Patient engagement and satisfaction with early phase cell therapy clinical trials at a tertiary inflammatory bowel disease center.

Several clinical trials are underway investigating cell and gene therapy, and while these trials are meant to significantly impact patient care, they rely on patient engagement and participation. Unfortunately, clinical trials generally require extensive commitment by subjects. While several studies are using validated surveys to measure patient-reported outcomes, there is a lack of characterization of the patient experience as a subject in these trials. As such, we surveyed mesenchymal stromal cell (MSC) trial participants to understand their perspective. We found that there exists a reliance on one's gastroenterologist and colorectal surgeons for trial introduction and that time and cost were the main barriers to participation. Overall, participants demonstrated high satisfaction with MSC trial participation, but future protocols could incorporate increased use of virtual appointments to optimize patient experience.

A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease.

BACKGROUND: Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease. METHODS: A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes. RESULTS: A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.

Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months.

BACKGROUND: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.

Motives for Cannabis Use and Risky Decision Making Influence Cannabis Use Trajectories in Teens.

The current study will examine the interactive effects of motives for cannabis use (i.e., health or recreational) and risky decision making (DM) on cannabis use trajectories among adolescents. Data from 171 adolescents, aged 14-17 at the initial visit (baseline), were prospectively analyzed across five time points approximately six months apart. Latent growth curve modeling and linear regression analyses were used. We found a significant interactive effect of "recreational motives" and risky DM on the rate of cannabis use over time. Specifically, among those less likely to use cannabis for recreational purposes, riskier DM was associated with a faster increase in the rate of use over time relative to those with lower risky DM. Additionally, a significant main effect showed that those with a greater proclivity to use cannabis for health purposes had higher initial levels of use at baseline and faster increases in the rate of use over time. Regardless of risky DM, using cannabis for health purposes is associated with faster increases in cannabis use escalation. Additionally, risky DM does impact the association between recreational motives for use and cannabis use trajectories. Future work should examine these associations with additional motives for cannabis use that have been previously validated within the literature.

Chromobacterium violaceum in a U.S. Marine: A Case Report.

Chromobacterium violaceum is associated with severe sepsis leading to cutaneous and visceral organ abscesses, with mortality rates up to 73%. Around 200 cases of C. violaceum infection have been reported globally. We report a case of a 27-year-old female U.S. Marine recruit who presented with fever, chills, myalgias, arthralgias, headache, and nodules on her extremities. Physical examination revealed multiple small skin abscesses on her extremities. Abdominal imaging with contrast revealed large liver abscesses requiring drainage. Both blood and wound cultures grew C. violaceum. The patient was successfully treated with meropenem and ciprofloxacin. At 3 months, symptoms had resolved, and labs and imaging were normal. Though rare, C. violaceum infection rates are increasing. Severe infection develops rapidly and invasive disease is not uncommon. Early detection and appropriate antibiotic treatment are key in preventing mortality.

A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease. METHODS: This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points. RESULTS: Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.

Modelling climate variabilities and global rice production: A panel regression and time series analysis.

Climate change threatens agriculture and it remains a present global challenge to food security and Sustainable Development Goals. The potential impact on the supply of crops such as rice is seen as a major food security issue that requires intervention on several fronts. The literature on rice production, climate variations and climate change show several studies outlining various impacts on rice supply as a result of variations in temperature and rainfall. This study intends to further explore the impacts on rice production caused by temperature changes and rainfall variation by analyzing and modelling the production of rice by the top rice-producing countries globally. A time series of the national rice production and yield along with national average annual temperature and rainfall were sourced for 15 major rice-producing countries. The trends of the time series were then compared between the rice productivity variables and temperature and rainfall. A panel regression model was also developed to further assess the relationship between rice production and temperature and rainfall. The time series showed that rice production and yield are increasing for the majority of the countries analyzed. The panel regression model however showed that continued increase in temperature can result in decreased production of rice and that rainfall volume directly impacts rice output and therefore shows rice production is highly susceptible to flooding and drought events caused by climate variabilities.

An exploratory follow-up study of cannabis use and decision-making under various risk conditions within adolescence.

OBJECTIVE: Studies examining the associations between decision-making (DM) and cannabis use (CU) often use cross-sectional, adult samples, and composite scores or single tasks to assess DM. The present study explored differential associations between tasks assessing DM under various risk conditions (i.e., ambiguous vs. explicit; gain vs. loss) and CU frequency, CU-related problems, and CU disorder (CUD) onset across a 2-year period within adolescence. METHOD: Adolescents (n = 401, 90% Hispanic) aged 14-17 at baseline participated in five biannual assessments. CU frequency, CU-related problems, and CUD were assessed using the Drug Use History Questionnaire, Marijuana Problems Scale, and Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, respectively. DM was assessed using the Iowa gambling task (IGT), Game of Dice Task (GDT), and Cups Task. We used latent growth curve modeling to examine bidirectional associations between DM and escalation in CU frequency and CU-related problems, and discrete time survival analyses to determine whether baseline performance across DM tasks predicted CUD onset. RESULTS: Baseline performance on the GDT predicted greater escalation in CU (ß = .200, p = .008) and CU-related problems (ß = .388, p = .035). No other significant associations were found. CONCLUSIONS: DM under explicit risk may be a more salient risk factor for escalating CU and CU-related problems than DM under ambiguous risk. Deficits in executive functioning could partially explain the results. Findings suggest that neurocognitive development should inform prevention and intervention efforts focused on reducing CU. Given the exploratory nature of the present study, replication of findings is needed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cannabis use and episodic memory performance among adolescents: Moderating effects of depression symptoms and sex.

OBJECTIVE: Cannabis use has been linked to poorer episodic memory. However, little is known about whether depression and sex may interact as potential moderators of this association, particularly among adolescents. The current study addresses this by examining interactions between depression symptoms and sex on the association between cannabis use and episodic memory in a large sample of adolescents. METHOD: Cross-sectional data from 360 adolescents (M age = 17.38, SD = .75) were analyzed at the final assessment wave of a two-year longitudinal study. We used the Drug Use History Questionnaire to assess for lifetime cannabis use, and the Computerized Diagnostic Interview Schedule for Children, Fourth edition to assess the number of depression symptoms in the past year. Subtests from the Wechsler Memory Scale, Fourth Edition and the California Verbal Learning Test, Second Edition were used to assess episodic memory performance. RESULTS: The effect of the three-way interaction among cannabis use, depression symptoms, and sex did not have a significant impact on episodic memory performance. However, follow-up analyses revealed a significant effect of the two-way interaction of cannabis use and depression symptoms on episodic memory, such that associations between cannabis use and episodic memory were only significant at lower and average levels of depression symptoms. CONCLUSIONS: Contrary to our hypotheses, we found that as depression symptoms increased, the negative association between cannabis use and episodic memory diminished. Given the use of a predominantly subsyndromic sample, future studies should attempt to replicate findings among individuals with more severe depression.

Lesbian Gay Bisexual Transgender and Queer Health-Care Experiences in a Military Population.

ABTRACTThis study aimed to understand the experiences of lesbian, gay, bisexual, transgender, and queer of former military service members. Data for this analysis was collected from the two open-ended survey questions as part of a larger online survey. The analysis was performed using the web-based data analysis application Dedoose. Eighty-eight qualitative responses were used. Analysis of the responses revealed five main themes: (1) identity, (2) negative experiences, (3) impact of experiences, (4) policy, and (5) positive experiences. These findings can influence future military research by focusing on the effects of the Don't Ask Don't Tell policy, negative and positive experiences, and the impact of those experiences.

Implementation of Columbia Suicide Severity Rating Scale (C-SSRS) as a Universal Suicide Risk Screening tool in a High Volume Emergency Department.

OBJECTIVE: To examine clinical and demographic parameters with regards to efficacy, resource utilization, and clinician burden associated with implementation of universal suicide screening by Columbia Suicide Severity Rating Scale (C-SSRS) in a single high-volume emergency department. METHODS: This retrospective cohort study, performed via chart review, included 10,197 adult patients seen in the emergency department over two specific time frames (4935 pre- and 5262 post-implementation of the screening tool). All visits with psychiatry consultation underwent further chart review (172 pre- and 217 post-) to compare number, length of stay (LOS) and demographics for psychiatric evaluations pre- and post- use of C-SSRS screening. RESULTS: Both groups were predominantly male with previous psychiatric diagnoses. Within the post-screening group, individuals tended to be older with lower likelihood of previously diagnosed psychiatric illness. No significant differences were seen in gender, psychiatric diagnosis, or outpatient psychiatric treatment. Incidence of psychiatric evaluation was slightly higher post-screening (18%) without meeting statistical significance, with more patients discharged home in the post- cohort. LOS was slightly lower after implementation of C-SSRS, without reaching statistical significance. CONCLUSIONS: Implementation of universal screening showed increased demand for psychiatric evaluations, without meeting clinical significance in this limited analysis. Although there were slightly more psychiatric evaluations, more patients were discharged to home. LOS showed no statistical increase, even trending toward shorter duration for patients screened to be evaluated by psychiatry. Based on these results, efficient suicide screening may help identify at-risk individuals without overwhelming psychiatric resources or causing unnecessary increase in LOS. HighlightsRapid identification of suicide risk is important in an emergency department environment.Universal suicide screening has limitations, with concerns for emergency department resources.Use of C-SSRS for universal screening does not show significant burden to this department.

County-level associations between food retailer availability and violent crime rate.

BACKGROUND: Violent crime (i.e., homicide, armed robbery, aggravated assault, and rape) continues to be a major public health concern in America. Several studies have linked the availability and density of specific features of the retail food environment, such as convenience stores and liquor stores, to violent crime rates due to the criminal activity that often occurs in and near these retailers. Nevertheless, there continues to be limited understanding of how other features (e.g., grocery stores, supercenters, restaurants, etc.) are associated with violent crime occurrence. This study aimed to fill this gap in knowledge by examining U.S. county-level associations between food retailer availability and violent crime rate. METHODS: We analyzed 2014 data on 3108 counties from the U.S. Department of Agriculture's Food Environment Atlas and Department of Justice's Unified Crime Reporting Program. Per capita food retailer measures represented the number of stores per 10,000 county residents. Violent crime rate represented the number of police reported violent crimes per 10,000 county residents. We used spatial lag regression models to assess associations between per capita retailer availability and violent crime rate after adjusting for potential confounders (e.g., % under 18, % Black, % Hispanic, % poverty, population density, etc.). In addition, we examined stratified OLS regression models to evaluate associations by metropolitan county status. RESULTS: Adjusted spatial regression models revealed that greater supercenter availability [ß: 2.42; 95% CI: 0.91-3.93; p-value: 0.001] and greater fast food restaurant availability [ß: 0.30; 95% CI: 0.18-0.42; p-value: < 0.001] were associated with higher violent crime rate. Greater availability of farmers' markets [ß: -0.42; 95% CI: -0.77 - - 0.07); p-value: 0.02] was associated with lower violent crime rate. Associations varied between metropolitan and non-metropolitan counties. Stratified OLS models revealed that greater grocery store availability was associated with lower violent crime rate among metropolitan counties only. Greater fast food restaurant availability was associated with lower violent crime rate among non-metropolitan counties only. CONCLUSIONS: Certain features of the retail food environment appear to be associated with county-level violent crime rates in America. These findings highlight the need for additional research on the influence of food retail and food landscape on violent crime occurrence at the community level.

Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery. By examining chemical shift perturbations in 2D [1H, 13C-HSQC] spectra of isotopically labeled IL17A, we discovered fragments binding the cytokine at a previously undescribed site near the IL17A C-terminal region, albeit with weak affinity (> 250 µM). Importantly this binding location was distinct from previously known chemical matter modulating cytokine responses. Subsequently through analog screening, we identified related compounds that bound symmetrically in this novel site with two copies. From this observation we employed a linking strategy via structure-based drug design and obtained compounds with increased binding affinity (< 50 nM) and showed functional inhibition of IL17A-induced cellular signaling (IC50~1 µM). We also describe a fluorescence-based probe molecule suitable to discern/screen for additional molecules binding in this C-terminal site.

An Innovation 10 Years in the Making: The Stories in the Pages of ACS Medicinal Chemistry Letters.

Innovation in medicinal chemistry has been at the heart of ACS Medicinal Chemistry Letters since the journal's founding 10 years ago. In his inaugural editorial, Editor-in-Chief Dennis Liotta laid out a vision for the journal to become the "premier international journal for rapid communication of cutting-edge studies," and, after 10 years, it has become exactly that. The great hope of drug discovery scientists is that their innovations will lead to new therapeutics to treat unmet medical needs. In the spirit of innovation and in celebration of the recent 10th anniversary of ACS Med. Chem. Lett., we highlight five therapeutics that were first reported or first comprehensively characterized within ACS Med. Chem. Lett.. This overview also serves to introduce the expansion of the scope of the Innovations article type to include Topical Innovations. With this extension, the journal hopes to provide a forum to showcase concise (rather than comprehensive) reviews of topics that are both timely and of great interest to the medicinal chemistry community. Moreover, these articles will emphasize the next steps to move the field toward new areas of interest in medicinal chemistry. Appropriate topics might include case studies of clinical candidates or approved drugs, new assay technologies in drug discovery, novel target classes, and innovative new approaches towards modulation of human physiology. Since its founding 10 years ago, ACS Med. Chem. Lett. has established itself as a venue for the rapid communication of studies in medicinal chemistry and drug discovery. There have been several drugs and clinical candidates that were first reported or first comprehensively characterized in ACS Med. Chem. Lett. In celebration of the 10th anniversary of ACS Med. Chem. Lett. this Topical Innovations article highlights five of these compounds: Ivosidenib, Siponimod, Glasdegib, Parsaclisib, and Dabrafenib.

Time Perspective and Substance Use: An Examination Across Three Adolescent Samples.

Time perspective is conceptualized as a multidimensional construct that assesses individuals' feelings and thoughts about the past, present, and future. The current study examined relationships between feelings (time attitudes) and thoughts (time orientation) about time and substance use behaviors across three adolescent samples. Participants included a high-risk sample of adjudicated youth (N=124; M age =15.54, SD=1.69; 51.61% female) and two general population school samples (N=777; M age =15.82, SD=1.23; 53.41% female; N=1873; M age =15.87, SD=1.28; 52.22% female). Cross-sectional survey data were collected from samples in schools during 2010, 2016, and 2011, respectively. Poisson and negative binomial regression analyses indicated that overall, more positive feelings about time were associated with fewer substances used and, conversely, more negative feelings about time were associated with more substances used. These findings were particularly salient for participants with stronger positive and negative feelings toward the past and present time periods. Further, across the three samples, adolescents with a balanced time orientation (i.e., equal emphasis on all three time periods) generally reported less substance use than individuals who emphasized only one or two time periods. Findings highlight relationships between time perspective dimensions and substance use across diverse samples and illustrate opportunities for adapting time perspective-based substance use interventions for adolescents.

Interactive Effects of HIV Infection and Cannabis Use on Insula Subregion Functional Connectivity.

Chronic inflammation in the central nervous system is one mechanism through which human immunodeficiency virus (HIV) may lead to progressive cognitive decline. Given cannabis's (CB's) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and evidence implicating the insula in both, we examined independent and interactive effects of HIV and CB on insular circuitry, cognition, and immune function. We assessed resting-state functional connectivity (rsFC) of three insula subregions among 106 participants across four groups (co-occurring: HIV+/CB+; HIV-only: HIV+/CB-; CB-only: HIV-/CB+; controls: HIV-/CB-). Participants completed a neurocognitive battery assessing functioning across multiple domains and self-reported somatic complaints. Blood samples quantified immune function (T-cell counts) and inflammation (tumor necrosis factor alpha [TNF-α]). We observed interactive HIV × CB effects on rsFC strength between two anterior insula (aI) subregions and sensorimotor cortices such that, CB appeared to normalize altered rsFC among non-using PLWH. Specifically, compared to controls, HIV-only and CB-only groups displayed decreased dorsal anterior insula (DI) - postcentral gyrus rsFC and increased ventral anterior insula (VI) - supplementary motor area rsFC, whereas the co-occurring group displayed DI and VI rsFC more akin to that of controls. Altered DI - postcentral rsFC correlated with decreased processing speed and somatic complaints, but did not significantly correlate with inflammation (TNF-α). These outcomes implicate insula - sensorimotor neurocircuitries in HIV and CB and are consistent with prior work suggesting that CB use may normalize insula functioning among PLWH.

Bringing Assessment-to-Instruction (A2i) Technology to Scale: Exploring the Process from Development to Implementation.

Bringing effective, research-based literacy interventions into the classroom is challenging, especially given the cultural and linguistic diversity of today's classrooms. We examined the promise of Assessment-to-Instruction (A2i) technology redesigned to be used at scale to support teachers' implementation of the individualized student instruction (ISI) intervention from kindergarten through third grade. In seven randomized controlled trials, A2i and ISI have demonstrated efficacy. However, the research version of A2i was not scalable. In order to bring A2i to scale in schools serving linguistically diverse students, we carried out the current study across two phases. This study represents both an exploration of what it takes to bring an educational intervention to scale (Phase 1) and a quasi-experiment on the literacy outcomes of learners whose teachers used the technology (Phase 2). We integrated assessments of vocabulary, word decoding, and reading comprehension; revised the A2i algorithms to account for the constellation of skills English learners (ELs) bring to the classroom; updated the user interfaces and added new graphic features; and improved bandwidth and stability of the technology. Findings were mixed, including several non-significant results, a marginally significant intent-to-treat effect on word reading in kindergarten and first grade for English monolingual students and ELs, and one significant interaction effect, which suggested ELs and students with less developed reading skills in second and third grade benefitted most from the intervention. With some caution, we conclude that A2i demonstrates potential to be used at scale and promise of effectiveness for improving code-focused skills for diverse learners.