Prediction of adolescent weight status by machine learning: a population-based study.

BACKGROUND: Adolescent weight problems have become a growing public health concern, making early prediction of non-normal weight status crucial for effective prevention. However, few temporal prediction tools for adolescent four weight status have been developed. This study aimed to predict the short- and long-term weight status of Hong Kong adolescents and assess the importance of predictors. METHODS: A population-based retrospective cohort study of adolescents was conducted using data from a territory-wide voluntary annual health assessment service provided by the Department of Health in Hong Kong. Using diet habits, physical activity, psychological well-being, and demographics, we generated six prediction models for successive weight status (normal, overweight, obese and underweight) using multiclass Decision Tree, Random Forest, k-Nearest Neighbor, eXtreme gradient boosting, support vector machine, logistic regression. Model performance was evaluated by multiple standard classifier metrics and the overall accuracy. Predictors' importance was assessed using Shapley values. RESULTS: 442,898 Primary 4 (P4, Grade 4 in the US) and 344,186 in Primary 6 (P6, Grade 6 in the US) students, with followed up until their Secondary 6 (Grade 12 in the US) during the academic years 1995/96 to 2014/15 were included. The XG Boosts model consistently outperformed all other model in predicting the long-term weight status at S6 from P4 or P6. It achieved an overall accuracy of 0.72 or 0.74, a micro-averaging AUC of 0.92 or 0.93, and a macro-averaging AUC of 0.83 or 0.86, respectively. XG Boost also demonstrated accurate predictions for each predicted weight status, surpassing the AUC values obtained by other models. Weight, height, sex, age, frequency and hours of aerobic exercise were consistently the most important predictors for both cohorts. CONCLUSIONS: The machine learning approaches accurately predict adolescent weight status in both short- and long-term. The developed multiclass model that utilizing easy-assessed variables enables accurate long-term prediction on weight status, which can be used by adolescents and parents for self-prediction when applied in health care system. The interpretable models may help to provide the early and individualized interventions suggestions for adolescents with weight problems particularly.

Review on the screening of urine glucose for early diagnosis of type 2 diabetes mellitus in school children and adolescents with obesity in Hong Kong.

OBJECTIVES: Obesity and type 2 diabetes mellitus (T2DM) are growing health concerns. Since 2005, Student Health Service (SHS) and Hong Kong Paediatric Society formulated a protocol on urine glucose screening (UGS) for early diagnosis of T2DM in students with obesity in Hong Kong. This study reviews students with T2DM captured by this screening program and compare the data with the Hong Kong Children Diabetes Registry (HKCDR) database, to see if the UGS program facilitates early diagnosis of T2DM. METHODS: Students between the ages of 10-18 years old with age- and sex-specific body mass index (BMI) >97th percentile who attended SHS between the school years from 2005/06 to 2017/18 were recruited for UGS. Those tested positive for random urine glucose underwent diagnostic testing for T2DM according to ADA guidelines. Demographic data and investigatory results from UGS and HKCDR within the same time period were compared. RESULTS: A total of 216,526 students completed UGS in the said period; 415 (0.19 %) students were tested positive for urine glucose of which 121 students were diagnosed with T2DM. UGS picked up 23 % of the newly diagnosed T2DM cases. When compared to the HKCDR database, students diagnosed via UGS were significantly younger, less obese, and had fewer diabetic related complications. The negative predictive value of UGS is high and can effectively rule out T2DM. CONCLUSIONS: Urine glucose screening is an inexpensive and simple test that allows for early diagnosis of T2DM among obese school students. Other methods including POCT HbA1c can be explored to improve program effectiveness.

High-throughput screening of compounds targeting RNA editing in Trypanosoma brucei: Novel molecular scaffolds with broad trypanocidal effects.

Mitochondrial uridine insertion/deletion RNA editing, catalyzed by a multiprotein complex (editosome), is essential for gene expression in trypanosomes and Leishmania parasites. As this process is absent in the human host, a drug targeting this mechanism promises high selectivity and reduced toxicity. Here, we successfully miniaturized our FRET-based full-round RNA editing assay, which replicates the complete RNA editing process, adapting it into a 1536-well format. Leveraging this assay, we screened over 100,000 compounds against purified editosomes derived from Trypanosoma brucei, identifying seven confirmed primary hits. We sourced and evaluated various analogs to enhance the inhibitory and parasiticidal effects of these primary hits. In combination with secondary assays, our compounds marked inhibition of essential catalytic activities, including the RNA editing ligase and interactions of editosome proteins. Although the primary hits did not exhibit any growth inhibitory effect on parasites, we describe eight analog compounds capable of effectively killing T. brucei and/or Leishmania donovani parasites within a low micromolar concentration. Whether parasite killing is - at least in part - due to inhibition of RNA editing in vivo remains to be assessed. Our findings introduce novel molecular scaffolds with the potential for broad antitrypanosomal effects.

In vitro and in vivo modelling of mutant JAK3/STAT5 signaling in leukemia.

Mutations within the IL7-R-JAK-STAT signaling pathway are important drivers of T-cell acute lymphoblastic leukemia (T-ALL). Here we describe the important steps required to generate retroviral particles for the stable expression of mutant JAK3 constructs that induce constitutive JAK/STAT signaling. These are subsequently used for the viral transduction of the IL-3 cytokine-dependent Ba/F3 cell line or murine hematopoietic stem and progenitor cells (HSPCs) for in vitro and in vivo modelling of cytokine-independent growth or leukemia initiation respectively.

Effectiveness of distance learning for preclinical periodontal education.

INTRODUCTION: This study aimed to investigate the effectiveness of distance learning (DL) for the second-year periodontics course compared to classroom learning (CL). MATERIALS AND METHODS: DL for Class A (n1 = 126) and CL for Class B (n2 = 133) were implemented. The same instructors recorded or delivered the same lectures in the two learning modules during the second-year periodontics course. Classes A and B took the same final examinations (a total % score of 200). General linear model (GLM) and ordinal logistic regression (OLR) analyses were conducted after considering individual first-year final % scores as a covariate to test if the second-year final % scores and the distributions of letter grades were significantly different between Class A and B. RESULTS: The mean second-year final % score of the DL group (166.4) was significantly higher than that of the CL group (160.8) (independent t-test, p = .019). However, in GLM, the first-year final % scores significantly affected the second-year scores (p = .016); the second-year final % scores between the two groups were not significantly different (p = .268) after considering the individual first-year scores. In OLR, there was no difference in the likelihood of getting lower grades in the second-year course between the two groups (odds ratio = 1.6; 95% confidence interval = [0.95, 2.72], p = .078) after considering the first-year final % scores. CONCLUSION: Within the limitations of the study, the DL for preclinical periodontics resulted in comparable student learning outcomes when compared to the traditional CL.

Analysis of Time to Diagnosis and Outcomes Among Adults With Primary Hyperparathyroidism.

Importance: Despite access to routine laboratory evaluation, primary hyperparathyroidism (PHP) remains underdiagnosed and undertreated. Objective: To determine the consequences associated with missed diagnoses and prolonged time to diagnosis and treatment of PHP. Design, Setting, and Participants: This is a retrospective cohort study of patients older than 40 years with 2 instances of hypercalcemia during 2010 to 2020 and 3 years of follow-up. Patients were recruited from 63 health care organizations in the TriNetX Research Network. Data analysis was performed from January 2010 to September 2020. Exposures: Elevated serum calcium. Main Outcomes and Measures: Existing symptoms and diagnoses associated with PHP (osteoporosis, fractures, urolithiasis, major depressive disorder, anxiety, hypertension, gastroesophageal reflux disease, malaise or fatigue, joint pain or myalgias, constipation, insomnia, polyuria, weakness, abdominal pain, headache, nausea, amnesia, and gallstones) compared in patients deemed high-risk and without a diagnosis and matched controls, and those who experienced times from documented hypercalcemia to diagnosis and diagnosis to treatment within or beyond 1 year. Results: There were 135 034 patients analyzed (96 554 women [72%]; 28 892 Black patients [21%] and 88 010 White patients [65%]; 3608 Hispanic patients [3%] and 98 279 non-Hispanic patients [73%]; mean [SD] age, 63 [10] years). Two groups without a documented diagnosis of PHP were identified as high risk: 20 176 patients (14.9%) with parathyroid hormone greater than or equal to 50 pg/mL and 24 905 patients (18.4%) with no parathyroid hormone level obtained or recorded explanation for hypercalcemia. High-risk patients experienced significantly increased rates of all associated symptoms and diagnoses compared with matched controls. Just 9.7% of those with hypercalcemia (13 136 patients) had a diagnosis of PHP. Compared with individuals who received a diagnosis within 1 year of hypercalcemia, those whose workup exceeded 1 year had significantly increased rates of major depressive disorder, anxiety, hypertension, gastroesophageal reflux disease, malaise or fatigue, joint pain or myalgias, polyuria, weakness, abdominal pain, and headache at 3 years. The rate of osteoporosis increased from 17.1% (628 patients) to 25.4% (935 patients) over the study period in the group with delayed diagnosis. Among those with a diagnosis, 5280 patients (40.2%) underwent parathyroidectomy. Surgery beyond 1 year of diagnosis was associated with significantly increased rates of osteoporosis and hypertension at 3 years after diagnosis compared with those treated within 1 year. Conclusions and Relevance: Many patients were at high risk for PHP without a documented diagnosis. Complications in these patients, as well as those who received a diagnosis after prolonged workup or time to treatment, resulted in patient harm. System-level interventions are necessary to ensure proper diagnosis and prompt treatment of PHP.

An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase.

In Plasmodium, the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making PfGluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N-(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective PfGluPho inhibitor with robust nanomolar activity against recombinant PfGluPho, PvG6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H2O2 homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.

Recombinant single-chain factor VIII in severe hemophilia: Long-term safety and efficacy in previously treated patients in the AFFINITY extension study.

BACKGROUND: rVIII-SingleChain is a recombinant single-chain factor VIII used to treat people with hemophilia A. OBJECTIVES: The aim of this extension study was to investigate the long-term safety and efficacy of rVIII-SingleChain prophylaxis in ≥200 previously treated patients (PTPs) with hemophilia A with ≥100 exposure days (EDs). METHODS: In total, 222 patients were enrolled, of which 204 rolled over from prior rVIII-SingleChain studies. The median age was 21 years (range, 2-65 years), including 155 patients ≥12 years and 67 patients <12 years. Patients continued with their previously assigned dose and regimen, or switched at the investigator's discretion. Patients were treated for a mean duration of 31 months (range, 1-47 months), the mean ED was 342 (standard deviation, 135.5), and 212 (95.5%) patients achieved >100 EDs. When the study ended, most patients were on either a prophylaxis regimen of 34.9 (17-62) IU/kg, 3×/week (N = 88; 39.6%), or 37.2 (13-65) IU/kg, 2×/week regimen (N = 72; 32.4%). RESULTS: Hemostatic efficacy was rated excellent or good in 87.1% of assessed bleeds. The median (range) annualized bleeding rate was 1.21 (0.0-42.6), and the annualized spontaneous bleeding rate (AsBR) was 0.32 (0.0-33.0) for prophylaxis regimens. Median AsBR was similar for patients treated 3×/week and 2×/week (0.31 and 0.30, respectively). Surgical hemostatic efficacy was rated excellent or good in 100% of surgeries. No inhibitors, anaphylactic reactions, or thromboembolic events were reported in PTPs. CONCLUSION: These results confirm the safety and efficacy of rVIII-SingleChain as a long-term prophylaxis treatment modality for PTPs with severe hemophilia A.

Worsening trends in self-rated health and correlates in Chinese adolescents in Hong Kong: a population-based panel study from 1999/2000 to 2014/15.

OBJECTIVES: To examine the 15-year secular trends of self-rated health (SRH) and correlates in Chinese adolescents in Hong Kong. DESIGN: A territory-wide population-based panel data study. SETTING: Anonymised records of the annual health examination from the Student Health Service, Department of Health in Hong Kong. PARTICIPANTS: 397 324 students in Secondary 2 (US grade 8), 335 902 in Secondary 4 and 113 892 in Secondary 6 during the academic year 1999/2000 and 2014/15. OUTCOME MEASURES: SRH and lifestyles were self-reported using standardised questionnaires. Sex-standardised and age-standardised prevalence of very poor/poor SRH and its secular annual changes across sex, grade, weight status, breakfast habits, and frequency/duration of aerobic exercises were examined. Their disparities over time were examined by interactions with the academic year in generalised estimating equations. RESULTS: The overall prevalence of very poor/poor SRH increased from 9.3% (95% CI: 8.9% to 9.7%) in 1999/2000 to 15.5% (15.1% to 15.8%) in 2014/15. Very poor/poor SRH was more prevalent in girls (adjusted OR: 1.02), in those having unemployed parents (1.29), being overweight (1.42) or obese (2.62), eating breakfast away from home (1.27) and skipping breakfast (1.49) or doing <1 time/week or ≤60 min/week aerobic exercises (1.78 and 1.88, respectively) than others. The corresponding disparities increased over time (ratios of OR: 1.006-1.042). CONCLUSIONS: Increasing prevalence of very poor/poor SRH from 1999/2000 to 2014/15 was found among Hong Kong Chinese adolescents, which was greater in girls, adolescents being overweight/obese and those having unemployed parents or unhealthy lifestyles. Strategies to reduce health inequality should consider multiple factors, especially modifiable factors including lifestyles.

Late-onset or chronic overweight/obesity predicts low self-esteem in early adolescence: a longitudinal cohort study.

BACKGROUND: How weight status changes with time may affect self-esteem was seldom studied. We identified the distinct trajectories of overweight/obesity over age and assessed their associations with different domains of self-esteem in Hong Kong Chinese children. METHODS: Territory-wide longitudinal data of 48,558 children (girls: 50.0%; 6.3 ± 0.51 years) studying Primary 1 in the academic cohorts of 1995/96 and 1996/97 followed till Primary 6 were obtained from the Student Health Service of Hong Kong. Weight was annually measured and categorized as underweight/normal and overweight/obese and self-esteem was measured in Primary 6. Distinct trajectories of weight status were first identified using growth mixture modeling and their associations with low self-esteem were assessed by logistic regression. RESULTS: Four distinct overweight/obesity trajectories were identified: never (76.8%), late-onset (8.1%), early-onset (4.2%) and chronic (10.9%) overweight/obesity. Compared with children who were never overweight/obese, more of those in the late-onset or chronic overweight/obesity group showed low self-esteem and specific domains including general, social and academic/school-related (adjusted odds ratios: 1.20 - 1.43, all P < 0.001) except parent/home-related self-esteem (P = 0.36), whereas children being in the early-onset overweight/obesity group showed no significant difference (P ≥ 0.53) except a lower risk of low social self-esteem (adjusted odds ratio = 0.82, P = 0.03). CONCLUSIONS: Late-onset or chronic overweight/obesity predicted low general, social and academic/school-related self-esteem. Children who successfully reduced weight may have equal levels of self-esteem or even better social self-esteem than those being always underweight/normal weight. Overweight/obese children had a vulnerability to self-esteem in non-domestic environments.

Evaluating the Effect of Recurrent Respiratory Papillomatosis on Work Productivity.

OBJECTIVE: Patients with recurrent respiratory papillomatosis (RRP) have significant vocal dysfunction which affects their performance at work. This study aimed to evaluate voice-related work productivity before and after ablative treatment for RRP. METHODS: This is a prospective case series conducted at 2 academic laryngology outpatient clinics. Adult employed patients with RRP completed the Work Productivity & Activity Impairment instrument (WPAI), Voice Handicap Index (VHI-10), WorkHoarse, Hospital Anxiety and Depression Scale (HADS), and a demographics questionnaire immediately before and 1 month after ablative treatment of papilloma. The primary outcome measure was the change in work productivity impairment domain of the WPAI, and changes in ratings before and after ablation were compared using a Wilcoxon Signed-Rank test. RESULTS: The 32 participants (mean age 45, 84% male) had a median (interquartile range) voice-related work productivity impairment score of 48.8% (30.0) at baseline which was improved to 5.0% (10.0) at 1 month after surgical ablation of papillomata (difference 30.0% (30.0) improvement). For the secondary outcome measures, there were significant improvements in VHI-10 (P < .001), self-reported voice quality (P = .002), and Workhoarse (P = .001), but no significant change in HADS. CONCLUSION: Patients with RRP experience significant voice-related work productivity impairment, and ablation of papillomata significantly improves work productivity.

Skipping Breakfast and Eating Breakfast Away From Home Were Prospectively Associated With Emotional and Behavioral Problems in 115,217 Chinese Adolescents.

BACKGROUND: Breakfast is deemed the most important meal of the day. We examined the prospective associations of breakfast habits with emotional/behavioral problems in adolescents and potential effect modification. METHODS: 115,217 Primary 6 students (United States Grade 6; mean age, 11.9; standard deviation [SD], 0.59 years) who attended the Student Health Service of Department of Health in Hong Kong in 2004/05, 2006/07, 2008/09 were followed till Secondary 6 (United States Grade 12). Emotional/behavioral problems were biennially examined using Youth Self-Report since Secondary 2 (United States Grade 8). Lifestyles were biennially examined using standardized questionnaires since Primary 6. Prospective associations of breakfast habit with emotional/behavioral problems and potential effect modification were examined using generalized estimating equations. RESULTS: Compared with eating breakfast at home, eating breakfast away from home was significantly associated with total emotional/behavioral problems and seven syndromes, including withdrawal, somatic complaints, anxiety/depression, thought problems, attention problems, delinquent behaviors, and aggressive behaviors (adjusted odds ratios [AORs] 1.22-2.04), while skipping breakfast showed stronger associations with the above problems and social problems (AORs 1.34-2.29). Stronger associations were observed in younger students for total and attention problems (P < 0.03) and in those with lower weight status for delinquent behaviors (P = 0.005). CONCLUSION: Eating breakfast away from home and especially skipping breakfast were prospectively associated with adolescent emotional/behavioral problems. The associations weakened with increasing age for total emotional/behavioral and attention problems, and weakened with higher weight status for delinquent behaviors, highlighting the vulnerability of younger and underweight children. If the associations are causal, increasing home breakfast may reduce adolescent emotional/behavioral problems and benefit psychosocial health.

Knowledge and Attitudes of Potential Community Health Worker Employers: Findings from the State of Arkansas, USA.

Community health workers (CHWs) are critical to health equity efforts, but sustaining CHW programs is challenging. Understanding stakeholders' knowledge and attitudes about CHWs can inform strategies to advance this important workforce. The authors implemented an online survey of potential CHW employers to learn their perceptions of CHWs' roles, outcomes, and abilities to affect important health outcomes, and of key issues that affect CHW employment. The survey was disseminated statewide to a diverse group of stakeholders working in healthcare in Arkansas. A total of 151 surveys were collected and included in the analysis. The organizations represented by respondents primarily included state and local agencies and clinics, followed by healthcare systems. The main professional roles of survey respondents were administrators and clinicians, followed by healthcare staff. Over 90% of respondents agreed that CHWs have the ability to conduct community outreach, serve as a liaison, navigate health systems, provide coaching support, and participate in care coordination. Over 90% of healthcare administrators, clinicians, and policymakers agreed that standardized training and a clear definition of role and scope of practice are important to CHW employment. However, almost two-thirds of respondents' organizations were not employing CHWs, adding to previous research which has primarily focused on CHW employers' attitudes. Understanding and addressing attitudes of those who lack experience with CHWs can help to identify actions needed to promote and increase adoption of CHWs. The authors share how they are using these data to engage stakeholders in decision-making and adoption of CHWs in their state.

Ablative-Transarterial Radioembolization resulting in complete histopathological response of hepatocellular carcinoma in the resected liver specimen after salvage hepatectomy.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common disease. Many patients at the time of diagnosis of HCC are in advanced stages and cannot benefit from curative treatment. Palliative treatments remain the only treatment option. Advances in palliative treatment can occasionally downstage HCC and induce enough liver hypertrophy to allow salvage hepatectomy to be performed on patients with initially unresectable HCC. We herein present a patient who underwent salvage hepatectomy after successful Ablative-Transarterial Radioembolization (A-TARE) with complete histopathologic response in the resected liver specimen. CASE REPORT: A 67-year old obese patient presented with a 9.7 cm HCC at liver segment 8, with local tumour extension to involve segments 4,5 and 7. Initial workup suggested the tumour to be unresectable. A-TARE with yttrium-90 microspheres was given. Further workup 4 months after A-TARE showed the tumour to be downstaged with adequate hypertrophy of future liver remnant. Salvage hepatectomy became possible and the patient underwent salvage trisectionectomy 5 months after A-TARE. He recovered uneventfully from the operation. Histopathological examination of the resected liver specimen showed no viable tumour cells inside a fibrous mass which corresponded to the radiologic residual tumour. DISCUSSION: Salvage hepatectomy should be offered to patients after tumour downstaging with A-TARE as viable malignant cells are likely to persist. Complete response with no viable tumour cells in the resected liver specimen, to our knowledge, has never been reported in literature. CONCLUSION: A-TARE was able to induce complete histopathological response in a patient who initially presented with a large and unresectable HCC mass.

Using Ultrasound to Screen for Scoliosis to Reduce Unnecessary Radiographic Radiation: A Prospective Diagnostic Accuracy Study on 442 Schoolchildren.

Scoliosis screening is important for timely initiation of brace treatment to mitigate curve progression in skeletally immature children and adolescents. School scoliosis screening programs in Hong Kong follow the protocol of referring children screened positive with a scoliometer and Moiré topography for confirmatory standard radiography. Despite being highly sensitive (88%) in detecting those who require specialist referral, the screening program was found to have a false-positive rate >50%, which could lead to unnecessary X-ray radiation. Radiation-free ultrasound has been reported to be valid and reliable for quantitative assessment of curve severity in scoliosis patients. The aim of this prospective diagnostic accuracy study was to determine the accuracy of ultrasound in determining the threshold of referral that requires X-ray for children screened positive with the scoliometer and Moiré topography. Our study recruited 442 schoolchildren with a mean Cobb angle of 14.0 ± 6.6°. The sensitivity and specificity of ultrasound in predicting the correct referral status, confirmed by X-ray, were 92.3% and 51.6%, with positive and negative predictive values of 29.0% and 96.9%, respectively. Receiver operating characteristic curve analysis revealed area under the curve values of 0.735 for ultrasound alone and 0.832 for ultrasound in combination with measurement of angle of trunk rotation. The finding supports the accuracy of using ultrasound to determine referral status, which could result in a >50% reduction of unnecessary radiation for children undergoing scoliosis screening.

Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP).

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as "undruggable" and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer's disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson's disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets.

Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase.

Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.

Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells.

PURPOSE: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity. EXPERIMENTAL DESIGN: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. RESULTS: As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody (P < 0.05). CONCLUSIONS: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.See related commentary by de Miguel and Pardo, p. 5546.

Will esports result in a higher prevalence of problematic gaming? A review of the global situation.

BACKGROUND AND AIMS: Video gaming is highly prevalent in modern culture, particularly among young people, and a healthy hobby for the majority of users. However, in recent years, there has been increasing global recognition that excessive video gaming may lead to marked functional impairment and psychological distress for a significant minority of players. Esports is a variant of video gaming. It is a relatively new phenomenon but has attracted a considerable number of followers across the world and is a multimillion dollar industry. The aim of this briefing paper is to review the global situation on esports and related public health implications. METHODS: A non-systematic review was conducted. Information obtained from the Internet and PubMed was collated and presented as genres of games, varieties and magnitudes of impacts, popularity, fiscal impact in monetary terms, government involvement, and public health implications. RESULTS: There are several different kinds of esports but there was no clear categorization on the genre of games. Many tournaments have been organized by gaming companies across the world with huge prize pools, and some of these events have government support. Little information on the health effects associated with esports was identified. DISCUSSION AND CONCLUSIONS: A majority of the sources of information were from commercial settings, and failed to declare conflicts of interest, which may result in a biased picture of the current situation. When gaming activity is being further promoted under the umbrella of esports, it seems reasonable to expect an increase in problematic gaming and thus increased prevalence of gaming disorder and hazardous gaming. With increasing demand for treatment services for gaming addition/disorder in different countries across the world, it is a significant public health concern. More empirically based research on this topic is needed.

Discovery of ß-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators.

Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.