X-linked hyper-immunoglobulin M syndrome harboring a novel CD40-ligand gene mutation: a case report.

The X-linked hyper-IgM syndrome (X-HIGM1) is a rare primary immunodeficiency disorder (PID) caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). X-HIGM1 is characterized by normal or elevated serum levels of IgM in association with decreased levels of IgG, IgA, and IgE. The CD40LG protein expressed on activated T cells interacts with its receptor protein, CD40, on B lymphocytes and dendritic cells. Mutations in the CD40LG gene lead to the production of an abnormal CD40L protein that fails to attach to its receptor, CD40 on B cells resulting in failure to produce IgG, IgA, and IgE antibodies. In the present study, we investigated the molecular defects underlying such a PID in a patient presenting with clinical history of pneumonia and acute respiratory distress syndrome (ARDS) at 7 months of age and diagnosed as transient hypogammaglobulinemia with decreased levels of IgG and increased levels of IgM. We have identified a novel and yet to be reported frame shift deletion of a single base pair (c.229delA) in exon 2 (p.Arg77AspfsTer6) of the CD40L gene ensuing the premature truncation of the protein by 6 amino acids by targeted gene sequencing. This frame shift mutation identified as a CD40L variant was found to be pathogenic which was also validated by Sanger sequencing. The in-silico analysis of c.229 del A mutation also predicted the change to be pathological affecting the structure and function of the CD40L (CD40L, CD154) protein and its protein-protein interaction properties.

Approaches to Prevent and Manage Cardiovascular Disease in Patients Receiving Therapy for Prostate Cancer.

PURPOSE OF REVIEW: Prostate cancer (PCa) is amongst the most common cancers in men worldwide. Cardiovascular (CV) risk factors and CV disease (CVD) are common comorbidities in this patient population, posing a challenge for PCa-directed therapies which can cause or worsen CVRFs and CVDs. Herein, we summarize the approaches to prevent and manage CVD in patients with PCa receiving therapy. RECENT FINDINGS: While patients with locally advanced and metastatic PCa benefit from hormonal therapy, these treatments can potentially cause CV toxicity. Androgen receptor targeting therapies, such as androgen deprivation therapy (ADT), can induce metabolic changes and directly impact cardiovascular function, thereby reducing cardiorespiratory fitness and increasing CV mortality. Moreover, more than half of the PCa patients have poorly controlled CV risk factors at baseline. Hence, there is an urgent need to address gaps in preventing and managing CVD in PCa patients. Screening and optimizing CV risk factors and CVD in patients undergoing ADT are essential to reduce CV mortality, the leading non-cancer cause of death in PCa survivors. The risk of CV morbidity and mortality can be further mitigated by considering the patient's cardiovascular risk profile when deciding the choice and duration of ADT. A multidisciplinary team-based approach is crucial to achieve the best outcomes for PCa patients undergoing therapy.

Calcification Detection in Intravascular Ultrasound (IVUS) Images Using Transfer Learning Based MultiSVM model.

Cardiovascular disease serves as the leading cause of death worldwide. Calcification detection is considered an important factor in cardiovascular diseases. Currently, medical practitioners visually inspect the presence of calcification using intravascular ultrasound (IVUS) images. The study aims to detect the extent of calcification as belonging to class I, II as mild calcification, and class III, IV as dense calcification from IVUS images acquired at 40 MHz. To detect calcification, the features were extracted using improved AlexNet architecture and then were fed into machine learning classifiers. The experiments were carried out using 14 real IVUS pullbacks of 10 patients. Experimental results show that the combination of traditional machine learning with deep learning approaches significantly improves accuracy. The results show that support vector machines outperform all other classifiers. The proposed model is compared with two other pre-trained models GoogLeNet (98.8%), SqueezeNet (99.2%), and exhibits considerable improvement in classification accuracy (99.8%). In the future other models such as Vision Transformers could be explored with additional feature selection methods such as ReliefF, PSO, ACO, etc. to improve the overall accuracy of diagnosis.

Machine Learning Analytic-Based Two-Staged Data Management Framework for Internet of Things.

In applications of the Internet of Things (IoT), where many devices are connected for a specific purpose, data is continuously collected, communicated, processed, and stored between the nodes. However, all connected nodes have strict constraints, such as battery usage, communication throughput, processing power, processing business, and storage limitations. The high number of constraints and nodes makes the standard methods to regulate them useless. Hence, using machine learning approaches to manage them better is attractive. In this study, a new framework for data management of IoT applications is designed and implemented. The framework is called MLADCF (Machine Learning Analytics-based Data Classification Framework). It is a two-stage framework that combines a regression model and a Hybrid Resource Constrained KNN (HRCKNN). It learns from the analytics of real scenarios of the IoT application. The description of the Framework parameters, the training procedure, and the application in real scenarios are detailed. MLADCF has shown proven efficiency by testing on four different datasets compared to existing approaches. Moreover, it reduced the global energy consumption of the network, leading to an extended battery life of the connected nodes.

Non-Ceruloplasmin Copper Identifies a Subtype of Alzheimer's Disease (CuAD): Characterization of the Cognitive Profile and Case of a CuAD Patient Carrying an RGS7 Stop-Loss Variant.

Alzheimer's disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin Cu (non-Cp Cu) levels were increased in serum/plasma samples. Non-Cp Cu was advocated as a stratification add-on biomarker of a Cu subtype of AD (CuAD subtype). To further circumstantiate this concept, we evaluated non-Cp Cu reliability in classifying subtypes of AD based on the characterization of the cognitive profile. The stratification of the AD patients into normal AD (non-Cp Cu ≤ 1.6 µmol/L) and CuAD (non-Cp Cu > 1.6 µmol/L) showed a significant difference in executive function outcomes, even though patients did not differ in disease duration and severity. Among the Cu-AD patients, a 76-year-old woman showed significantly abnormal levels in the Cu panel and underwent whole exome sequencing. The CuAD patient was detected with possessing the homozygous (c.1486T > C; p.(Ter496Argext*19) stop-loss variant in the RGS7 gene (MIM*602517), which encodes for Regulator of G Protein Signaling 7. Non-Cp Cu as an add-on test in the AD diagnostic pathway can provide relevant information about the underlying pathological processes in subtypes of AD and suggest specific therapeutic options.

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).

BACKGROUND: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer. METHODS: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960. FINDINGS: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug. INTERPRETATION: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination. FUNDING: Exelixis.

The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. METHODS: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. RESULTS: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). CONCLUSIONS: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.

Can a Hip Brace Improve Short-Term Hip-Related Quality of Life for People With Femoroacetabular Impingement and Acetabular Labral Tears: An Exploratory Randomized Trial.

OBJECTIVES: To examine whether a hip brace can improve hip health quality-of-life (QoL) and is well-tolerated in people with femoroacetabular impingement syndrome (FAIS) or symptomatic labral tears after 6 weeks of wear. DESIGN: Parallel, two-arm, exploratory randomized trial. SETTING: Hospital and private clinics of orthopaedic surgeons. PARTICIPANTS: Individuals >18 years with FAIS or labral tears. INTERVENTIONS: Usual conservative care versus usual conservative care plus a hip brace. MAIN OUTCOMES: Patient-reported outcomes were assessed with the International Hip Outcome Tool (iHOT-33), and Copenhagen Hip and Groin Outcome Scores (HAGOS). Brace acceptability was measured using the Quebec User Evaluation of Satisfaction with Assistive Technology survey. Independent t-tests assessed between-group differences. RESULTS: Thirty-eight participants were recruited, 19 each group, 60% women, mean age 39.3 ± 11.8 years, body mass index 25.3 ± 4.4 kg/m2, iHOT-33 36.6 ± 24.8. Three participants dropped out (one usual care, 2 braced). The mean between-group difference for iHOT-33 was 19.4 (95% confidence interval [CI] 1.68-37.06, P = 0.03) favoring the brace. There were improvements in most HAGOS subscale scores favoring the brace. Issues with brace tolerability for some participants were perceived comfort and effectiveness. Three brace-related adverse events were reported. CONCLUSION: Between-group differences favored the braced group for hip health QoL, pain, symptoms, and function. Although these were promising results, the CIs for the estimates were wide, the small sample size likely a contributing factor. Our results suggest that further investigation of the brace is warranted, we calculated sample sizes and made recommendations for the design of a future trial.

Evaluation of air pollution tolerance index and anticipated performance index of selected roadside tree species in Ludhiana, India.

Air quality has deteriorated in most big cities and becoming the fifth major cause of mortality in India. Among others, vehicle gaseous emission is a major contributor. Plants have different tolerance levels, which can be identified based on Air Pollution Tolerance Index (APTI). The objectives were to study the morphological and biochemical parameters for Air Pollution Tolerance Index (APTI) of selected roadside tree species (Acacia auriculiformis, Alstonia scholaris, Chukrasia tabularis, Cassia fistula, Cassia siamea, Dalbergia sissoo, Heterophragma adenophyllum, and Putranjiva roxburghii) at control (PAU campus) and polluted sites (roadside) during summer and winter seasons. The total chlorophyll content, ascorbic acid, leaf extract pH, leaf relative water content, total soluble sugar, phenols, and carotenoids ranged from 0.59 to 4.16 mg g-1, 1.03 to 3.75 mg g-1, 3.16 to 7.04, 46.01 to 71.65%, 10.78 to 23.83 mg g-1, 0.51 to 1.35 mg -1, and 0.19 to 1.96 mg g-1, respectively. The Air Pollution Tolerance Index of the selected trees ranged between7.65 and 11.19 and followed an order of Cassia fistula > Acacia auriculiformis > Dalbergia sissoo > Alstonia scholaris > Putranjiva roxburghii > Heterophragma adenophyllum > Cassia siamea > Chukrasia tabularis. The evaluation of Anticipated Performance Index (API) categorized the trees into poor (Dalbergia sissoo and Cassia siamea), moderate (Cassia fistula), and good (Acacia auriculiformis, Alstonia scholaris, Chukrasia tabularis, Heterophragma adenophyllum, and Putranjiva roxburghii) categories.

Maternal vitamin B12 in mice positively regulates bone, but not muscle mass and strength in post-weaning and mature offspring.

Vitamin B12 deficiency has been shown to affect bone mass in rodents and negatively impact bone formation in humans. In this study using mouse models, we define the effect of B12 supplementation in the wild-type mother and B12 deficiency in a mouse genetic model (Gif-/- mice) during gestation on bone and muscle architecture and mechanical properties in the offspring. Analysis of bones from 4-wk-old offspring of the wild-type mother following vehicle or B12 supplementation during gestation (from embryonic day 0.5 to 20.5) showed an increase in bone mass caused by an isolated increase in bone formation in the B12-supplemented group compared with vehicle controls. Analysis of the effect of B12 deficiency in the mother in a mouse genetic model (Gif-/- mice) on the long bone architecture of the offspring showed a compromised cortical and trabecular bone mass, which was completely prevented by a single injection of B12 in the B12-deficient Gif-/- mothers. Biomechanical analysis of long bones of the offspring born from B12-supplemented wild-type mothers showed an increase in bone strength, and conversely, offspring born from B12-deficient Gif-/- mothers revealed a compromised bone strength, which could be rescued by a single injection of B12 in the B12-deficient Gif-/- mother. Muscle structure and function analysis however revealed no significant effect on muscle mass, structure, and grip strength of B12 deficiency or supplementation in Gif-/- mice compared with littermate controls. Together, these results demonstrate the beneficial effect of maternally derived B12 in the regulation of bone structure and function in the offspring.

Primary Hyperparathyroidism Masquerading as Acute Pancreatitis.

Acute pancreatitis as an initial manifestation of primary hyperparathyroidism (PHPT) is a rare occurrence and timely diagnosis of PHPT is crucial in preventing repeat attack of pancreatitis. The study aimed at evaluating the clinico-radiological profile of patients admitted with acute pancreatitis as the index presentation of PHPT and to determine the factors associated with development of severe pancreatitis. This series included retrospective analysis of medical records of 30 patients admitted with acute pancreatitis as initial manifestation of PHPT. Additionally, we analyzed the data of another 30 patients admitted with PHPT but without any evidence of pancreatitis, to serve as control group. The mean age of the subjects was 44.9±13.9 years with male to female ratio of 1.30. The mean serum calcium level was 12.24±2.79 mg/dl and five (16.6%) patients had normocalcemia at time of presentation. Presence of nephrolithiasis was significantly associated with severe pancreatitis. One patient had refractory hypercalcemia associated with renal failure and was successfully managed with denosumab. Patients with PHPT associated with acute pancreatitis had significantly higher calcium levels and lower frequency of skeletal involvement as compared to PHPT patients without pancreatitis. PHPT masquerading as acute pancreatitis is rare and high index of suspicion is required to diagnose this condition especially in the presence of normocalcemia at presentation. Patients with PHPT associated pancreatitis had male preponderance, higher calcium levels, and lower frequency of skeletal involvement as compared to PHPT patients without pancreatitis.

Optimal pathological response after neoadjuvant chemotherapy for muscle-invasive bladder cancer: results from a global, multicentre collaboration.

OBJECTIVES: To evaluate outcomes of patients achieving a post-treatment pathological stage of

No Difference in Functional, Radiographic, and Survivorship Outcomes Between Direct Anterior or Posterior Approach THA: 5-Year Results of a Randomized Trial.

BACKGROUND: Both the direct anterior approach (DAA) and posterior approach (PA) to THA have known advantages and disadvantages. The comparison between DAA and PA THA has been widely explored during the early postoperative period. However, few randomized trials have compared these approaches at a minimum follow-up of 5 years; doing so would be important to establish any differences in mid-term outcomes or complications. QUESTIONS/PURPOSES: We performed a randomized trial comparing DAA and PA in THA in terms of (1) patient-reported outcome scores, (2) quality of life and functional outcomes assessed by the EQ-5D and 10-meter walk test results, (3) radiographic analysis, and (4) survivorship and surgical complications at a minimum of 5 years follow-up. METHODS: Two hip specialist surgeons performed both DAA and PA THA using the same THA components at two hospital sites. One hundred twelve patients on the elective THA surgical waitlist were invited to participate in the study. Thirty-four patients did not meet the study's inclusion criteria and were excluded, and three patients declined to participate in the study. The remaining 75 patients who were eligible were randomized into DAA and PA groups. Thirty-seven patients were initially randomized to receive DAA THA, but two did not and were excluded, resulting in 48% (35 of 73) of patients who received DAA THA; 52% (38 of 73) of patients were randomized into and received PA THA. Over a minimum 5 years of follow-up, 3% (1 of 35) of DAA patients were lost to follow-up, and none of the patients undergoing PA THA were lost. A per-protocol analysis was adopted, resulting in further patients being excluded from analysis. Of the 73 study patients, 99% (72; DAA: 35, PA: 37) were analyzed at 1 year, 95% (69; DAA: 34, PA: 35) were analyzed at 2 years, and 72% (52; DAA: 23, PA: 29) were analyzed at 5 years. The primary outcome was the Oxford Hip Score (OHS) and WOMAC score. Secondary outcomes included the EQ-5D and EQ-5D VAS scores, 10-meter walk test results, radiographic evidence of loosening (femoral: lucency > 2 mm at the implant-bone interface, subsidence > 2 mm; acetabular: migration or change in inclination), 5-year survivorship analysis from all-cause revisions, and surgical complications. The study was powered to detect a 10-point difference in the WOMAC score, which is equivalent to the minimum clinically important difference (MCID). RESULTS: There were no differences in primary outcomes (OHS and WOMAC scores) or secondary outcomes (EQ-5D scores, EQ-5D VAS scores, and 10-meter walk test result) between the DAA and PA groups at the 5-year follow-up interval. The median (range) OHS at 5 years was 46 (16 to 48) for DAA and 47 (18 to 48) for PA groups (p = 0.93), and the median WOMAC score was 6 (0 to 81) for DAA and 7 (0 to 59) for PA groups (p = 0.96). The median EQ-5D score was 1 (0.1 to 1) for DAA and 1 (0.5 to 1) for PA groups (p = 0.45), and the median EQ-5D VAS score was 85 (60 to 100) for DAA and 95 (70 to 100) for PA groups (p = 0.29). There were no cases of component loosening on radiographs. There was no difference in component survival between the two approaches at 5 years (DAA: 97% [95% CI 85% to 100%] versus PA: 97% [95% CI 87% to 100%]). Eight of 23 patients in the DAA group reported decreased sensation in the lateral femoral cutaneous nerve distribution. CONCLUSION: DAA and PA are both effective approaches in performing primary THA. Each approach has its associated risks and complications. The choice of THA should be based on individual patient factors, surgeon experience, and shared decision-making. Early registry data indicate DAA and PA THA are comparable, but longer-term data with larger numbers of patients will be required before one can safely conclude equal survivorship between both approaches. LEVEL OF EVIDENCE: Level I, therapeutic study.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial.

BACKGROUND: Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. METHODS: Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. RESULTS: Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI - 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). CONCLUSION: The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. TRIAL REGISTRATION DETAILS: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

Ability of triage nurses to predict, at the time of triage, the eventual disposition of patients attending the emergency department (ED): a systematic literature review and meta-analysis.

INTRODUCTION: Exit block is the most significant cause of poor patient flow and crowding in the emergency department (ED). One proposed strategy to reduce exit block is early admission predictions by triage nurses to allow proactive bed management. We report a systematic review and meta-analysis of the accuracy of nurse prediction of admission at triage. METHODOLOGY: We searched MEDLINE, Cochrane, Embase, CINAHL and grey literature, up to and including February 2019. Our criteria were as follows: prospective studies analysing the accuracy of triage nurse intuition-after gathering standard triage information-for predicting disposition for adult ED patients. We analysed the results of this test-nurse prediction of disposition-in a diagnostic test analysis review style, assessing methodology with the Quality Assessment of Diagnostic Accuracy Studies 2 checklist. We generated sensitivity, specificity and likelihood ratios (LRs). We used LRs and pretest probability of admission (baseline admission rate) to find positive and negative post-test probabilities. RESULTS: We reviewed 10 articles. Of these, seven had meta-analysable data (12 282 participants). The studies varied in participant selection and admission rate, but the majority were of moderate quality and exclusion of each in sensitivity analyses made little difference. Sensitivity was 72% and specificity was 83%. Pretest probability of admission was 29%. Positive and negative post-test probabilities of admission were 63% and 12%, respectively. CONCLUSION: Triage nurse prediction of disposition is not accurate enough to expedite admission for ED patients on a one-to-one basis. Future research should explore the benefit, and best method, of predicting total demand.

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma.

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.Trial Registration NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).

Accuracy of the Actigraph wGT3x-BT for step counting during inpatient spinal cord rehabilitation.

STUDY DESIGN: Cross-sectional. OBJECTIVES: (1) Assess the accuracy of the Actigraph wGT3x-BT accelerometer to count steps taken by inpatients with incomplete spinal cord injury (iSCI) in physical therapy (PT) sessions and self-directed activities, and (2) compare the number of steps/min taken in PT sessions to that in self-directed activities during inpatient rehabilitation. SETTING: Inpatient spinal cord injury rehabilitation. METHODS: Seventeen individuals with subacute motor iSCI were observed for up to 45-min of both PT and self-directed activities, during which steps were simultaneously tracked by the Actigraph wGT3x-BT and a researcher using a hand tally counter. Accuracy was evaluated with an intraclass correlation coefficient (ICC) for the entire PT session and self-directed activities, as well as for periods of walking. RESULTS: There was excellent agreement between the Actigraph wGT3x-BT and manually counted steps for entire PT sessions (ICC = 0.86) and walking periods (PT walking, ICC = 0.99; self-directed walking, ICC = 0.99). There was poor agreement for entire self-directed sessions (ICC = 0.15). Visual analysis of Bland-Altman plots supported these findings. Participants took more steps/min in PT sessions compared to self-directed activities (p = 0.023). CONCLUSION: The Actigraph wGT3x-BT accurately counts steps during PT sessions and walking periods in individuals with subacute motor iSCI. Clinically, this may enable physical therapists to track walking repetitions during inpatient rehabilitation more effortlessly.

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery.

Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure-based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.