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Purpose: The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts. Patients and Methods: In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). Results: In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance Conclusions: Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL (

There are no evidence-based guidelines to inform genetic counseling for consanguineous couples and their offspring. This focused revision builds on the expert opinions from the original publication of "Genetic Counseling and Screening of Consanguineous Couples and Their Offspring," based on a review of literature published since 2002.

PURPOSE To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4–negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering–defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4–negative patients.

Background: Loss of laryngeal function after congenital cardiac surgery causes morbidity and prolongs hospitalization. Early diagnosis of vocal fold immobility (VFI) and referral to pediatric otolaryngology (pOTO) aids in laryngeal rehabilitation. Understanding the incidence and recovery rates of VFI enables counseling for families of infants undergoing high-risk surgery. Methods: A retrospective chart review from November 2014 to July 2019 of infants postcardiac surgery where the aortic arch or surrounding structures were manipulated and were screened via flexible fiberoptic laryngoscopy (FFL) at a single institution was performed. Patients were divided into five surgical categories: Norwood procedure, aortic arch augmentation via median sternotomy, arterial switch operation, coarctation repair via lateral thoracotomy, and cardiac surgeries including ligation of a patent ductus arteriosus (PDA). Patients undergoing isolated PDA ligation were excluded. Results: One hundred ninety-nine qualifying operations occurred during this period; 28 patients did not undergo FFL before discharge and were excluded from the analysis. Immediately following cardiac surgery, 34% (58 of 171 patients) had VFI. Follow-up was completed by 38 of 58 patients with VFI. Complete recovery was demonstrated in 63% (24 of 38) of patients by 6 months and in 86% (33 of 38) within 18 months. The highest risk occurred with the Norwood procedure and arch augmentation via median sternotomy. Conclusions: Infants undergoing surgery involving the aortic arch and surrounding structures have high rates of VFI. Follow-up by pOTO is recommended to optimize laryngeal rehabilitation. Most patients have spontaneous recovery within 18 months of cardiac surgery.

The Arba'een pilgrimage in Iraq is now the largest annual gathering in a single place worldwide. To monitor and address the health needs of pilgrims in field clinics near the pilgrimage route, a syndromic surveillance system was designed and implemented by Global Health Development/Eastern Mediterranean Public Health Network in collaboration with Iraq Ministry of Health. This study aimed to analyze the effectiveness of the surveillance system and the data it gathered in evaluating the burden of common acute and infectious conditions, chronic conditions, and trauma and injuries during the Arba'een pilgrimage in 2018. Data were collected at 152 field clinics located across 11 governorates in Iraq at strategic points along the Arba'een pilgrimage route from all governorates to Karbala between October 8 and November 3, 2018. A team of 24 surveillance supervisors trained, oversaw, and provided technical support for 304 data collectors. The data collectors recorded data from 338,399 patients (42.5% female and 57.5% male) in the span of 26 days. The vast majority of patients were from Iraq (n = 294,260, 87.6%) and Iran (n = 34,691, 10.3%). Of the 338,399 patients whose data were recorded by the surveillance system, 246,469 (72.8%) reported acute and infectious conditions, 202,032 (59.70%) reported chronic conditions, and 6,737 (2.0%) reported traumas and injuries. Many patients reported several conditions in multiple categories. The most prevalent acute condition treated was influenza-like illness, identified through patients exhibiting a combination of fever and cough symptoms. Findings from this study will help inform future planning efforts so healthcare workers can be better prepared for treating such cases at mass gatherings. With the latest challenges posed by the COVID-19 pandemic, preparations for a possible future outbreak of the novel coronavirus are also discussed. The information from this study serves as a foundation to inform and optimize future planning of wide-scale surveillance efforts and address challenges in health service delivery and health security.

Psychological factors, such as mental illness, mental health, attitudes, emotions, and coping styles, are known to impact the success of audiological rehabilitation. However, evidence suggests that audiologists are not sufficiently addressing client psychological factors. Psychologically informed practice, implemented in other healthcare professions, is a framework that guides clinicians in addressing both the physical and psychological factors of a condition throughout rehabilitation. Psychologically informed practice may also be an appropriate framework to improve client outcomes in audiology. The objectives of this study were (1) to determine the barriers and facilitators to audiologists addressing client mental health, psychological symptoms, emotions, and feelings, and (2) to determine audiologists' preparedness and willingness to implement aspects of psychologically informed practice in audiological rehabilitation.A cross-sectional survey was conducted with a convenience sample of 118 Australian clinical audiologists (83.1%, n = 98 female) working in adult audiological rehabilitation.Most participants (91.5%) reported at least one barrier to discussing mental health with clients, with the most common being insufficient knowledge and skills in mental health (39.8%). Applying the COM-B model of behavior change, audiologists reported that factors related to motivation were primarily facilitators, and factors related to opportunity (e.g., lack of time) and capabilities (e.g., insufficient knowledge) were barriers to discussing client mental health. Many participants (83.1%) reported willingness to incorporate a clear protocol, including when and how to refer to psychological services, within audiological rehabilitation.Audiologists were generally motivated to incorporate psychologically informed practice into audiological rehabilitation; however, lack of knowledge and organizational barriers would need to be overcome. The insights gained in this study provide a foundation for developing a viable approach to psychologically informed practice, which may ultimately encourage audiologists to engage in person-centered care more actively.

ObjectivesTo assess the prevalence and incidence of diabetes among Aboriginal peoples in remote communities of the Northern Territory (NT), Australia.DesignRetrospective cohort analysis of linked clinical and administrative data sets from 1 July 2012 to 30 June 2019.SettingRemote health centres using the NT Government Primary Care Information System (51 out of a total of 84 remote health centres in the NT).ParticipantsAll Aboriginal clients residing in remote communities serviced by these health centres (N=21 267).Primary outcome measuresDiabetes diagnoses were established using hospital and primary care coding, biochemistry and prescription data.ResultsDiabetes prevalence across all ages increased from 14.4% (95% CI: 13.9% to 14.9%) to 17.0% (95% CI: 16.5% to 17.5%) over 7 years. Among adults (≥20 years), the 2018/2019 diabetes prevalence was 28.6% (95% CI: 27.8% to 29.4%), being higher in Central Australia (39.5%, 95% CI: 37.8% to 41.1%) compared with the Top End region (24.2%, 95% CI: 23.3% to 25.1%, pConclusionsThe burden of diabetes in the remote Aboriginal population of the NT is among the highest in the world. Strengthened systems of care and public health prevention strategies, developed in partnership with Aboriginal communities, are needed.

Cavities in the hippocampus are morphological variants of uncertain significance. Aberrant neurodevelopment along with vascular and inflammatory etiologies have been proposed. We sought to characterize these cavities and their potential risk factors in a marginally housed population, with high rates of viral infection, addiction, and mental illness. (1) The volume of hippocampal cavities (HCavs) is greater in this highly multimorbid population compared to the general population. (2) Conventional vascular risk factors such as greater age and systolic blood pressure are associated with higher HCav volume. (3) Nonprescribed substance-related risk factors such as stimulant use or dependence, and smoking are associated with increased HCav volume independent of vascular risk factors. This is a retrospective analysis of an ongoing prospective study. We analyzed baseline data, including medical history, physical exam, psychiatric diagnosis, and MRI from a total of 375 participants. Hippocampal cavities were defined as spaces isointense to CSF on T1 MRI sequences, bounded on all sides by hippocampal tissue, with a volume of at least 1 mm

von Willebrand factor (VWF) is an essential hemostatic protein that is synthesized in endothelial cells and stored in Weibel-Palade bodies (WPBs). Understanding the mechanisms underlying WPB biogenesis and exocytosis could enable therapeutic modulation of endogenous VWF, yet optimal targets for modulating VWF release have not been established. Because biogenesis of lysosomal related organelle-2 (BLOC-2) functions in the biogenesis of platelet dense granules and melanosomes, which like WPBs are lysosome-related organelles, we hypothesized that BLOC-2–dependent endolysosomal trafficking is essential for WPB biogenesis and sought to identify BLOC-2–interacting proteins. Depletion of BLOC-2 caused misdirection of cargo-carrying transport tubules from endosomes, resulting in immature WPBs that lack endosomal input. Immunoprecipitation of BLOC-2 identified the exocyst complex as a binding partner. Depletion of the exocyst complex phenocopied BLOC-2 depletion, resulting in immature WPBs. Furthermore, releasates of immature WPBs from either BLOC-2 or exocyst-depleted endothelial cells lacked high-molecular weight (HMW) forms of VWF, demonstrating the importance of BLOC-2/exocyst-mediated endosomal input during VWF maturation. However, BLOC-2 and exocyst showed very different effects on VWF release. Although BLOC-2 depletion impaired exocytosis, exocyst depletion augmented WPB exocytosis, indicating that it acts as a clamp. Exposure of endothelial cells to a small molecule inhibitor of exocyst, Endosidin2, reversibly augmented secretion of mature WPBs containing HMW forms of VWF. These studies show that, although BLOC-2 and exocyst cooperate in WPB formation, only exocyst serves to clamp WPB release. Exocyst function in VWF maturation and release are separable, a feature that can be exploited to enhance VWF release.

Background and Purpose: We aim to describe the burden, characteristics, and cognitive associations of cerebral small vessel disease in a Canadian sample living with multimorbidity in precarious housing. Methods: Participants received T1, T2-fluid-attenuated inversion recovery, and susceptibility-weighted imaging 3T magnetic resonance imaging sequences and comprehensive clinical, laboratory, and cognitive assessments. Cerebral small vessel disease burden was characterized using a modified Small Vessel Disease (mSVD) score. One point each was given for moderate-severe white matter hyperintensities, ≥1 cerebral microbleeds, and ≥1 lacune. Multivariable regression explored associations between mSVD score, risk factors, and cognitive performance. Results: Median age of the 228 participants (77% male) was 44.7 years (range, 23.3–63.2). In n=188 participants with consistent good quality magnetic resonance imaging sequences, mSVD scores were 0 (n=127, 68%), 1 (n=50, 27%), and 2 (n=11, 6%). Overall, one-third had an mSVD ≥1 n=61 (32%); this proportion was unchanged when adding participants with missing sequences n=72/228 (32%). The most prevalent feature was white matter hyperintensities 53/218 (24%) then cerebral microbleed 16/191 (8%) and lacunes 16/228 (7%). Older age (odds ratio, 1.10 [95% CI, 1.05–1.15], P P =0.008), and a history of injection drug use (odds ratio, 3.13 [95% CI, 1.07–9.16], P =0.037) had significant independent associations with a mSVD score of ≥1 in multivariable analysis. mSVD ≥1 was associated with lower performance on tests of verbal memory, sustained attention, and decision-making, contributing 4% to 5% of the variance in each cognitive domain. Conclusions: The 32% prevalence of cerebral small vessel disease in this young, socially marginalized cohort was higher than expected for age and was associated with poorer cognitive performance.

PURPOSE Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)–directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity. METHODS Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy. RESULTS Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes. CONCLUSION To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

Introduction Long-term effects of physical activity and television (TV) viewing on mortality have been inferred from observational studies. The associations observed do not allow for inferences about the effects of population interventions and could be subject to bias due to time-varying confounding. Methods Using data from the Australian Diabetes, Obesity and Lifestyle Study, collected in 1999–2000 (T0), 2004–2005 (T1), and 2011–2012 (T2), we applied the parametric g-formula to estimate cumulative risks of death under hypothetical interventions on physical activity and/or TV viewing determined from self-report while adjusting for time-varying confounding. Results In the 6377 participants followed up for 13 yr from 2004 to 2005 to death or censoring in 2017, 781 participants died. The observed cumulative risk of death was 12.2%. The most effective hypothetical intervention was to increase weekly physical activity to >300 min (risk ratio (RR), 0.66 (0.46–0.86) compared with a “worst-case” scenario; RR, 0.83 (0.73–0.94) compared with no intervention). Reducing daily TV viewing to

BACKGROUND Depression continues to be a public health crisis for young adults. For high school students, past research has identified trauma as a significant predictor of depression. Congruent with the theory of cumulative stress, the present study hypothesized that the effect of sexual assault on depression would be stronger among lesbian, gay, and bisexual (LGB) students than among their straight peers. METHODS Using the Youth Risk Behavior Survey completed by students attending Duval County Public Schools in Florida (N = 3053), this study used secondary data analysis to conduct 2 regression analyses, one for boys and one for girls. RESULTS LGB status was associated with 3-fold increase in the odds of reporting depression for both boys and girls. History of sexual assault was associated with a significant increase in reporting depression. There was also a significant interaction effect between sexual orientation and history of sexual assault among male students only (p

Cancer vaccine development has proven challenging with the exception of some virally induced cancers for which prophylactic vaccines exist. Currently, there is only one FDA approved vaccine for the treatment of prostate cancer and as such prostate cancer continues to present a significant unmet medical need. In this study, we examine the effectiveness of a therapeutic cancer vaccine that combines the ISCOMATRIX™ adjuvant (ISCOMATRIX) with the Toll-like receptor 3 agonist, polyinosinic–polycytidylic acid (Poly I:C), and Flt3L, FMS-like tyrosine kinase 3 ligand. We employed the TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) model of prostate cancer and the self-protein mPAP (prostatic acid phosphatase) as the tumor antigen. ISCOMATRIX™–mPAP–Poly I:C–Flt3L was delivered in a therapeutic prime-boost regime that was consistently able to achieve complete tumor regression in 60% of animals treated and these tumor-free animals were protected upon rechallenge. Investigations into the underlying immunological mechanisms contributing to the effectiveness of this vaccine identified that both innate and adaptive responses are elicited and required. NK cells, CD4+ T cells and interferon-γ were all found to be critical for tumor control while tumor infiltrating CD8+ T cells became disabled by an immunosuppressive microenvironment. There is potential for broader application of this cancer vaccine, as we have been able to demonstrate effectiveness in two additional cancer models; melanoma (B16-OVA) and a model of B cell lymphoma (Eµ-myc-GFP-OVA). Electronic supplementary material The online version of this article (10.1007/s00262-020-02597-6) contains supplementary material, which is available to authorized users.

Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).

Few studies have assessed whether children exposed to in utero hyperglycaemia experience different growth trajectories compared to unexposed children.To assess association of type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) with early childhood weight, length/height and body mass index (BMI) trajectories, and with timing and magnitude of peak BMI in infancy.PANDORA is a birth cohort recruited from an Australian hyperglycaemia in pregnancy register, and women with normoglycaemia recruited from the community. Offspring growth measures were obtained from health records over a median follow-up of 3.0 years (interquartile range 1.9-4.0). This analysis included children born to Aboriginal mothers with in utero normoglycaemia (n = 95), GDM (n = 228) or T2D (n = 131). Growth trajectories (weight, length/height and BMI) were estimated using linear mixed models with cubic spline functions of child age.After adjustment for maternal factors (age, BMI, parity, smoking, and socioeconomic measures) and child factors (age, gestational age at birth, and sex), children born to mothers with T2D or GDM had lower weight, length/height and BMI trajectories in infancy than children born to mothers with normoglycaemia, but similar weight and BMI by completion of follow-up. Children exposed to T2D had lower mean peak BMI 17.6 kg/mMaternal hyperglycaemia was associated with differences in early childhood growth trajectories after adjustment for maternal BMI. Exploration of associations between in utero hyperglycaemia exposure and growth trajectories into later childhood is required.

Objectives and importance of study: Interventions are needed to help general practitioners (GPs) better support clients living with age-related hearing loss. This project canvassed stakeholder views regarding how GPs might better support people with hearing loss. Study type: A group concept-mapping approach was used to identify enablers to improving the way in which GPs could support people with age-related hearing loss. Methods: Concept-mapping techniques were used to gather the perspectives of GPs (n = 7), adults with hearing loss (n = 21), and professionals working with GPs (n = 4) in Australia. Participants generated statements in response to the question, “What would enable GPs to better support people with hearing loss?” Participants then grouped and ranked these statements via an online portal. Results: Five concepts were identified: 1) making hearing assessment part of routine care; 2) asking questions and raising concerns; 3) listening with empathy and respect; 4) having knowledge and understanding; 5) being connected to expert hearing professional networks. Statements contained within all five concepts were deemed to be highly beneficial in this context, with no individual concept identified to be more or less beneficial than any of the other four concepts. Conclusions: A wide range of hearing-specific and general communication approaches were identified that could potentially help GPs to better support their adult patients with age-related hearing loss.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Epidemiological studies have described higher rates of psychotic disorder diagnoses in transgender, as compared to cisgender, individuals. With the exception of this work and a small number of published case studies, however, there has been little consideration of gender diversity in psychosis research or clinical care. In this paper, we will review and critically evaluate the limited literature on gender diversity and clinical psychosis and articulate the critical need for more work in this field, more specifically on the following areas and how they bear on clinical care: 1) diagnostic biases; 2) how chronic non-affirmation and bias, gender dysphoria, and other gender minority stressors may operate as trauma and can contribute to clinically significant psychotic symptoms; 3) the potential impact of gender-affirming care, such as hormone therapies, on mental health and barriers for receiving such care in transgender and nonbinary individuals; and 4) culturally-sensitive and gender-affirming approaches for addressing psychosis. Finally, we consider ways in which researchers may engage in ethical, gender-affirming, and accurate approaches to better address gender identity in psychosis research. We hope that such research will aid in the creation of clinical guidelines for understanding, diagnosing, and treating psychosis in gender diverse individuals.

A 29-year-old man with schizophrenia treated with aripiprazole 15 mg/d visited his psychiatrist accompanied by his mother, who mentioned that although her son is doing well, she must remind him to take his medication. The psychiatrist offered the patient injectable aripiprazole once monthly (AOM)

Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK) approved in the United States and European Union for adult patients with CLL [1], has helped shift the treatment par...

The objectives of this study were to investigate the occurrence, types and severity of malocclusions in children with speech sound disorder (SSD) persisting after 6 years of age, and to compare these findings to a control group of children with typical speech development (TSD).In total, 105 children were included: 61 with SSD and motor speech involvement (mean age 8:5 ± 2:8 years; range 6:0-16:7 years, 14 girls and 47 boys) and 44 children with TSD (mean age 8:8 ± 1:6; range 6:0-12:2 years, 19 girls and 25 boys). Extra-oral and intra-oral examinations were performed by an orthodontist. The severity of malocclusion was scored using the IOTN-DHC Index.There were differences between the SSD and TSD groups with regard to the prevalence, type, and severity of malocclusions; 61% of the children in the SSD group had a malocclusion, as compared to 29% in the TSD group. In addition, the malocclusions in the SSD group were rated as more severe. Functional posterior crossbite and habitual lateral and/or anterior shift appeared more frequently in the SSD group. Class III malocclusion, anterior open bite and scissors bite were found only in the SSD group.Children with SSD and motor speech involvement are more likely to have a higher prevalence of and more severe malocclusions than children with TSD.

Pain and related consequences could contribute to comorbid illness and premature mortality in homeless and precariously housed persons. We analyzed longitudinal data from an ongoing naturalistic prospective study of a community-based sample (n = 370) to characterize risk factors and consequences of bodily pain. The aims were to describe bodily pain and associations with symptoms and psychosocial function, investigate factors that may increase or ameliorate pain, and examine the consequences of pain for symptoms, functioning, and all-cause mortality. Bodily pain severity and impact were rated with the 36-item Short Form Health Survey Bodily Pain Scale monthly over 5 years. Mixed-effects linear regression models estimated the effects of time-invariant and time-varying risk factors for pain, verified by reverse causality and multiple imputation analysis. Regression models estimated the associations between overall person-mean pain severity and subsequent functioning and suicidal ideation, and Cox proportional hazard models assessed association with all-cause mortality. Bodily pain of at least moderate severity persisted (3 months) in 64% of participants, exceeding rates expected in the general population. Greater pain severity was associated with depressive symptom severity and month-to-month opioid use, overlaid on enduring risk associated with age, arthritis, and posttraumatic stress disorder. The frequency of prescribed and nonprescribed opioid use had nonlinear relationships with pain: intermittent use was associated with severe pain, without reverse association or change with the overdose epidemic. Greater longitudinal mean pain severity was associated with premature mortality, poorer functioning, and suicidal ideation. Considering the relationships between pain, intermittent opioid use, and depressive symptoms could improve health care for precariously housed patients.

opioid use, which includes both prescribed and non-prescribed drugs, is relatively common amongst marginalized populations. Past research has shown that among those who use non-prescribed or diverted opioids recreationally, many were first exposed to the drug as prescribed pain medication.

School-based health centers (SBHCs) are an essential part of a comprehensive approach to address the health needs of youth. SBHCs that provide sexual health services (SHS) show promising results in improving reproductive health outcomes among youth. Despite the positive impact SBHCs can have, few school districts have SBHCs, and even fewer provide SHS. This article describes a successful 5-year project to provide SHS through SBHCs in a large county in the southeast United States. A community collaborative, including the schools, health department, community agencies and a local university, was created to address the project goals and objectives. Various steps were taken to plan for the SBHCs, including documenting community support for SHS offered through SBHCs, identifying school sites for SBHCs, and the process for offering pregnancy, STD (sexually transmitted disease), and HIV testing, treatment, and referrals. Protocols for clinic flow, testing, staffing, training, and student recruitment were developed. The staff at the SBHCs were successful in recruiting students to attend educational sessions and to receive testing and treatment. Student feedback was overwhelmingly positive. Lessons learned about the importance of the partnership’s collaboration, using recommended clinic protocol, ensuring clear communication with school staff, and employing youth friendly recruitment and clinic practices are shared.

Summary Background Homelessness is a global public health concern, and traumatic brain injury (TBI) could represent an underappreciated factor in the health trajectories of homeless and marginally housed individuals. We aimed to evaluate the lifetime prevalence of TBI in this population, and to summarise findings on TBI incidence and the association between TBI and health-related or functioning-related outcomes. Methods For this systematic review and meta-analysis, we searched without date restrictions for original research studies in English that reported data on the prevalence or incidence of TBI, or the association between TBI and one or more health-related or function-related outcome measures. Studies were included if they had a group or clearly identifiable subgroup of individuals who were homeless, marginally housed, or seeking services for homeless people. With use of random-effects models, we calculated pooled estimates of the lifetime prevalence of any severity of TBI and the lifetime prevalence of moderate or severe TBI. We used meta-regression and subgroup analysis to evaluate potential moderators of prevalence estimates and the leave-one-out method for sensitivity analyses. We then summarised findings from all studies that evaluated TBI incidence and the association between TBI and health-related or functioning-related outcomes. All statistical analyses were done using R version 3.5.1. The study is registered with PROSPERO, number CRD42019119678. Findings Of 463 potentially eligible studies identified by the search, 38 studies were included in the systematic review and 22 studies were included in the meta-analysis. The lifetime prevalence of any severity of TBI in homeless and marginally housed individuals (18 studies, n=9702 individuals) was 53·1% (95% CI 46·4–59·7; I2=97%) and the lifetime prevalence of moderate or severe TBI (nine studies, n=5787) was 22·5% (13·5–35·0; I2=99%). The method used to ascertain TBI history, the age of the sample, and the sample size significantly moderated estimated lifetime prevalence of any severity of TBI. TBI was consistently associated with poorer self-reported physical and mental health, higher suicidality and suicide risk, memory concerns, and increased health service use and criminal justice system involvement. Interpretation The lifetime prevalence of TBI is high among homeless and marginally housed individuals, and a history of TBI is associated with poorer health and general functioning. Health-care providers and public health officials should have an increased awareness of the burden of TBI in this population. Prospective and longitudinal studies are needed to better understand how the health of this population is affected by TBI. Funding Canadian Institutes of Health Research.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton’s tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and

Aggressive induction chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) is a standard option for the initial management of transplant-eligible mantle cell lymphoma (MCL).1-3 However, the optimal induction regimen before ASCT is unknown. Cytarabine-based induction achieves excellent response rates and higher rates of minimal residual disease (MRD) negativity compared with anthracycline-based induction regimens.4-6 While effective, most cytarabine-based induction regimens require inpatient hospitalization and are associated with significant hematologic and nonhematologic toxicities.4-6 Rituximab-bendamustine (RB) is a less intensive, outpatient-based chemoimmunotherapy regimen with excellent long-term efficacy and good tolerability in transplant-ineligible MCL patients.7-9 However, its role as a pretransplant induction strategy has not been formerly evaluated. S1106 is a randomized phase 2 multi-institutional clinical trial comparing induction R-hyper-CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and methotrexate/cytarabine (RH) with RB followed by ASCT in newly diagnosed MCL patients. We previously reported that the 2-year progression-free survival (PFS) and overall survival (OS) were similar with either regimen. However, RH was more toxic than RB, had higher stem cell mobilization failure rates, and prompted protocol-specified early study closure.10 While premature closure limited the sample size, we demonstrated for the first time in a prospective setting that outpatient RB treatment can achieve excellent MRD negativity and could serve as an induction strategy worthy of further study. Given the increased survival of MCL patients,2 critical assessment of long-term efficacy and toxicity is needed. Here, we report the 5-year follow-up (FU) of the S1106 study.

Background Aboriginal and Torres Strait Islander women experience high rates of diabetes in pregnancy (DIP), contributing to health risks for mother and infant, and the intergenerational cycle of diabetes. By enhancing diabetes management during pregnancy, postpartum and the interval between pregnancies, the DIP Partnership aims to improve health outcomes and reduce risks early in the life-course. We describe a mixed methods formative study of health professional’s perspectives of antenatal and post-partum diabetes screening and management, including enablers and barriers to care. Methods Health professionals involved in providing diabetes care in pregnancy, from a range of health services across the Northern Territory, completed the survey (n = 82) and/or took part in interviews and/or focus groups (n = 62). Results Qualitative findings highlighted factors influencing the delivery of care as reported by health professionals, including: whose responsibility it is, access to care, the baby is the focus and pre-conception care. The main challenges were related to: disjointed systems and confusion around whose role it is to provide follow-up care beyond six weeks post-partum. Quantitative findings indicated that the majority of health professionals reported confidence in their own skills to manage women in the antenatal period (62%, 40/79) and slightly lower rates of confidence in the postpartum interval (57%, 33/58). Conclusion These findings regarding whose role it is to provide postpartum care, along with opportunities to improve communication pathways and follow up care have informed the design of a complex health intervention to improve health systems and the provision of DIP related care.

Prospective, community-based studies allow evaluation of associations between cognitive functioning and synaptic measures, controlled for age-related pathologies. Findings from400 community-based participants are reviewed. Levels of two presynaptic proteins, complexin-I (inhibitory terminals), and complexin-II (excitatory terminals) contributed to cognitive variation from normal to dementia. Adding the amount of protein-protein interaction between two others, synaptosome-associated protein-25 and syntaxin, explained 6% of overall variance. The presynaptic protein Munc18-1 long variant was localized to inhibitory terminals, and like complexin-I, was positively associated with cognition. Associations depended on Braak stage, with the level of complexin-I contributing nearly 15% to cognitive variation in stages 0-II, while complexin-II contributed 7% in stages V-VI. Non-denaturing gels identified multiple soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein-protein (SNARE) complexes in frontal and in temporal lobes, making specific contributions to cognitive functions. Multiple mechanisms of presynaptic plasticity contribute to cognitive function during aging. .Los estudios prospectivos realizados en la comunidad permiten evaluar las asociaciones entre el funcionamiento cognitivo y las mediciones sinápticas, controladas por patologías relacionadas con la edad. Se revisan los hallazgos de más de 400 participantes de la comunidad. Los niveles de dos proteínas presinápticas, complexina-I (terminales inhibitorios) y complexina-II (terminales excitatorios) contribuyeron a la variación cognitiva entre la situación normal y la demencia. Al agregar la interacción proteína-proteína entre la proteína 25 asociada al sinaptosoma y la sintaxina, se explicó el 6% de la varianza general. La variante larga de la proteína presináptica Munc 18-1 se localizó en terminales inhibitorios y, al igual que la complexina I, se asoció positivamente con la cognición. Las asociaciones dependían de la etapa de Braak, siendo el nivel de complexina-I responsable de casi el 15% de la variación cognitiva para las etapas 0-II, mientras que la complexina-II contribuyó con el 7% en las etapas V-VI. Los geles no desnaturalizantes identificaron múltiples complejos de proteína-proteína del receptor de proteína de unión al factor sensible a N-etilmaleimida soluble (SNARE) en los lóbulos frontales y temporales, los cuales contribuyen de manera específica a las funciones cognitivas. Durante el envejecimiento participan múltiples mecanismos de plasticidad presináptica en la función cognitiva.Des études prospectives communautaires permettent d’évaluer des associations entre le fonctionnement cognitif et des mesures synaptiques, contrôlées pour des pathologies liées à l’âge. Des résultats issus de plus de 400 participants communautaires sont analysés. Les taux de complexine-I (terminaisons inhibitrices) et de complexine-II (terminaisons excitatrices), deux protéines présynaptiques, contribuent aux variations cognitives de la normalité à la démence. S’y ajoute l’interaction protéine-protéine entre la protéine SNAP25 (protéine 25 associée au synaptosome) et la syntaxine, expliquant 6 % de la variance totale. Le variant long de la protéine pré-synaptique Munc18-1 est localisé sur les terminaisons inhibitrices et associé positivement à la cognition, comme la complexine-I. Les associations dépendent du stade Braak, le taux de complexine-I étant responsable de presque 15 % de la variation cognitive pour les stades 0-II alors que la complexine-II contribue pour 7 % aux stades V-VI. Des gels non dénaturants identifient des complexes multiples protéine-protéine SNARE (Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptor) dans les lobes frontaux et temporaux, contribuant spécifiquement aux fonctions cognitives. Au cours du vieillissement, de nombreux mécanismes de plasticité présynaptique participent à la fonction cognitive.

Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled trials, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on S0816 (NCT00822120). Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete remission (CR) on PET2 (Deauville Score{less than or equal to}3) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 (Deauville Scoreg3) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. We report the 5-year follow-up of S0816. A subset of 336 eligible patients were analyzed (331 had central review of PET2). PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS was 74% (95%CI:69%-79%). For patients with PET2-, the 5-year PFS was 76% (95%CI:70-81%). For patients with PET2+, the 5-year PFS was 66% (95% CI:52-76%). For all patients, the estimated 5-year overall survival (OS) was 94% (95%CI:91%-96%). There were 7 (14%) reported cases of second cancers in patients treated with eBEACOPP and 6 (2%) in patients treated with ABVD (P=0.001). The long-term OS of HL patients treated on S0816 remains high. However, nearly 25% of patients with PET2- experienced relapse events, demonstrating limitations of frontline ABVD therapy and in the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice. Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected. Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose. Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Schizophrenia and stimulant-induced psychosis (SIP) represent two different forms of psychotic disorder, with different etiologies. While many of the symptoms of psychosis are common to both disorders, there have been few direct comparisons between these conditions, especially when controlling for stimulant use in individuals with schizophrenia. We directly compared both psychotic disorders with a comprehensive battery of clinical, neurocognitive and neuroanatomical measures. This included one group with SIP (and concurrent stimulant dependence) and two groups with schizophrenia (either with or without concurrent stimulant dependence). Ninety-six participants were recruited from a marginalized urban population, which included 39 with SIP (and concurrent stimulant dependence), 18 with schizophrenia (without stimulant dependence), and 39 with schizophrenia (with concurrent stimulant dependence). All subjects had extensive clinical and neurocognitive evaluations, complemented with structural MRI including diffusion tensor imaging (DTI) sequences to determine regional brain volumes and white matter connectivity. Both positive and negative symptoms were greater in the SZ-dependent group than the other two. Neurocognitive function was broadly similar. The structural brain imaging revealed lateralized changes to the left parietal/temporal lobe, in which regional volumes were smaller in the SZ-dependent than the SZ-non-dependent group. DTI analysis indicated extensive decreases in fractional anisotropy, with parallel increases in radial diffusivity, in the SIP group compared to the SZ-dependent group. These findings reveal both similarities and differences between SIP and schizophrenia. Furthermore, schizophrenia with concurrent stimulant dependence may be associated with a different clinical and neuroanatomical profile as compared to schizophrenia alone.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with

The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax

To assess associations of hyperglycemia in pregnancy with the risk of postpartum hemorrhage (PPH) in a prospective cohort of Indigenous and non-Indigenous women, compared with normoglycemia.Data were from 1102 (48% Indigenous) women of the Pregnancy And Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study. Age-adjusted associations of gestational diabetes mellitus (GDM) or pre-existing type 2 diabetes mellitus (T2DM), obstetric and demographic covariables with PPH (blood loss ≥500 ml) were assessed using logistic regression. Multivariable-adjusted models included Indigenous ethnicity, diabetes type and their interaction.A higher proportion of Indigenous women developed PPH than non-Indigenous women (32% versus 22%; P 0.001). Compared with non-Indigenous women with normoglycemia, risks of PPH for Indigenous women with GDM or T2DM were higher (odds ratio [OR] 1.83, 95% confidence intervals [CI] 1.11-3.02, and OR 1.72, 95% CI 0.99-3.00 after age adjustment, OR 1.84, 95% CI 1.06-3.19, and OR 1.33, 95% CI 0.70-2.54 after adjustment for school education and delivery mode, and OR 1.62, 95% CI 0.95-2.77, and OR 0.99, 95% CI 0.53-1.86 after adjustment for birth weight). Importantly, Indigenous women without hyperglycemia in pregnancy were not at increased risk of PPH.The significantly higher rates of PPH experienced by Indigenous women compared with non-Indigenous women may be explained by a greater effect of GDM among Indigenous women that was only partly accounted for by birth weight.

Aim Long-acting injectable antipsychotic drugs (LAIs) are often used as an alternative to oral antipsychotics (OAPs) in individuals with psychosis who demonstrate poor medication adherence. Previous meta-analyses have found mixed results on the efficacy of LAIs, compared to OAPs, in patients with psychotic disorders. The objective of this meta-analysis was to compare the effectiveness of using LAIs versus OAPs in the early stages of psychosis. Methods Major electronic databases were used to search for any studies examining the comparative effectiveness (i.e., relapse, adherence, hospitalization, and all-cause discontinuation) of any LAIs versus OAPs in early stages of psychosis. Studies published up to 6 June, 2019 were included and no language restriction was applied. Inclusion criteria were a diagnosis of schizophrenia or related disorder, where patients were in their first episode or had a duration of illness ≤5 years. Data were analysed using a random-effects model. Results Fifteen studies (n = 10 584) were included, of which were 7 RCTs, 7 observational studies, and 1 post-hoc analysis. We found that LAIs provided advantages over OAPs in terms of relapse rates. No significant differences were found between LAI and OAP groups in terms of all-cause discontinuation, hospitalization, and adherence rates. However, considering only RCTs revealed advantages of LAIs over OAPs in terms of hospitalization rates. Conclusions LAIs may provide benefits over OAPs with respect to reducing relapse and hospitalization rates in early psychosis patients. There is a need for larger and better-designed studies comparing OAPs and LAIs specifically in early psychosis patients.

Objective: Traumatic brain injury (TBI) is increasingly recognized as a common and impactful health determinant in homeless and precariously housed populations. We sought to describe the history of TBI in a precariously housed sample and evaluate how TBI was associated with the initial loss and lifetime duration of homelessness and precarious housing. Method: We characterized the prevalence, mechanisms, and sex difference of lifetime TBI in a precariously housed sample. We also examined the impact of TBI severity and timing on becoming and staying homeless or precariously housed; 285 precariously housed participants completed the Brain Injury Screening Questionnaire in addition to other health assessments. Results: A history of TBI was reported in 82.1% of the sample, with 64.6% reporting > 1 TBI, and 21.4% reporting a moderate or severe TBI. Assault was the most common mechanism of injury overall, and females reported significantly more traumatic brain injuries due to physical abuse than males (adjusted OR = 1.26, 95% CI = 1.14 to 1.39, P < 0.0001). The first moderate or severe TBI was significantly closer to the first experience of homelessness ( b = 2.79, P = 0.003) and precarious housing ( b = 2.69, P < 0.0001) than was the first mild TBI. In participants who received their first TBI prior to becoming homeless or precariously housed, traumatic brain injuries more proximal to the initial loss of stable housing were associated with a longer lifetime duration of homelessness (RR = 1.04, 95% CI = 1.02 to 1.06, P < 0.0001) and precarious housing (RR = 1.03, 95% CI = 1.01 to 1.04, P < 0.0001). Conclusions: These findings demonstrate the high prevalence of TBI in this vulnerable population, and that aspects of TBI severity and timing are associated with the loss and lifetime duration of stable housing.

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Background Although clozapine is the gold standard for treatment-resistant schizophrenia, more than 30% of patients remain unresponsive to clozapine monotherapy and may benefit from augmentation strategies. Fluvoxamine augmentation of clozapine may be beneficial in treatment resistance because of pharmacokinetic interactions, allowing for lower clozapine dosages with higher clozapine serum levels and an increased clozapine-to-norclozapine ratio, which can modify adverse effects. An augmentation strategy using higher fluvoxamine doses may also improve persistent negative, anxiety, and obsessive-compulsive symptoms through fluvoxamine's serotonergic activity. Methods Through chart review, we identified 4 cases of patients with treatment-resistant psychosis who underwent high-dose fluvoxamine augmentation of clozapine to target residual negative symptoms, refractory psychosis, anxiety, and obsessive-compulsive symptoms. Findings This augmentation strategy continued in 2 patients after discharge who showed clinical improvement without significant adverse effects. Two patients experienced adverse effects that led to the fluvoxamine discontinuation. Despite the fact that fluvoxamine augmentation led to symptom improvement in only 2 patients, all patients achieved high serum clozapine levels. Hematologic parameters were monitored in all patients, and no abnormalities were observed. No severe adverse effects of clozapine were experienced. Conclusions Although high variability of responses and adverse effects were observed during fluvoxamine augmentation to clozapine, this strategy was successful in increasing clozapine serum levels. Through fluvoxamine's serotonergic effects, this strategy may confer benefit to residual negative, obsessive, and anxiety symptoms. Limitations of this case series include the retrospective nature, absence of controls, diversity of diagnoses, multiple interventions in each patient, and lack of masked raters.