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Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.

Objective: Limitations of traditional geospatial measures, like the modified Retail Food Environment Index (mRFEI), are well documented. In response, we aimed to: (1) extend existing food environment measures by inductively developing subcategories to increase the granularity of healthy v. less healthy food retailers; (2) establish replicable coding processes and procedures; and (3) demonstrate how a food retailer codebook and database can be used in healthy public policy advocacy. Design: We expanded the mRFEI measure such that ‘healthy’ food retailers included grocery stores, supermarkets, hypermarkets, wholesalers, bulk food stores, produce outlets, butchers, delis, fish and seafood shops, juice/smoothie bars, and fresh and healthy quick-service retailers; and ‘less healthy’ food retailers included fast-food restaurants, convenience stores, coffee shops, dollar stores, pharmacies, bubble tea restaurants, candy stores, frozen dessert restaurants, bakeries, and food trucks. Based on 2021 government food premise licences, we used geographic information systems software to evaluate spatial accessibility of healthy and less healthy food retailers across census tracts and in proximity to schools, calculating differences between the traditional v. expanded mRFEI. Setting: Calgary and Edmonton, Canada. Participants: N/A. Results: Of the 10 828 food retailers geocoded, 26 % were included using traditional mRFEI measures, while 53 % were included using our expanded categorisation. Changes in mean mRFEI across census tracts were minimal, but the healthfulness of food environments surrounding schools significantly decreased. Conclusions: Overall, we show how our mRFEI adaptation, and transparent reporting on its use, can promote more nuanced and comprehensive food environment assessments to better support local research, policy and practice innovations.

RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL. Significance: METTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171

Purpose: Interprofessional practice within early intervention is underscored by policy, research, and recommended practices. The purpose of this study was to explore the impact of a brief interprofessional training on preservice speech-language pathology, early intervention/early childhood special education, physical therapy, and occupational therapy students' knowledge, beliefs, and attitudes about teaming and collaboration. Students' satisfaction with and perspectives of the training were also examined. Method: A one-group, pretest–posttest design was used to examine differences in 36 students' knowledge, attitudes, and beliefs around interprofessional practice after the training. Descriptive approaches were used to analyze student satisfaction data and focus group data in order to evaluate student perceptions of the interprofessional training. Results: A paired–samples t test showed preservice students demonstrated increased scores in self-perceived ability, value, and comfort in working with others after the training institute. Descriptive analyses illustrated students gained a richer knowledge and appreciation for other disciplines and perceived the practice of interprofessional collaboration as a valuable learning experience. Conclusion: The interprofessional training procedures, evaluation of impacts, and future directions are discussed.

Young children's social communication is key to their development and well-being. Naturalistic interventions can promote social communication in young children. Anyone concerned about children's social communication—families, professionals, planning teams, referral sources, funders, and policymakers—should understand the complementary roles of behavior analysts (BCBAs) and speech-language pathologists (SLPs), who both utilize naturalistic interventions. Resistance to collaboration may be rooted in broader conversations about differing theories of language development. BCBAs and SLPs likely have similar overarching goals and expectations, but collaboration has been unfortunately rare, due to field-specific training and recommendations. BCBAs and SLPs who adopt a unified theory of practice will place children, families, and educators at the center of all decisions. An interdisciplinary model rooted in research about naturalistic interventions, collaboration, and equitable practices that incorporates feedback from providers and researchers in each field, could address challenges. This model highlights (a) understanding key tenets from each respective field, (b) developing interdisciplinary teams, (c) measuring and evaluating collaborative planning, and (d) promoting mutual respect and equity. Children benefit when professionals collaborate.

PURPOSE Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia–mutated ( ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL. METHODS We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion. RESULTS Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays. CONCLUSION Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.

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There is conflicting evidence on whether people, particularly those with preexisting mental health problems, have worse mental health during and after extended solitary confinement (SC) stays. Using administrative data on 843 men, we examined within-person changes in mental health functioning and service use surrounding long-term stays in SC in Florida correctional facilities. During these stays, service use increased, psychological functioning improved, and mental health crises declined. The former two associations persisted during step-down placements in lower levels of restrictive housing and during the month following restrictive housing stays. The same associations were observed among men with and without serious mental illnesses, though they were more muted among the former group. The increased provision of treatment might prevent mental health problems from developing or worsening among those held in long-term SC and might even improve psychological functioning relative to when the same people are in general population housing.

To determine the extent to which secure attachment moderates the effects of previous child abuse history on the intermediate variables (putative mediators) of emotion dysregulation and coping, which, in turn, influence adult behavioral health and mental health problems. Black women (

The 2014 Canadian Pig Code of Practice includes a recommendation to provide stall-housed gestating pigs with periodic exercise. The objective of this study was to evaluate the effects of periodic exercise on sow performance and placental and piglet characteristics. Sows ( n = 180) were assigned to one of three gestation treatments: stall-housed sows (Control: C), stall-housed sows given weekly exercise (Exercise: E—10 min of walking per week), and group-housed sows (Group: G). Sows were distributed among three parity groups: young (parity 0–1), mid (parity 2–4), and old (parity 5–7). Old C sows had a higher number of total born than G sows, and E sows were intermediate; mid G sows had a higher total born than E and C sows ( P = 0.023). Old E and G sows had similar numbers of total live-born piglets, which were higher than in old C sows ( P = 0.033). Periodic exercise did not influence placental and piglet characteristics in the current study. In conclusion, periodic exercise benefited only the reproductive performance of older parity sows, increasing the number of live-born piglets in E and G sows compared to C sows.

The World Health Organization recommends same-day initiation of antiretroviral therapy (ART) for all persons diagnosed with HIV and ready to start treatment. Evidence, mainly from randomized trials, indicates offering same-day ART increases engagement in care and viral suppression during the first year. In contrast, most observational studies using routine data find same-day ART to be associated with lower engagement in care. We argue that this discrepancy is mainly driven by different time points of enrolment leading to different denominators. While randomized trials enroll individuals when tested positive, most observational studies start at the time-point when ART is initiated. Thus, most observational studies omit those who are lost between diagnosis and treatment, thereby introducing a selection bias in the group with delayed ART. In this viewpoint, we summarize the available evidence and argue that the benefits of same-day ART outweigh a potential higher risk of attrition from care after ART initiation.

Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported but remain poorly understood. Here we analyze longitudinal tumor samples from eleven patients with disease progression on venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at their post-treatment timepoint. We found the previously described acquired BCL2-G101V mutation in only 4/11 patients with 2 patients showing very low variant allele fraction (VAF; 0.03-4.68%). Whole exome sequencing (WES) revealed acquired loss(8p) in 4/11 patients of which 2 patients also have gain (1q21.2-21.3) in the same cells, affecting the MCL-1 gene. In vitro experiments showed that CLL cells from the four patients with loss(8p) were more resistant to venetoclax than those without it, while the cells from two patients also carrying gain (1q21.2-21.3) showed increased sensitivity to MCL-1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to combination MCL-1 inhibitor with venetoclax. Differential gene expression analysis comparing bulk RNAseq data from pre-treatment and progression time points of all patients showed upregulation of proliferation, BCR and NFKB gene sets including MAPK genes. Cells from progression timepoints demonstrated upregulation of surface immunoglobulin M (sIgM) and higher pERK levels compared to the pre-timepoint, suggesting an upregulation of BCR signaling that activates the MAPK pathway. Overall, our data suggest several mechanisms of acquired resistance to venetoclax in CLL that could pave the way for rationally designed combination treatments for venetoclax resistant CLL patients.

Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective in chronic lymphocytic leukemia (CLL). However, the severe toxicity profile associated with the first-generation inhibitors idelalisib and duvelisib, combined with the availability of other more tolerable agents, have limited their use. CLL is still considered incurable, and relapse after treatment, development of resistance, and treatment intolerance are common. It is therefore of interest to optimize the administration of currently approved PI3K inhibitors and to develop next-generation agents to improve tolerability, so that this class of agents will be considered an effective and safe treatment option when needed. These efforts are reflected in the large number of emerging clinical trials with PI3K inhibitors in CLL. Current strategies to overcome treatment limitations include intermittent dosing, which is established for copanlisib and zandelisib and under investigation for duvelisib and parsaclisib. A second strategy is to combine the PI3K inhibitor with another novel agent, either as a continuous regimen or a fixedduration regimen, to deepen responses. In addition to these approaches, it is of interest to identify higher-resolution actionable biomarkers that can predict treatment responses and toxicity, and inform personalized treatment decisions. Here, we discuss the current status of PI3K inhibitors in CLL, factors limiting the use of currently approved PI3K inhibitors in CLL, current strategies to overcome these limitations, and where to go next.

The punitive era in the United States and other countries has included reliance on long-term restrictive housing (LTRH)—consisting of solitary confinement with few privileges—as a means of managing violent and disruptive individuals in prison. We examine how work in such housing may influence how personnel, including officers and staff, view individuals in prison and assess two hypotheses. First, those who work in LTRH will be more likely to hold a dehumanized view of these individuals. Second, the theoretical mechanisms through which such a view may arise involve brutalization, organizational context and culture, role conflict and distancing, and empathy fatigue. We assess these hypotheses using a mixed-methods study, analyzing data from a large-scale prison personnel survey ( n = 9,656) and qualitative focus group and interview data ( n = 144). Implications of the study’s findings for theory and research on restrictive housing, corrections, and the punitive era are discussed.

HIV programmes across many countries in Africa have recently transitioned people living with HIV from efavirenz (EFV)- to dolutegravir (DTG)-containing antiretroviral therapy (ART). As both drugs are associated with neuropsychiatric adverse effects, this study assessed the mental health and HIV/ART-associated symptoms of people living with HIV before and after transition to DTG.The prospective DO-REAL cohort enrolled people starting DTG-based ART in Lesotho from February to December 2020. For this analysis within DO-REAL, we included adults changing from tenofovir disoproxil fumarate (TDF)/lamivudine (3TC)/EFV to TDF/3TC/DTG within first-line therapy. At transition and 16 weeks thereafter, participants completed the Patient Health Questionnaire-9 (PHQ-9; depression screening), the 12-item Short-Form Health Survey (SF-12; mental and physical health), and a modified HIV Symptom Index (mHSI; HIV/ART-related symptoms). We also assessed weight change. We used McNemar tests with Bonferroni corrections to assess binary outcomes.gov: NCT04238767.Among 1228 participants, 1131 completed follow-up. Of these, 60.0% were female, the median age was 46 years (interquartile range [IQR] 38-55), and the median time taking ART was 5.7 years (IQR 3.5-8.9). No change was observed for weight or overall PHQ-9 or SF-12 outcomes. However, three mHSI items decreased at follow-up: 'feeling sad/down/depressed' (bothered 6.0% vs. 3.3% of participants at least 'a little' before vs. after transition; adjusted p = 0.048); 'feeling nervous/anxious' (7.4% vs. 3.4%; adjusted p = 0.0009); and 'nightmares, strange/vivid dreams' (6.3% vs. 3.5%; adjusted p = 0.027). Individual PHQ-9 or SF-12 items also improved. Being symptom free across all measures increased from 5.1% to 11.4% (p 0.0001).We observed no negative impacts and potential moderate improvements with DTG, providing further support for the rollout of DTG.

ADAM metallopeptidase domain 9 (ADAM9) is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non–small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an IHC screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody–drug conjugate (ADC) development. Here, we describe the preclinical evaluation of IMGC936, a novel ADC targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. In addition, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).

BACKGROUND: Individuals with pain prescribed opioids experience high rates of comorbid depression. The aim of this study was to characterize pain, substance use, and health status as a function of depressive symptom level in individuals filling an opioid prescription at a community pharmacy. METHODS: Participants (N=1,268) filling an opioid prescription enrolled in a study validating a prescription drug monitoring metric completed an online survey assessing sociodemographics, depressive symptoms, substance use, prescription opioid misuse, overdose history, general health, and pain severity and interference. RESULTS: Approximately one-fifth (19.3%) had a positive depression screen. In covariate-adjusted logistic regression analyses, individuals with a positive depression screen were more likely to have moderate/high substance use risk scores for: prescription opioids (AOR=2.06; 95% CI: 1.51-2.79); street opioids (AOR=7.18; 95% CI: 2.57-20.01); cannabis (AOR=2.00; 95% CI: 1.34-3.00); cocaine (AOR=3.46; 95% CI: 1.46-8.22); tobacco (AOR=1.59; 95% CI: 1.18-2.15); methamphetamine (AOR=7.59; 95% CI: 2.58-22.35); prescription stimulants (AOR=2.95; 95% CI: 1.59-5.49); and sedatives (AOR=3.41; 95% CI: 2.43-4.79). Individuals with a positive depression screen were more likely to misuse prescription opioids (AOR=3.46; 95% CI: 2.33-5.15), experience a prior overdose (AOR=2.69; 95% CI: 1.76-4.11), report poorer general health (AOR=.25, 95% CI: .18-.35), and report moderate/severe pain severity (AOR=4.36, 95% CI: 2.80-6.77) and interference (AOR=6.47, 95% CI: 4.08-10.26). CONCLUSIONS: Individuals prescribed opioids with heightened depression were more likely to report other substance use, prescription opioid misuse, prior overdose, greater pain, and poorer health.

Odronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.This single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951.From Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30).Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.Regeneron Pharmaceuticals.