Clinical outcomes of chronic myeloid leukaemia patients taking asciminib through a Managed Access Programme (MAP) in Australia.

Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real-world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)-resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib-pretreated cohort.

Smokers' utilization of quitting methods and vaping during pregnancy: an empirical cluster analysis of 2016-2018 Pregnancy Risk Assessment Monitoring System (PRAMS) data in seven US states.

BACKGROUND: Patterns of utilization of numerous smoking cessation methods among pregnant women amidst the increasing popularity of vaping (use of e-cigarettes) remains unknown. METHODS: This study included 3,154 mothers who self-reported smoking around the time of conception and delivered live births in 2016-2018 in seven US states. Latent class analysis was used to identify subgroups of smoking women based on their utilization of 10 surveyed quitting methods and vaping during pregnancy. RESULTS: We identified four subgroups of smoking mothers with different utilization patterns of quitting methods during pregnancy: 22.0% reported "not trying to quit"; 61.4% tried to "quit on my own" without any behavioral or pharmacological assistance; 3.7% belonged to the "vaping" subgroup; and 12.9% utilized "wide-ranging methods" with higher use rate of multiple approaches, such as quit line and nicotine patch. Compared to mothers "not trying to quit," the subgroup trying to "quit on my own" were more likely to be abstinent (adjusted OR 4.95, 95% CI 2.82-8.35) or to reduce the number of cigarettes smoked daily (adjusted OR 2.46, 95% CI 1.31-4.60) in late pregnancy, and these improvements lasted into early postpartum. We did not observe a measurable reduction in smoking among the "vaping" subgroup or women trying to quit with "wide-ranging methods". CONCLUSIONS: We identified four subgroups of smoking mothers with different utilization patterns of eleven quitting methods during pregnancy. Pre-pregnancy smokers who tried to "quit on my own" were most likely to be abstinent or to reduce smoking amount.

A double-blind, placebo-controlled, single-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue, in healthy subjects.

AIM: To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue under development, in healthy males and females presenting with no childbearing potential. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, single-ascending dose study was conducted in 56 subjects who randomly received a single subcutaneous dose of HM15136 or its matching placebo at a ratio of 6:2 at 10, 20, 30, 50, 80, 100, and 120 µg/kg. RESULTS: All adverse events were mild and transient. Neither serious adverse events nor discontinuation as a result of adverse events occurred. The most frequent adverse drug reaction was nausea (5.3%, only in the 100- and 120-µg/kg groups). HM15136, particularly at doses of 50 µg/kg or higher, increased fasting blood glucose, with a maximum increase and area under the curve of 1.5 mmol/L at day 10 (P = .006) and 166.3 day·mmol/L (P = .022) at the dose of 80 µg/kg, while suppressing the secretion of endogenous glucagon, which continued until day 17. HM15136 also significantly reduced gluconeogenic and ketogenic amino acids. Compensatory changes in endogenous insulin and incretin hormones by HM15136 were not apparent. HM15136 was slowly but steadily absorbed and reached a peak concentration at 46-68 hours after a single subcutaneous injection. HM15136 was eliminated with a terminal phase half-life of 77.1-101.1 hours. CONCLUSIONS: A single subcutaneous dose of HM15136 at 10-120 µg/kg was safe and well tolerated. The long half-life of HM15136, coupled with an increase in blood glucose for ~2 weeks, may warrant a weekly dosing regimen.

Salmonella Genomics and Population Analyses Reveal High Inter- and Intraserovar Diversity in Freshwater.

Freshwater can support the survival of the enteric pathogen Salmonella, though temporal Salmonella diversity in a large watershed has not been assessed. At 28 locations within the Susquehanna River basin, 10-liter samples were assessed in spring and summer over 2 years. Salmonella prevalence was 49%, and increased river discharge was the main driver of Salmonella presence. The amplicon-based sequencing tool, CRISPR-SeroSeq, was used to determine serovar population diversity and detected 25 different Salmonella serovars, including up to 10 serovars from a single water sample. On average, there were three serovars per sample, and 80% of Salmonella-positive samples contained more than one serovar. Serovars Give, Typhimurium, Thompson, and Infantis were identified throughout the watershed and over multiple collections. Seasonal differences were evident: serovar Give was abundant in the spring, whereas serovar Infantis was more frequently identified in the summer. Eight of the ten serovars most commonly associated with human illness were detected in this study. Crucially, six of these serovars often existed in the background, where they were masked by a more abundant serovar(s) in a sample. Serovars Enteritidis and Typhimurium, especially, were masked in 71 and 78% of samples where they were detected, respectively. Whole-genome sequencing-based phylogeny demonstrated that strains within the same serovar collected throughout the watershed were also very diverse. The Susquehanna River basin is the largest system where Salmonella prevalence and serovar diversity have been temporally and spatially investigated, and this study reveals an extraordinary level of inter- and intraserovar diversity.IMPORTANCESalmonella is a leading cause of bacterial foodborne illness in the United States, and outbreaks linked to fresh produce are increasing. Understanding Salmonella ecology in freshwater is of importance, especially where irrigation practices or recreational use occur. As the third largest river in the United States east of the Mississippi, the Susquehanna River is the largest freshwater contributor to the Chesapeake Bay, and it is the largest river system where Salmonella diversity has been studied. Rainfall and subsequent high river discharge rates were the greatest indicators of Salmonella presence in the Susquehanna and its tributaries. Several Salmonella serovars were identified, including eight commonly associated with foodborne illness. Many clinically important serovars were present at a low frequency within individual samples and so could not be detected by conventional culture methods. The technologies employed here reveal an average of three serovars in a 10-liter sample of water and up to 10 serovars in a single sample.

Smoking and use of electronic cigarettes (vaping) in relation to preterm birth and small-for-gestational-age in a 2016 U.S. national sample.

Women who smoke may be motivated to switch to vaping (use electronic cigarettes, e-cigs) around pregnancy in seeking to alleviate known hazards of smoking. E-cigs typically contain nicotine but either eliminates or greatly reduces exposure to the combustion products of tobacco. We studied a U.S.-wide representative sample of 31,973 live singleton births in 2016. In the three months before pregnancy, 5029 (14%) mothers exclusively smoked tobacco ("sole smokers") and 976 (3%) used both tobacco and e-cigs ("dual-users"). Among pre-pregnancy sole smokers, 44% continued to only smoke while 1% became dual-users in late pregnancy. Logistic regression models were used to assess the adjusted odds ratios (aOR) for preterm and small-for-gestational-age (SGA) by reported smoking or vaping in late pregnancy. Compared to women who used neither product ("non-users"), late-pregnancy sole smokers had increased risks for preterm birth (aOR 1.6, 95% CI 1.2-2.0) and SGA (aOR 2.4, 95% CI 1.8-2.9), after adjusting for their pre-pregnancy smoking or vaping status and other confounders. The adjusted models also showed that late-pregnancy sole vapers had similar risk of preterm birth as non-users (aOR 1.2, 95% CI 0.5-2.7). Late-pregnancy dual-users also had similar risk of preterm birth as non-users (aOR 1.3, 95% CI 0.8-2.3). However, late-pregnancy sole vapers and dual-users had increased risk of SGA compared to non-users (aOR 2.4, 95% CI 1.0-5.7 for sole vapers, and aOR 2.3 95% CI 1.3-4.1 for dual-users). These findings suggest that vapers during pregnancy had similar risk of preterm as non-users but still had elevated risk for restricted fetal growth.

Analysis of PGT-M and PGT-SR outcomes at a Canadian fertility clinic.

OBJECTIVE: Outcomes from in vitro fertilization (IVF)/intrauterine insemination (ICSI) cycles for patients who underwent preimplantation genetic testing for monogenic/single gene (PGT-M) and structural chromosome rearrangements (PGT-SR) patients were reviewed. Patients pursuing PGT-M and PGT-SR often do not have pre-existing fertility issues and therefore may have uncertain expectations of successful outcomes. Before pursuing PGT-M and PGT-SR, patients require evidence-based counseling regarding the probability of having a healthy child. METHOD: Retrospective review from a single private IVF clinic of 73 PGT patients, from whom a total of 437 blastocysts were biopsied and screened. Embryo results and pregnancy outcomes were analyzed. RESULTS: Of the 45 PGT-M patients, 64.4% had at least one euploid unaffected embryo. The cumulative pregnancy rate for patients who had embryo transfers in this group was 89.7%, with an ongoing pregnancy or delivery rate of 48.9%. For the 28 PGT-SR patients, 60.7% had at least one euploid unaffected embryo. The cumulative pregnancy rate for patients who had embryo transfers in this group was 87.5%, with an ongoing pregnancy or delivery rate of 42.9%. CONCLUSION: This information can supplement the existing data in the literature to counsel new patients in terms of realistic expectations of success following PGT-M and PGT-SR.

Early Magnetic Resonance Imaging Decreases Hospital Length of Stay in Patients with Ischemic Stroke.

BACKGROUND: Imaging modalities are important part of stroke evaluation. Noncontrast head computed tomography (CT) is the initial imaging modality in acute stroke and although important to rule out acute hemorrhage and making a decision on thrombolytic treatment, ischemic changes may not be visible on CT for up to 24 hours. Magnetic resonance imaging (MRI) brain is an invaluable tool to confirm an ischemic stroke and facilitates stroke evaluation. Objective of this study was to investigate the correlation between time to MRI and length of hospital stay. METHODS: A total of 432 patients admitted to Hartford Hospital (Comprehensive Stroke Center) with a focal neurological deficit in the year 2014 and got a CT head and MRI brain were enrolled in the study. Data collection was done via stroke database and retrospective chart review. Patients with any hemorrhage or age <18 years were excluded from the study. Patients were categorized as having had an early (within 12 hours) or a late (more than 12 hours) MRI. We used chi-square and Wilcoxon ranked sum test to compare time from arrival to MRI and length of stay in the hospital. RESULTS: There was a statistically significant difference in hospital length of stay between patients who obtained MRI within 12 hours, as compared with patients who had MRI greater than 12 hours after admission, early MRI group 3 days (1.8, 4.9) versus 4 days (2.6, 7.0), P < .001. CONCLUSIONS: Our study suggests that brain MRI performed within 12 hours of admission facilitates stroke evaluation and decreases hospital length of stay. It provides evidence for cost effectiveness of MRI in ischemic stroke.

Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy.

Metformin, an oral antihyperglycemic, is increasingly being prescribed to pregnant women with gestational diabetes. Metformin is a hydrophilic cation and relies on organic cation transporters to move across cell membranes. We previously demonstrated that human and mouse placentas predominantly express organic cation transporter 3 (OCT3), but the impact of this transporter on maternal and fetal disposition of metformin is unknown. Using immunofluorescence colocalization studies in term human placenta, we showed that OCT3 is localized to the basal (fetal-facing) membrane of syncytiotrophoblast cells with no expression on the apical (maternal-facing) membrane. OCT3 positive staining was also observed in fetal capillaries. To determine the in vivo role of OCT3 in maternal and fetal disposition of metformin, we determined metformin maternal pharmacokinetics and overall fetal exposure in wild-type and Oct3-null pregnant mice. After oral dosing of [14C]metformin at gestational day 19, the systemic drug exposure (AUC0-∞) in maternal plasma was slightly reduced by ∼16% in the Oct3-/- pregnant mice. In contrast, overall fetal AUC0-∞ was reduced by 47% in the Oct3-/- pregnant mice. Consistent with our previous findings in nonpregnant mice, metformin tissue distribution was respectively reduced by 70% and 52% in the salivary glands and heart in Oct3-/- pregnant mice. Our in vivo data in mice clearly demonstrated a significant role of Oct3 in facilitating metformin fetal distribution and exposure during pregnancy. Modulation of placental OCT3 expression or activity by gestational age, genetic polymorphism, or pharmacological inhibitors may alter fetal exposure to metformin or other drugs transported by OCT3.

Risk Factors for Catheter Associated Urinary Tract Infections in a Pediatric Institution.

PURPOSE: Catheter associated urinary tract infections are an essential measure for health care quality improvement that affects reimbursement through hospital acquired condition reduction programs in adult patients. With the mounting importance of preventing such infections we evaluated risk factors for acquiring catheter associated urinary tract infections in pediatric patients. MATERIALS AND METHODS: All catheter associated urinary tract infections were identified at 1 pediatric institution from September 2010 to August 2014 from a prospective database maintained by the infection control office. To identify risk factors patients with a catheter associated urinary tract infection were individually matched to control patients with a urinary catheter but without infection by age, gender, date and the hospital location of the infection in 1:2 fashion. RESULTS: A total of 50 patients with catheter associated urinary tract infection were identified and matched to 100 control patients. Compared to controls the patients with infection were more likely to have a catheter in place for longer (2.9 days, OR 1.08, 95% CI 1.01, 1.15, p = 0.02). They were also more likely to be on contact precautions (OR 4.00, 95% CI 1.73, 9.26, p = 0.001), and have concurrent infections (OR 3.04, 95% CI 1.39, 6.28, p = 0.005) and a history of catheterization (OR 3.24, 95% CI 1.55, 6.77, p = 0.002). Using a conditional multivariate regression model the 3 most predictive variables were duration of catheter drainage, contact isolation status and history of catheterization. CONCLUSIONS: Longer duration of urinary catheter drainage, positive contact precautions status and a history of catheterization appear to be associated with a higher risk of catheter associated urinary tract infection in hospitalized pediatric patients. Physicians should attempt to decrease the duration of catheterization, especially in patients who meet these criteria, to minimize the risk of catheter associated urinary tract infection.

Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands.

Drug-induced taste disturbance is a common adverse drug reaction often triggered by drug secretion into saliva. Very little is known regarding the molecular mechanisms underlying salivary gland transport of xenobiotics, and most drugs are assumed to enter saliva by passive diffusion. In this study, we demonstrate that salivary glands selectively and highly express OCT3 (organic cation transporter-3), a polyspecific drug transporter in the solute carrier 22 family. OCT3 protein is localized at both basolateral (blood-facing) and apical (saliva-facing) membranes of salivary gland acinar cells, suggesting a dual role of this transporter in mediating both epithelial uptake and efflux of organic cations in the secretory cells of salivary glands. Metformin, a widely used anti-diabetic drug known to induce taste disturbance, is transported by OCT3/Oct3 in vitro. In vivo, metformin was actively transported with a high level of accumulation in the salivary glands of wild-type mice. In contrast, active uptake and accumulation of metformin in salivary glands were abolished in Oct3(-/-) mice. Oct3(-/-) mice also showed altered metformin pharmacokinetics and reduced drug exposure in the heart. These results demonstrate that OCT3 is responsible for metformin accumulation and secretion in salivary glands. Our study uncovered a novel carrier-mediated pathway for drug entry into saliva and sheds new light on the molecular mechanisms underlying drug-induced taste disorders.

Evaluation of prenatal hydronephrosis: novel criteria for predicting vesicoureteral reflux on ultrasonography.

PURPOSE: Radiographic evaluation for prenatal hydronephrosis often includes voiding cystourethrography to ascertain whether vesicoureteral reflux is present. We sought to determine whether use of voiding cystourethrography could be limited to those patients at greatest risk for vesicoureteral reflux. We hypothesized that vesicoureteral reflux could be predicted by findings on renal/bladder ultrasonography of hydroureter, renal dysmorphia and/or duplication. MATERIALS AND METHODS: We reviewed the records of patients with prenatal hydronephrosis who underwent initial postnatal ultrasonography and voiding cystourethrography during a 3-year period. The presence of vesicoureteral reflux on voiding cystourethrogram was correlated to ultrasound findings, including hydronephrosis grade, presence of hydroureter, renal dysmorphia or duplication, with ultrasound considered positive for any of the latter 3 findings. RESULTS: Of 262 patients 47 (18%) had vesicoureteral reflux. Ultrasound was positive in 24 of 29 patients (83%) with high grade reflux and 12 of 18 (67%) with low grade reflux. If ultrasonography showed any of the 3 positive findings, the odds ratio of detecting vesicoureteral reflux was 8.07 (95% CI 3.86, 16.87). Using these criteria, among all cases of prenatal hydronephrosis 5 (2%) with high grade vesicoureteral reflux and 6 (2%) with low grade reflux would have been missed. Among the 47 cases of reflux overall 5 of 29 high grade (17%) and 6 of 18 low grade cases (33%) would have been missed. CONCLUSIONS: By using ultrasonography criteria of hydroureter, duplication and renal dysmorphia for patients with prenatal hydronephrosis, vesicoureteral reflux can be detected more specifically. Using our criteria, 165 of 262 voiding cystourethrograms (63%) could have been avoided in patients with prenatal hydronephrosis during a 3-year period. Reducing these evaluations may decrease risks regarding radiation exposure, family anxiety and health care costs.

Thrombosis in patients with immune thrombocytopenia: incidence, risk, and clinical outcomes.

Background: There is evidence that patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis. However, the association of clinical- and treatment-related factors with thrombosis remains controversial. Objectives: To evaluate the incidence and impact of risk factors for arterial and venous thromboembolism (VTE) in patients with ITP and characterize the clinical features and management of patients. Methods: We performed a retrospective cohort study (January 1, 2011, to October 30, 2022) of adult patients diagnosed with ITP from an Australian tertiary hospital. The incidence rates of thrombosis were calculated in terms of person-years of follow-up. Multiadjusted Cox regression was used to estimate associations. Results: A total of 220 patients with 1365 person-years of follow-up since ITP diagnosis revealed 26 (11.8%) patients with a total of 37 thrombosis events, 29 (78%) VTE and 8 (22%) arterial thromboembolism (ATE). The incidence rate of thrombosis was 2.71 (95% CI, 1.97-3.72) (0.66 [95% CI, 0.33-1.26] for arterial thromboembolism and 2.05 [95% CI, 1.42-2.95] for VTE) per 100 person-years. Mean age and median time to first thrombosis diagnosis was 56 and 2.13 years, respectively. Age, secondary ITP, lines of therapy, thrombosis risk factors, and thrombopoietin receptor agonist therapy were independently associated with thrombosis. Almost all patients (25 of 26, [96%]) had good ITP disease control prior to thrombosis diagnosis, and antithrombotic therapy was deliverable and well tolerated. Conclusion: Diagnosis of thrombosis in patients with ITP, while infrequent, is of clinical significance. We identified from a heterogeneous real-world cohort that older patients with multiply-treated secondary ITP receiving thrombopoietin receptor agonists are at the highest risk.

Patient-specific tissue engineered vascular graft for aortic arch reconstruction.

Objectives: The complexity of aortic arch reconstruction due to diverse 3-dimensional geometrical abnormalities is a major challenge. This study introduces 3-dimensional printed tissue-engineered vascular grafts, which can fit patient-specific dimensions, optimize hemodynamics, exhibit antithrombotic and anti-infective properties, and accommodate growth. Methods: We procured cardiac magnetic resonance imaging with 4-dimensional flow for native porcine anatomy (n = 10), from which we designed tissue-engineered vascular grafts for the distal aortic arch, 4 weeks before surgery. An optimal shape of the curved vascular graft was designed using computer-aided design informed by computational fluid dynamics analysis. Grafts were manufactured and implanted into the distal aortic arch of porcine models, and postoperative cardiac magnetic resonance imaging data were collected. Pre- and postimplant hemodynamic data and histology were analyzed. Results: Postoperative magnetic resonance imaging of all pigs with 1:1 ratio of polycaprolactone and poly-L-lactide-co-ε-caprolactone demonstrated no specific dilatation or stenosis of the graft, revealing a positive growth trend in the graft area from the day after surgery to 3 months later, with maintaining a similar shape. The peak wall shear stress of the polycaprolactone/poly-L-lactide-co-ε-caprolactone graft portion did not change significantly between the day after surgery and 3 months later. Immunohistochemistry showed endothelization and smooth muscle layer formation without calcification of the polycaprolactone/poly-L-lactide-co-ε-caprolactone graft. Conclusions: Our patient-specific polycaprolactone/poly-L-lactide-co-ε-caprolactone tissue-engineered vascular grafts demonstrated optimal anatomical fit maintaining ideal hemodynamics and neotissue formation in a porcine model. This study provides a proof of concept of patient-specific tissue-engineered vascular grafts for aortic arch reconstruction.

Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy.

There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy. The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy. Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (P < 0.05) on gestational days (GD) 15 and 19 compared with the non-pregnant controls. There was no change (P > 0.05) in Cyp2d9 and Cyp2d10 mRNA. In agreement with the increased Cyp2d mRNA, Cyp2d-mediated dextrorphan formation from dextromethorphan was increased 2.7-fold (P < 0.05) on GD19 (56.8±39.4 pmol/min/mg protein) when compared with the non-pregnant controls (20.8±11.2 pmol/min/mg protein). An increase in Cyp26a1 mRNA (10-fold) and retinoic acid receptor (Rar)ß mRNA (2.8-fold) was also observed during pregnancy. The increase in Cyp26a1 and Rarß mRNA during pregnancy indicates increased retinoic acid signaling in the liver during pregnancy. A putative retinoic acid response element was identified within the Cyp2d40 promoter and the mRNA of Cyp2d40 correlated (P < 0.05) with Cyp26a1 and Rarß. These results show that Cyp2d mRNA is increased during mouse pregnancy the and mouse may provide a suitable model to investigate the mechanisms underlying the increased clearance of CYP2D6 probes observed during human pregnancy. Our findings also suggest that retinoic acid signaling in the liver is increased during pregnancy, which may have broader implications to energy homeostasis in the liver during pregnancy.

Effect of gestational age on mRNA and protein expression of polyspecific organic cation transporters during pregnancy.

Polyspecific organic cation (OC) transporters play important roles in the disposition of clinically used drugs, including drugs used during pregnancy. Pregnancy is known to alter the expression of drug-metabolizing enzymes and transporters, but its specific effect on OC transporters has not been well defined. Using quantitative polymerase chain reaction and liquid chromatography coupled with tandem mass spectrometry targeted proteomics, we determined the effect of pregnancy and gestational age on mRNA and protein expression of major OC transporters in the kidney, liver, and placenta in mice with timed pregnancies. Human organic cation transporter 3 (hOCT3) expression was further investigated in human placentas from the first and second trimesters and at term. Our results showed that pregnancy had a marginal effect on renal mouse organic cation transporter 1/2 (mOct1/2) expression but significantly reduced mouse multidrug and toxin extrusion transporter 1 (mMate1) expression by 20%-40%. Hepatic expression of mOct1 and mMate1 was minimally affected by pregnancy. Human and mouse placentas predominantly expressed OCT3 with little expression of OCT1/2, MATE1/2, and plasma membrane monoamine transporter (PMAT). The hOCT3 protein in first and second trimester and term placentas was quantified to be 0.23 ± 0.033, 0.38 ± 0.072, and 0.36 ± 0.099 fmol/µg membrane protein, respectively. In contrast with the moderate increase in hOCT3 protein during human pregnancy, mOct3 expression in the mouse placenta was highly dependent on gestational age. Compared with gestational day (gd) 10, placental mOct3 mRNA increased by 37-fold and 46-fold at gd 15 and 19, leading to a 56-fold and 128-fold increase in mOct3 protein, respectively. Our study provides new insights into the effect of pregnancy on the expression of polyspecific OC transporters and supports an important role of OCT3 in OC transport at the placental barrier.

Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial.

Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). Main Outcomes and Measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). Conclusions and Relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. Trial Registration: ANZCTR Identifier: ACTRN12618000811202.

Age and sex differences in the association between neighborhood socioeconomic environment and incident diabetes: Results from the diabetes location, environmental attributes and disparities (LEAD) network.

Objective: Worse neighborhood socioeconomic environment (NSEE) may contribute to an increased risk of type 2 diabetes (T2D). We examined whether the relationship between NSEE and T2D differs by sex and age in three study populations. Research design and methods: We conducted a harmonized analysis using data from three independent longitudinal study samples in the US: 1) the Veteran Administration Diabetes Risk (VADR) cohort, 2) the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, and 3) a case-control study of Geisinger electronic health records in Pennsylvania. We measured NSEE with a z-score sum of six census tract indicators within strata of community type (higher density urban, lower density urban, suburban/small town, and rural). Community type-stratified models evaluated the likelihood of new diagnoses of T2D in each study sample using restricted cubic splines and quartiles of NSEE. Results: Across study samples, worse NSEE was associated with higher risk of T2D. We observed significant effect modification by sex and age, though evidence of effect modification varied by site and community type. Largely, stronger associations between worse NSEE and diabetes risk were found among women relative to men and among those less than age 45 in the VADR cohort. Similar modification by age group results were observed in the Geisinger sample in small town/suburban communities only and similar modification by sex was observed in REGARDS in lower density urban communities. Conclusions: The impact of NSEE on T2D risk may differ for males and females and by age group within different community types.

Urodynamic findings in patients with Currarino syndrome.

PURPOSE: Currarino syndrome is an inherited disorder consisting of a triad of anorectal anomaly, sacrococcygeal defect and presacral mass. We evaluated the urological issues in patients with Currarino syndrome and sought to determine whether spinal cord detethering improves urinary tract function. MATERIALS AND METHODS: We retrospectively reviewed 14 patients diagnosed with Currarino syndrome. We evaluated urinary signs/symptoms and urodynamic findings before and after spinal cord detethering. RESULTS: All patients with Currarino syndrome having a sacral defect and presacral mass were diagnosed between birth and 6 years. Of the patients 86% had a tethered spinal cord that was surgically detethered between 8 months and 6 years (average 3 years). Overall 10 of 12 children who underwent surgery had voiding complaints postoperatively, including urgency, frequency and incontinence. Five patients had recurrent urinary tract infections, of whom 3 had vesicoureteral reflux that resolved spontaneously. Three patients had mild unilateral hydronephrosis without reflux. Ten of 12 patients who underwent spinal cord detethering underwent comprehensive urodynamic evaluation. Of the 5 patients who underwent preoperative and postoperative urodynamic evaluation 3 showed improvement with resolution of detrusor overactivity or dyssynergia postoperatively, and 2 demonstrated no change. Of the 5 patients who underwent only postoperative urodynamic evaluation 4 had abnormal findings, including small capacity, poor compliance, detrusor overactivity, detrusor sphincter dyssynergia and/or high voiding pressure. No progressive denervation was seen on electromyography preoperatively or postoperatively. CONCLUSIONS: Currarino syndrome is a rare congenital disorder with few published reports regarding the long-term implications. Although no solid conclusions could be drawn regarding urodynamic improvement postoperatively due to our small sample size, spinal cord detethering did not lessen ongoing voiding complaints in the study patients.

In utero closure of myelomeningocele does not improve lower urinary tract function.

PURPOSE: Recent data comparing prenatal to postnatal closure of myelomeningocele showed a decreased need for ventriculoperitoneal shunting and improved lower extremity motor outcomes in patients who underwent closure prenatally. A total of 11 children whose spinal defect was closed in utero were followed at our spina bifida center. We hypothesized that in utero repair of myelomeningocele improves lower urinary tract function compared to postnatal repair. MATERIALS AND METHODS: Eleven patients who underwent in utero repair were matched to 22 control patients who underwent postnatal repair according to age, gender and level of spinal defect. Urological outcomes were retrospectively reviewed including urodynamic study data, need for clean intermittent catheterization, use of anticholinergic agents and prophylactic antibiotics, and surgical history. The need for ventriculoperitoneal shunting or spinal cord untethering surgery was also reviewed. RESULTS: Mean followup was 7.2 years for patients who underwent in utero repair and 7.3 years for those who underwent postnatal repair. Mean patient age at compared urodynamic studies was 5.9 years for in utero repair and 6.0 years for postnatal repair. The in utero repair group was comprised of 5 lumbar and 6 sacral level defects with equal matching (1:2) in the postnatal repair cohort. There were no differences between the groups in terms of need for clean intermittent catheterization, incontinence between catheterizations or anticholinergic/antibiotic use. Urodynamic parameters including bladder capacity, detrusor pressure at capacity, detrusor overactivity and the presence of detrusor sphincter dyssynergia were not significantly different between the groups. There was no difference in the rate of ventriculoperitoneal shunting (p = 0.14) or untethering surgery (p = 0.99). CONCLUSIONS: While in utero closure of myelomeningocele has been shown to decrease rates of ventriculoperitoneal shunting and improve motor function, it is not associated with any significant improvement in lower urinary tract function compared to repair after birth.