were alive. Three deaths were related to aortic pathology.FLE is an important endovascular adjunct to TEVAR promoting reverse aortic remodeling in select patients with chronic aortic dissection and persistent retrograde FL perfusion.

The variants of primary progressive aphasia (PPA) are predominantly diagnosed on the basis of specific profiles of language impairments. Deficits in other cognitive domains and their evolution over time are less well documented. This study examined the cognitive profiles of the PPA variants over time and determined the contribution of cognition on functional capacity. Longitudinal performance on the Addenbrooke’s Cognitive Examination-III (ACE-III) total and cognitive subdomains were investigated in 147 PPA individuals (41 logopenic [lv-PPA], 44 non-fluent [nfv-PPA], and 62 semantic variants [sv-PPA]). The relative contribution of ACE-III subdomain scores to overall functional capacity over time was identified using mixed and hierarchical regression modelling. The annual rate of global ACE-III decline was twice that in lv-PPA than in nfv-PPA and sv-PPA, despite lv-PPA performing intermediate to the other variants at baseline assessment. Notably, attention and visuospatial subdomains declined faster in lv-PPA than in nfv-PPA and sv-PPA; and memory impairment was more severe in lv-PPA than in nfv-PPA at all time points. Functional decline was comparable across PPA variants; however, the contribution of cognition on functional capacity varied across variants and over time. The cognitive profiles of the PPA variants are distinct at baseline and over time. Crucially, cognitive decline in lv-PPA was more widespread and pervasive than in nfv-PPA and sv-PPA. Our findings also demonstrate the complex interplay between cognition and functional capacity. This study underscores the importance of routinely assessing cognition and functional capacity in PPA to improve diagnostic accuracy and provide targeted support services.

BACKGROUND AND AIMS: Many patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for severe, refractory chronic pancreatitis or recurrent acute pancreatitis have a history of endoscopic retrograde cholangiopancreatography (ERCP). Using data from the multicenter POST (Prospective Observational Study of TPIAT) cohort, we aimed to determine clinical characteristics associated with ERCP and the effect of ERCP on islet yield. METHODS: Using data from 230 participants (11 centers), demographics, pancreatitis history, and imaging features were tested for association with ERCP procedures. Logistic and linear regression were used to assess association of islet yield measures with having any pre-operative ERCPs and with the number of ERCPs, adjusting for confounders. RESULTS: 175 (76%) underwent ERCPs [median number of ERCPs (IQR) 2 (1–4)]. ERCP was more common in those with obstructed pancreatic duct (p=0.0009), pancreas divisum (p=0.0009), prior pancreatic surgery (p=0.005), and longer disease duration (p=0.004). A greater number of ERCPs was associated with disease duration (p

Aims: The study was conducted to assess prevalence of malaria pre- and post-distribution of insecticide treated nets (ITNs) in Potiskum Local Government Area, Yobe State, Nigeria. Study Design: Retrospective and cross-sectional. Place of Study: Potiskum Local Government Area, Yobe State, Nigeria. Materials and Methods: Prevalence of malaria infection in ten political wards pre-distribution of ITNs was investigated using secondary data sources from Roll Back Malaria and Integrated Disease Surveillance and Response offices. Thin and thick blood smears used to evaluate malaria prevalence post-distribution of ITNs were prepared from blood samples of 520 patients seeking medical attention from the General Hospital, Potiskum. Questionnaires were also handed out to the same set of patients. Results: Prevalence of malaria infection pre- and post-distribution of ITNs in the study area was 57.9% and 22.9% respectively. Respondents to the questionnaire (n = 216) had mosquito nets, of whom 85% owned long-lasting ITNs and the remaining, conventional nets, but 35% used ITNs in their homes and 63% of those owning ITNs received them free-of-charge from local health centers. Conclusion: If the impact of ITNs as an effective malaria vector control measure must be sustained, there should be a corresponding awareness program, which should be aimed at encouraging proper and constant use of ITNs.

Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case-control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36-0.89], 0.56 [0.36-0.87], and 0.77 [0.43-1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41-0.89], 0.60 [0.43-0.84], and 0.49 [0.24-0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.

Changes in social behavior are recognized as potential symptoms of behavioral-variant frontotemporal dementia (bvFTD) and semantic dementia (SD), yet objective ways to assess these behaviors in natural social situations are lacking. This study takes a truly social (or second-person) approach and examines changes in real-world social behavior in different dementia syndromes, by analyzing non-scripted social interactions in bvFTD patients (n = 20) and SD patients (n = 20), compared to patients with Alzheimer's disease (AD) (n = 20). Video recordings of 10-min conversations between patients and behavioral neurologists were analyzed for the presence of socially engaging (e.g., nodding, smiling, gesturing) and disengaging behavior (e.g., avoiding eye contact, self-grooming, interrupting). Results demonstrated disease-specific profiles, with bvFTD patients showing less nodding and more looking away than AD, and SD patients showing more gesturing than AD. A principal components analysis revealed the presence of four unobserved components, showing atypical disengaging patterns of behavior. Whole-brain voxel-based morphometry analyses revealed distinct neurobiological bases for each of these components, with the brain regions identified previously associated with behavior selection, abstract mentalization and processing of multi-sensory and socially-relevant information, in mediating socially engaging and disengaging behavior. This study demonstrates the utility of systematic behavioral observation of social interactions in the differential diagnosis of dementia.

Summary Objective Guidelines recommend exercise as a core treatment for knee osteoarthritis. However, it is unclear how exercise affects measures of pain processing and motor function. The aim was to evaluate the effect of exercise on measures of pain processing and motor function in people with knee osteoarthritis. Methods We searched five electronic databases (MEDLINE, EMBASE, CINAHL, SCOPUS and Cochrane Central Register of Controlled Trials) for studies on knee osteoarthritis, of any design, evaluating pain processing and motor function before and after exercise. Data were pooled with random-effects meta-analysis. Study quality was assessed using the Downs and Black and quality of evidence was assessed using the GRADE. Results Eighteen studies were eligible and 16 were included. Following acute exercise, pressure pain threshold increased local to the study limb (standardised mean difference [95% confidence interval (CI)] 0.26, [0.02, 0.51], n = 159 from 5 studies), but there was no statistically significant change remote from the study limb (0.09, [-0.11, 0.29], n = 90 from 4 studies). Following an exercise program (range 5–12 weeks) there were no statistically significant changes in pressure pain threshold (local 0.23, [-0.01, 0.47], n = 218 from 8 studies; remote 0.33 [-0.13, 0.79], n = 76 from 4 studies), temporal pain summation (0.38 [-0.08, 0.85], n = 122 from 3 studies) or voluntary quadriceps muscle activation (4.23% [-1.84 to 10.30], n = 139 from 4 studies). Conclusion Very-low quality evidence suggests that pressure pain threshold increases following acute exercise. Very-low quality evidence suggests that pressure pain threshold, temporal pain summation or voluntary quadriceps activation do not change statistically significantly following exercise programs.

BACKGROUND. Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC. PATIENTS AND METHODS. Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case–control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS). RESULTS. Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (−)0.24, p = 0.007] and lymphovascular invasion [ATE = (−)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32). CONCLUSION. Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.

Background Early childhood (0–3 years) is a critical period for obesity prevention, when tendencies in eating behaviors and physical activity are established. Yet, little is understood about how the environment shapes children's genetic predisposition for these behaviors during this time. The Baylor Infant Twin Study (BITS) is a two phase study, initiated to study obesity risk factors from infancy. Data collection has been completed for Phase 1 in which three sub‐studies pilot central measures for Phase 2. A novel infant temperament assessment, based on observations made by trained researchers was piloted in Behavior Observation Pilot Protocol (BOPP) study, a new device for measuring infant feeding parameters (the “orometer”) in the Baylor Infant Orometer (BIO), and methods for analyzing DNA methylation in twins of unknown chorionicity in EpiTwin. Methods EpiTwin was a cross‐sectional study of neonatal twins, while up to three study visits occurred for the other studies, at 4‐ (BOPP, BIO), 6‐ (BOPP), and 12‐ (BOPP, BIO) of age. Measurements for BOPP and BIO included temperament observations, feeding observations, and body composition assessments while EpiTwin focused on collecting samples of hair, urine, nails, and blood for quantifying methylation levels at 10 metastable epialleles. Additional data collected include demographic information, zygosity, chorionicity, and questionnaire‐based measures of infant behaviors. Results Recruitment for all three studies was completed in early 2020. EpiTwin recruited 80 twin pairs (50% monochorionic), 31 twin pairs completed the BOPP protocol, and 68 singleton infants participated in BIO. Conclusions The psychometric properties of the data from all three studies are being analyzed currently. The resulting findings will inform the development of the full BITS protocol, with the goal of completing assessments at 4‐, 6‐, 12‐, and 14‐month of age for 400 twin pairs.

BACKGROUND: The Igls criteria assess islet function after islet allotransplant, based on C-peptide, insulin use, hemoglobin A1c, and severe hypoglycemia. However, these criteria as currently defined cannot be applied to total pancreatectomy islet autotransplant (TPIAT) patients. METHODS: We tested modified criteria for assessing islet function in a large cohort TPIAT patients (n=379). Metabolic outcomes were assessed. We assigned Auto-Igls class to each patient as able and evaluated the utility, validity, and perioperative risk factors of Auto-Igls at 1 year post-IAT. We tested the association of Auto-Igls with independent measures of islet graft function, specifically continuous glucose monitoring (CGM) data or acute C-peptide response to glucose (ACRglu) from intravenous glucose tolerance tests. RESULTS: An Auto-Igls class was assigned to 264 patients (69%). Among patients who could not be classified, most were missing exact insulin dose. Seventy-three percent of TPIAT recipients were classified as optimal or good at 1 year. The only significant predictor of Auto-Igls class was islet mass transplanted (p