Clinical effectiveness of a rehabilitation program integrating exercise, self-management, and active coping strategies for chronic knee pain: a cluster randomized trial.

OBJECTIVE: Chronic knee pain is a major cause of disability and health care expenditure, but there are concerns about efficacy, cost, and side effects associated with usual primary care. Conservative rehabilitation may offer a safe, effective, affordable alternative. We compared the effectiveness of a rehabilitation program integrating exercise, self-management, and active coping strategies (Enabling Self-management and Coping with Arthritic Knee Pain through Exercise [ESCAPE-knee pain]) with usual primary care in improving functioning in persons with chronic knee pain. METHODS: We conducted a single-blind, pragmatic, cluster randomized controlled trial. Participants age >/=50 years, reporting knee pain for >6 months, were recruited from 54 inner-city primary care practices. Primary care practices were randomized to continued usual primary care (i.e., whatever intervention a participant's primary care physician deemed appropriate), usual primary care plus the rehabilitation program delivered to individual participants, or usual primary care plus the rehabilitation program delivered to groups of 8 participants. The primary outcome was self-reported functioning (Western Ontario and McMaster Universities Osteoarthritis Index physical functioning [WOMAC-func]) 6 months after completing rehabilitation. RESULTS: A total of 418 participants were recruited; 76 (18%) withdrew, only 5 (1%) due to adverse events. Rehabilitated participants had better functioning than participants continuing usual primary care (-3.33 difference in WOMAC-func score; 95% confidence interval [95% CI] -5.88, -0.78; P = 0.01). Improvements were similar whether participants received individual rehabilitation (-3.53; 95% CI -6.52, -0.55) or group rehabilitation (-3.16; 95% CI -6.55, -0.12). CONCLUSION: ESCAPE-knee pain provides a safe, relatively brief intervention for chronic knee pain that is equally effective whether delivered to individuals or groups of participants

Predicting the points of interaction of small molecules in the NF-κB pathway

<p>Abstract</p> <p>Background</p> <p>The similarity property principle has been used extensively in drug discovery to identify small compounds that interact with specific drug targets. Here we show it can be applied to identify the interactions of small molecules within the NF-κB signalling pathway.</p> <p>Results</p> <p>Clusters that contain compounds with a predominant interaction within the pathway were created, which were then used to predict the interaction of compounds not included in the clustering analysis.</p> <p>Conclusions</p> <p>The technique successfully predicted the points of interactions of compounds that are known to interact with the NF-κB pathway. The method was also shown to be successful when compounds for which the interaction points were unknown were included in the clustering analysis.</p

Is there scope to improve the selection of patients with alcohol-related liver disease for referral to secondary care? A retrospective analysis of primary care referrals to a UK liver centre, incorporating simple blood tests

OBJECTIVES: Twenty per cent of people with alcohol use disorders develop advanced fibrosis and warrant referral to secondary care. Improving outcomes in alcohol-related liver disease (ArLD) relies on its earlier detection in primary care with non-invasive tests (NIT). We aimed to determine the proportion of alcohol-related referrals who were diagnosed with advanced fibrosis in secondary care, the prevalence of both alcohol and fatty liver disease ('BAFLD') and the potential impact of NIT on referral stratification. DESIGN/SETTING: Retrospective analysis of all general practitioner-referrals with suspected ArLD/non-alcoholic fatty liver disease (NAFLD) to a UK hepatology-centre between January 2015 and January 2018. PARTICIPANTS: Of 2944 new referrals, 762 (mean age 55.5±13.53 years) met inclusion criteria: 531 NAFLD and 231 ArLD, of which 147 (64%) could be reclassified as 'BAFLD'. PRIMARY OUTCOME MEASURE: Proportion of referrals with suspected ArLD/NAFLD with advanced fibrosis as assessed by tertiary centre hepatologists using combinations of FibroScan, imaging, examination and blood tests and liver histology, where indicated. SECONDARY OUTCOME MEASURES: Included impact of body mass index/alcohol consumption on the odds of a diagnosis of advanced fibrosis, and performance of NIT in predicting advanced fibrosis in planned post-hoc analysis of referrals. RESULTS: Among ArLD referrals 147/229 (64.2%) had no evidence of advanced fibrosis and were judged 'unnecessary'. Advanced fibrosis was observed in men drinking ≥50 units per week (U/w) (OR 2.74, 95% CI 1.51 to 5, p=0.001) and ≥35 U/w in women (OR 5.11, 95% CI 1.31 to 20.03, p=0.019). Drinking >14 U/w doubled the likelihood of advanced fibrosis in overweight/obesity (OR 2.11; 95% CI 1.44 to 3.09; p<0.001). Use of fibrosis 4 score could halve unnecessary referrals (OR 0.50; 95% CI 0.32 to 0.79, p=0.003) with false-negative rate of 22%, but was rarely used. CONCLUSIONS: The majority of referrals with suspected ArLD were deemed unnecessary. NIT could improve identification of liver damage in ArLD, BAFLD and NAFLD in primary care. Anecdotal thresholds for harmful drinking (35 U/w in women and 50 U/w in men) were validated. The impact of alcohol on NAFLD highlights the importance of multi-causality in chronic liver disease

Balloon-Expandable Stent Treatment of Experimental Coarctation of the Aorta: Early Hemodynamic and Pathological Evaluation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72292/1/j.1540-8183.1993.tb00843.x.pd

Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty

Context: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. Objective: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. Design: Retrospective study. Methods: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. Results: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. Conclusion: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately

The Cancer Hub Approach for Upper Gastrointestinal Surgery During COVID-19 Pandemic: Outcomes from a UK Cancer Centre.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused unprecedented disruption to global healthcare delivery. In England, the majority of elective surgery was postponed or cancelled to increase intensive care capacity. Our unit instituted the 'RM Partners Cancer Hub' at the Royal Marsden Hospital in London, to deliver ongoing cancer surgery in a 'COVID-lite' setting. This article describes the operational set-up and outcomes for upper gastrointestinal (UGI) cancer resections performed during this period. METHODS: From April 2020 to April 2021, the Royal Marsden Hospital formed the RM Partners Cancer Hub. This approach was designed to coordinate resources and provide as much oncological treatment as feasible for patients across the RM Partners West London Cancer Alliance. A UGI surgical case prioritisation strategy, along with strict infection control pathways and pre-operative screening protocols, was adopted. RESULTS: A total of 231 patients underwent surgery for confirmed or suspected UGI cancer during the RM Partners Cancer Hub, with 213 completed resections and combined 90-day mortality rate of 3.5%. Good short-term survival outcomes were demonstrated with 2-year disease free survival (DFS) and overall survival (OS) for oesophageal (70.8% and 72.9%), gastric (66.7% and 83.3%) and pancreatic cancer resections (68.0% and 88.0%). One patient who developed perioperative COVID-19 during the RM Partners Cancer Hub operation made a full recovery with no lasting clinical sequelae. CONCLUSION: Our experience demonstrates that the RM Partners Cancer Hub approach is a safe strategy for continuing upper gastrointestinal (GI) resectional surgery during future periods of healthcare service disruption

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P &lt; 0.001), age, bisphosphonate use, and rodding (P &lt; 0.05).ConclusionFrom the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves

Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 m from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na+/H+ exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer