Interventions for Managing Late Gastrointestinal Symptoms Following Pelvic Radiotherapy: a Systematic Review and Meta-analysis.

AIMS: Pelvic radiotherapy can induce gastrointestinal injury and symptoms, which can affect quality of life. We assessed interventions for managing these symptoms. MATERIALS AND METHODS: A review of randomised controlled trials published between January 1990 and June 2023 from databases including MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, ISRCTN and grey literature sources was conducted. Meta-analyses were carried out using the DerSimonian and Laird random effects model to produce overall treatment differences with 95% confidence intervals. RESULTS: Twenty-eight studies (2392 participants) of varying methodological quality were included. 4% formalin was superior to sucralfate for improving gastrointestinal symptom score (standardised mean difference [SMD] -1.07, 95% confidence interval -1.48 to -0.65). Argon plasma coagulation (APC) was inferior to sucralfate (SMD 1.22, 95% confidence interval 0.84 to 1.59). Counselling positively influenced symptom score (SMD -0.53, 95% confidence interval -0.76 to -0.29), whereas hyperbaric oxygen therapy showed conflicting results. Sucralfate combined with APC increased endoscopic markers of moderate-severe bleeding versus APC alone (risk ratio 2.26, 95% confidence interval 1.12 to 4.55). No definite conclusions on pain, incontinence, diarrhoea, tenesmus or quality of life interventions were confirmed. CONCLUSIONS: Small study sizes, methodological quality and heterogeneity limit support of any individual intervention. APC and 4% formalin seem to be promising interventions, with further larger randomised controlled trials now warranted.

Efficacy of cannabinoids in neurodevelopmental and neuropsychiatric disorders among children and adolescents: a systematic review.

A better understanding of the endocannabinoid system and a relaxation in regulatory control of cannabis globally has increased interest in the medicinal use of cannabinoid-based products (CBP). We provide a systematic review of the rationale and current clinical trial evidence for CBP in the treatment of neuropsychiatric and neurodevelopmental disorders in children and adolescents. A systematic search of MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Trials was performed to identify articles published after 1980 about CBP for medical purposes in individuals aged 18 years or younger with selected neuropsychiatric or neurodevelopmental conditions. Risk of bias and quality of evidence was assessed for each article. Of 4466 articles screened, 18 were eligible for inclusion, addressing eight conditions (anxiety disorders (n = 1); autism spectrum disorder (n = 5); foetal alcohol spectrum disorder (n = 1); fragile X syndrome (n = 2); intellectual disability (n = 1); mood disorders (n = 2); post-traumatic stress disorder (n = 3); and Tourette syndrome (n = 3)). Only one randomised controlled trial (RCT) was identified. The remaining seventeen articles included one open-label trial, three uncontrolled before-and-after trials, two case series and 11 case reports, thus the risk of bias was high. Despite growing community and scientific interest, our systematic review identified limited and generally poor-quality evidence for the efficacy of CBP in neuropsychiatric and neurodevelopmental disorders in children and adolescents. Large rigorous RCTs are required to inform clinical care. In the meantime, clinicians must balance patient expectations with the limited evidence available.

The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype.

Background: Oxytocin and vasopressin systems are altered in Prader Willi syndrome (PWS). However, investigations into endogenous oxytocin and vasopressin levels as well as clinical trials evaluating the effect of exogenous oxytocin on PWS symptoms have had mixed results. It is also unknown whether endogenous oxytocin and vasopressin levels are associated with certain PWS behaviours. Method: We compared plasma oxytocin and vasopressin and saliva oxytocin levels in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. We also compared neuropeptide levels between gender and genetic subtypes within the PWS cohort and examined the relationship between neuropeptide levels and PWS behaviours. Results: While we did not measure a group difference in plasma or saliva oxytocin levels, plasma vasopressin was significantly lower in individuals with PWS compared to controls. Within the PWS cohort, saliva oxytocin levels were higher in females compared to males and individuals with the mUPD compared to the deletion genetic subtype. We also found the neuropeptides correlated with different PWS behaviours for males and females and for genetic subtypes. For the deletion group, higher plasma and saliva oxytocin levels were related to fewer behaviour problems. For the mUPD group, higher plasma vasopressin levels were related to more behaviour problems. Conclusion: These findings support existing evidence of a vasopressin system defect in PWS and for the first time identify potential differences in the oxytocin and vasopressin systems across PWS genetic subtypes.

Gene-Folic Acid Interactions and Risk of Conotruncal Heart Defects: Results from the National Birth Defects Prevention Study.

Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (ORmeta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (ORmeta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (ORmeta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (ORmeta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.

Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240. RESULTS: Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative. DISCUSSION: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

PFAS levels and determinants of variability in exposure in European teenagers - Results from the HBM4EU aligned studies (2014-2021).

BACKGROUND: Perfluoroalkyl substances (PFAS) are man-made fluorinated chemicals, widely used in various types of consumer products, resulting in their omnipresence in human populations. The aim of this study was to describe current PFAS levels in European teenagers and to investigate the determinants of serum/plasma concentrations in this specific age group. METHODS: PFAS concentrations were determined in serum or plasma samples from 1957 teenagers (12-18 years) from 9 European countries as part of the HBM4EU aligned studies (2014-2021). Questionnaire data were post-harmonized by each study and quality checked centrally. Only PFAS with an overall quantification frequency of at least 60% (PFOS, PFOA, PFHxS and PFNA) were included in the analyses. Sociodemographic and lifestyle factors were analysed together with food consumption frequencies to identify determinants of PFAS exposure. The variables study, sex and the highest educational level of household were included as fixed factors in the multivariable linear regression models for all PFAS and each dietary variable was added to the fixed model one by one and for each PFAS separately. RESULTS: The European exposure values for PFAS were reported as geometric means with 95% confidence intervals (CI): PFOS [2.13 µg/L (1.63-2.78)], PFOA ([0.97 µg/L (0.75-1.26)]), PFNA [0.30 µg/L (0.19-0.45)] and PFHxS [0.41 µg/L (0.33-0.52)]. The estimated geometric mean exposure levels were significantly higher in the North and West versus the South and East of Europe. Boys had significantly higher concentrations of the four PFAS compared to girls and significantly higher PFASs concentrations were found in teenagers from households with a higher education level. Consumption of seafood and fish at least 2 times per week was significantly associated with 21% (95% CI: 12-31%) increase in PFOS concentrations and 20% (95% CI: 10-31%) increase in PFNA concentrations as compared to less frequent consumption of seafood and fish. The same trend was observed for PFOA and PFHxS but not statistically significant. Consumption of eggs at least 2 times per week was associated with 11% (95% CI: 2-22%) and 14% (95% CI: 2-27%) increase in PFOS and PFNA concentrations, respectively, as compared to less frequent consumption of eggs. Significantly higher PFOS concentrations were observed for participants consuming offal (14% (95% CI: 3-26%)), the same trend was observed for the other PFAS but not statistically significant. Local food consumption at least 2 times per week was associated with 40% (95% CI: 19-64%) increase in PFOS levels as compared to those consuming local food less frequently. CONCLUSION: This work provides information about current levels of PFAS in European teenagers and potential dietary sources of exposure to PFAS in European teenagers. These results can be of use for targeted monitoring of PFAS in food.

Drug utilization, clinical and economic outcomes of patients with osteoarthritis of the hip and/or knee treated with long-term use of traditional NSAIDs, topical NSAIDs, and COX-2 inhibitors.

OBJECTIVES: To describe and compare baseline characteristics, healthcare and drug utilization, and negative clinical outcomes of commercially-insured patients diagnosed with OA of the hip and/or knee who initiated treatment on traditional oral NSAIDs (tNSAIDs), topical NSAIDs, or cyclooxygenase-2 inhibitors (COX-2s). METHODS: A commercial claims database (1/2012-3/2017) was used to identify patients ≥18 years old, with ≥2 diagnoses of hip and/or knee OA, and ≥90 days supply of NSAIDs. Patients were assigned to cohorts based on the type of NSAID initially prescribed and observed in the 6 months before (baseline) and 36 months after (follow-up) the date of their first NSAID prescription after the first OA diagnosis. Analyses estimated baseline demographic and clinical characteristics and follow-up period drug utilization. Logistic regressions assessed the risk of gastrointestinal (GI) and acute renal failure (ARF) events. RESULTS: tNSAIDs were the most frequently prescribed treatment. During the follow-up period, less than 15% of patients prescribed tNSAIDs switched to either COX-2s or topical NSAIDs and 37% of patients prescribed a COX-2 and 56% of patients prescribed a topical NSAID switched to tNSAIDs. GI and ARF events during the follow-up period ranged from 7.3-8.1% and 8.0-11.0%, respectively, across cohorts. The tNSAIDs and COX-2s cohorts had increased risk of both types of events relative to patients prescribed topical NSAIDs, controlling for other characteristics. CONCLUSIONS: Analyses characterize the long-term real-world utilization of NSAIDs and associated outcomes for patients with OA of the hip and/or knee. Study results highlight the likelihood of switching and the risk of negative clinical outcomes associated with long-term use.

Incidence and prediction of HBsAg seroclearance in a prospective multi-ethnic HBeAg-negative chronic hepatitis B cohort.

BACKGROUND AND AIMS: Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics. METHODS: The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated. RESULTS: Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253 HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively. CONCLUSION: HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling.

Structural Characterization of Degrader-Induced Ternary Complexes Using Hydrogen-Deuterium Exchange Mass Spectrometry and Computational Modeling: Implications for Structure-Based Design.

The field of targeted protein degradation (TPD) has grown exponentially over the past decade with the goal of developing therapies that mark proteins for destruction leveraging the ubiquitin-proteasome system. One common approach to achieve TPD is to employ a heterobifunctional molecule, termed as a degrader, to recruit the protein target of interest to the E3 ligase machinery. The resultant generation of an intermediary ternary complex (target-degrader-ligase) is pivotal in the degradation process. Understanding the ternary complex geometry offers valuable insight into selectivity, catalytic efficiency, linker chemistry, and rational degrader design. In this study, we utilize hydrogen-deuterium exchange mass spectrometry (HDX-MS) to identify degrader-induced protein-protein interfaces. We then use these data in conjunction with constrained protein docking to build three-dimensional models of the ternary complex. The approach was used to characterize complex formation between the E3 ligase CRBN and the first bromodomain of BRD4, a prominent oncology target. We show marked differences in the ternary complexes formed in solution based on distinct patterns of deuterium uptake for two degraders, CFT-1297 and dBET6. CFT-1297, which exhibited positive cooperativity, altered the deuterium uptake profile revealing the degrader-induced protein-protein interface of the ternary complex. For CFT-1297, the ternary complexes generated by the highest scoring HDX-constrained docking models differ markedly from those observed in the published crystal structures. These results highlight the potential utility of HDX-MS to provide rapidly accessible structural insights into degrader-induced protein-protein interfaces in solution. They further suggest that degrader ternary complexes exhibit significant conformation flexibility and that biologically relevant complexes may well not exhibit the largest interaction surfaces between proteins. Taken together, the results indicate that methods capable of incorporating linker conformation uncertainty may prove an important component in degrader design moving forward. In addition, the development of scoring functions modified to handle interfaces with no evolved complementarity, for example, through consideration of high levels of water infiltration, may prove valuable. Furthermore, the use of crystal structures as validation tools for novel degrader methods needs to be considered with caution.

Slow and Steady Wins the Race: A Solid Case for a 3-Stage Approach in Ulcerative Colitis.

BACKGROUND: Approximately 10% to 20% of patients with ulcerative colitis require surgery during their disease course, of which the most common is the staged restorative proctocolectomy with IPAA. OBJECTIVE: The aim was to compare the rates of anastomotic leaks among all staged restorative proctocolectomy with IPAA procedures. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a single tertiary care IBD center. PATIENTS: All patients with ulcerative colitis or IBD-unspecified who underwent a primary total proctocolectomy with IPAA for medically refractory disease or dysplasia between 2008 and 2017 were identified. MAIN OUTCOME MEASURES: The primary outcome was anastomotic leak within a 6-month postoperative period. Univariate and multivariate logistic regression were used to compare patients with and without anastomotic leaks. RESULTS: The sample was composed of 584 nonemergent patients, of whom 50 (8.6%) underwent 1-stage, 162 (27.7%) underwent 2-stage, 58 (9.9%) underwent modified 2-stage, and 314 (53.7%) underwent a 3-stage total proctocolectomy with IPAA. The primary indication was medically refractory disease in 488 patients and dysplasia/cancer in 101 patients. Anastomotic leak occurred in 10 patients (3.2%) after 3-stage, 14 patients (8.6%) after 2-stage, 6 patients (10.3%) after modified 2-stage, and 10 patients (20.0%) after a 1-stage procedure. A 3-stage procedure had fewer leaks and additional procedures for leaks compared with 1- and modified 2-stage procedures (p < 0.03). The 3-stage procedure had fewer combined anastomotic leaks and pelvic abscesses than all of the other staged procedures (p < 0.05). LIMITATIONS: This study was limited by its retrospective design and evolving electronic medical charts system. CONCLUSIONS: The 3-stage total proctocolectomy with IPAA is the optimal staged method in ulcerative colitis to reduce leaks and related complications. See Video Abstract at http://links.lww.com/DCR/B693. LENTO Y CONSTANTE GANA LA CARRERA UN CASO SLIDO PARA UN ENFOQUE DE TRES ETAPAS EN LA COLITIS ULCEROSA: ANTECEDENTES:Aproximadamente el 10-20% de los pacientes con colitis ulcerosa requieren cirugía durante el curso de su enfermedad, de los cuales la más común es la proctocolectomía restauradora escalonada con anastomosis con bolsa ileo-anal.OBJETIVO:El objetivo fue comparar las tasas de fugas anastomóticas entre todos los procedimientos de proctocolectomía restauradora por etapas con procedimiento de anastomosis con bolsa ileo-anal.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLÍNICO:Este estudio se llevó a cabo en un único centro de atención terciaria de tercer nivel para enfermedades inflamatorias del intestino.PACIENTES:Se identificaron todos los pacientes con colitis ulcerosa o enfermedad inflamatoria intestinal inespecífica que se sometieron a una proctocolectomía total primaria mas anastomosis con bolsa ileo-anal por enfermedad médicamente refractaria o displasia entre 2008 y 2017.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la fuga anastomótica dentro de un período posoperatorio de seis meses. Se utilizó regresión logística univariante y multivariante para comparar pacientes con y sin fugas anastomóticas.RESULTADOS:La muestra estuvo compuesta por 584 pacientes no emergentes, de los cuales 50 (8,6%) se sometieron a una etapa, 162 (27,7%) se sometieron a dos etapas, 58 (9,9%) se sometieron a modificación en dos etapas y 314 (53,7%) se sometieron a una proctocolectomía total en tres tiempos mas anastomosis con bolsa ileo-anal. La indicación principal fue enfermedad médicamente refractaria en 488 pacientes y displasia / cáncer en 101 pacientes. Se produjo una fuga anastomótica en 10 (3,2%) pacientes después de tres etapas, 14 (8,6%) pacientes después de dos etapas, 6 (10,3%) pacientes después de dos etapas modificadas y 10 (20,0%) pacientes después de una etapa procedimiento. Un procedimiento de tres etapas tuvo menos fugas y procedimientos adicionales para las fugas en comparación con los procedimientos de una y dos etapas modificadas (p <0.03). El procedimiento de tres etapas tuvo menos fugas anastomóticas y abscesos pélvicos combinados que todos los demás procedimientos por etapas (p <0,05).LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo y su sistema de registros médicos electrónicos en evolución.CONCLUSIONES:La proctocolectomía total en tres etapas mas anastomosis con bolsa ileo-anal es el método óptimo por etapas en la colitis ulcerosa para reducir las fugas y las complicaciones relacionadas. Consulte Video Resumen en http://links.lww.com/DCR/B693.

Hepatitis B e antigen loss in adults and children with chronic hepatitis B living in North America: A prospective cohort study.

Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co-infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24 weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24-48 weeks. HBeAg loss was defined as first HBeAg-negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg-negative values ≥24 weeks apart. During a median follow-up of 1.8 years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8-13.3) per 100 person-years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre-core mutations versus wild type. Additionally, during follow-up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies.

Prostate cancer bone metastases confined to the distal left lower limb.

Bone metastases from prostate cancer most commonly affect the axial and proximal appendicular skeleton with rare involvement of the distal limbs. We describe a case of multiple bone metastases confined to the left lower limb in a patient with biochemical recurrence of prostate cancer. Following an initial post-operative PSA rise, the patient received a course of salvage radiotherapy to the pelvis, however, the PSA level continued to rise and two consequent staging CT scans were negative for local recurrence and metastatic disease. Subsequent development of left ankle pain and swelling led the patient to present to his General Practitioner, which triggered a series of imaging investigations that revealed isolated left lower limb bone metastases. This case report highlights the need to consider peripheral limb bone metastases in patients with biochemical recurrence of prostate cancer, particularly in the setting of a negative staging CT scan and/or bone pain.

Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease.

BACKGROUND: Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression. RESULTS: We identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues. CONCLUSIONS: Our results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs.

Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models.

Targeted, catalytic degradation of oncoproteins using heterobifunctional small molecules is an attractive modality, particularly for hematologic malignancies, which are often initiated by aberrant transcription factors and are challenging to drug with inhibitors. BRD4, a member of the bromodomain and extraterminal family, is a core transcriptional and epigenetic regulator that recruits the P-TEFb complex, which includes Cdk9 and cyclin T, to RNA polymerase II (pol II). Together, BRD4 and CDK9 phosphorylate serine 2 (pSer2) of heptad repeats in the C-terminal domain of RPB1, the large subunit of pol II, promote transcriptional elongation. Small-molecule degraders of BRD4 have shown encouraging efficacy in preclinical models for several tumor types but less efficacy in other cancers including small-cell lung cancer (SCLC) and pancreatic cancer. Here, we evaluated CFT-2718, a new BRD4-targeting degrader with enhanced catalytic activity and in vivo properties. In vivo, CFT-2718 has significantly greater efficacy than the CDK9 inhibitor dinaciclib in reducing growth of the LX-36 SCLC patient-derived xenograft (PDX) model and performed comparably to dinaciclib in limiting growth of the PNX-001 pancreatic PDX model. In vitro, CFT-2718 reduced cell viability in four SCLC and two pancreatic cancer models. In SCLC models, this activity significantly exceeded that of dinaciclib; furthermore, CFT-2718 selectively increased the expression of cleaved PARP, an indicator of apoptosis. CFT-2718 caused rapid BRD4 degradation and reduced levels of total and pSer2 RPB1 protein. These and other findings suggest that BRD-mediated transcriptional suppression merits further exploration in the setting of SCLC.

Clinical significance of quantitative e antigen in a cohort of hepatitis B virus-infected children and adults in North America.

BACKGROUND: In chronic hepatitis B (CHB) viral infection, e antigen positivity (HBeAg+) is associated with high levels of viral replication and infectivity. Furthermore, HBeAg-positive CHB is associated with a liver disease spectrum ranging from none to severe. AIM: To assess whether the level of circulating HBeAg is associated with different clinical presentations of HBeAg-positive CHB. METHODS: A cross-sectional analysis was conducted among HBV mono-infected participants enrolled in Hepatitis B Research Network (HBRN) cohorts to explore clinical and virological associations with quantitative HBeAg (qHBeAg). RESULTS: Among 763 HBeAg+ participants (56% female; 85% Asian; median age 26 years), multivariable median regression modelling significantly associated qHBeAg with liver injury (inverse qHBeAg association with ALT p<.001 and APRI p<.001), and with both race and age (p=0.01). Among Asians, qHBeAg was inversely related to age; a relationship less clear among Blacks and Whites. Among Asians also, median qHBeAg levels were higher among those infected with HBV genotype C versus B (p<0.001), suggesting causal virologic differences. Across all races, median qHBeAg was higher in women (p=.01). Independent of sex, age, race and HBV genotype, qHBeAg was higher in participants with predominant wild-type versus basal core promoter and/or precore 'stop' viral variants (p<0.001). CONCLUSION: Lower qHBeAg was observed among HBRN participants with the greatest degree of liver injury independent of demographics and HBV genotype. These data support longitudinal studies to examine the role of qHBeAg in modulating the host immune response and predicting the outcomes of chronic HBV infection.

Interobserver Agreement in the Diagnosis of Parkinson Disease with Cardiac 123I-Metaiodobenzylguanidine Scintigraphy.

The aim of this study was to analyze the interobserver agreement of visual and quantitative assessment of cardiac 123I-metaiodobenzylguanidine scintigraphy. Methods: Planar images were acquired using a low-energy collimator. The heart-to-mediastinum (HM) ratio was adjusted for the use of a low-energy collimator, using a published formula. Interpretation was undertaken both visually and after the addition of adjusted HM ratios. Image findings were classified as normal, abnormal, or borderline. Results: The cohort consisted of 10 patients. On visual interpretation only, there was strong agreement on the interpretation of the scan (κ = 0.82, P < 0.01). Adjusted HM ratios led to a significant increase in mean ratios (1.79 vs. 1.36, P = 0.02) and, when utilized in reporting, resulted in perfect agreement (κ = 1.0, P < 0.01). Conclusion: The use of quantified HM ratios adjusted for low-energy collimator use improves on visual assessment alone and allowed for excellent interobserver agreement.

Health Justice for LGBT Youths: Combining Public Health and Human Rights.

As a socially marginalized group, LGBT youths experience elevated rates of physical and mental health problems that are leading causes of mortality due to a variety of factors. Minority stress theory links exposure to stigma with health outcome disparities. Structural stigma including biased laws, policies, and societal norms predicts approximately 20% of elevated suicidality among LGBT youths. Comprehensive public health efforts to reduce mental health disparities among LGBT youths need to address structural stigma. An interdisciplinary Health Justice approach is described, in which public health evidence is integrated with human rights principles in keeping with the bioethical Justice Imperative. In this approach, epidemiological research is used to inform public health efforts to address health disparities in LGBT youths due to structural stigma in a way that is (1) empirical; (2) aimed at basic goals of reducing morbidity and mortality; (3) applicable to diverse cultural contexts; (4) capable of amending stigma-related power and associated health inequities; and (5) guided by human rights principles. By applying human rights principles to public health needs, this approach will help to achieve health equity for LGBT youths.

A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination.

Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin-proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.