Harnessing regulatory T cells to establish immune tolerance.

Engineered regulatory T (Treg) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered Treg cell therapies in treating autoimmune and other inflammatory diseases.

Teleassault: A Case of Patient Violence During a Telepsychiatry Encounter.

Background: Telemedicine in psychiatry (telepsychiatry) is an emerging and rapidly developing tool which is used in many areas of psychiatry. While telepsychiatry has been shown to be efficacious and improves access to psychiatric care, it can also help to mitigate the risk of bodily injury caused by patient assault. The telepsychiatry equipment, however, may be vulnerable to damage from patient assault. Patient Case: We present the case of a 24 year old man being treated for disorganized behaviors and delusional thoughts at a regional hospital. As the regional hospital did not have access to psychiatry, telepsychiatry consultation was used. This patient behaved with violence towards the telepsychiatry equipment. Discussion: There currently is no literature establishing best practices to minimize the risk of violence towards equipment during telepsychiatry encounters. Using this case report, we aim to illustrate the risk of violence in telepsychiatry encounters and to discuss best practices to minimize this risk.

Does KUB play a role in the diagnosis of bladder bowel dysfunction?

INTRODUCTION: Kidney ureter bladder radiography (KUB) is widely used for the evaluation of constipation in children with bladder and bowel dysfunction (BBD); however, there is varying evidence to support its routine diagnostic use. One drawback to KUB is radiation exposure. The dangers of radiation in children are well-documented, and per As Low As Reasonably Achievable, non-beneficial radiation should be avoided. This risk is especially high in children who undergo repeated imaging in the follow up of constipation treatment. OBJECTIVE: We sought to assess the utility of KUB in diagnosing children with BBD by comparing it to four diagnostic tests and/or validated instruments: the Dysfunctional Voiding Symptom Score (DVSS), Rome IV criteria, rectal diameter on ultrasound (RD), and the Bristol Stool Form Score (BSFS). STUDY DESIGN: We prospectively enrolled a cohort of patients presenting to an academic pediatric urology practice with symptoms of BBD. Severity of stool burden on KUB (mild, moderate, or severe), RD on ultrasound (≥3.4 cm), DVSS, Rome IV, and BSFS were obtained for each patient. All imaging was interpreted by a pediatric radiologist and pediatric urologist. Primary outcomes were the association between the four diagnostic tests and KUB stool burden. Bivariate analysis of all individual variables versus KUB was performed, as well as multivariate regressions to determine if multiple measures were predictive of KUB stool burden when combined. RESULTS: Between October 2020 and May 2022, 50 patients were enrolled. All children were under the age of 18, with a median age of 8 years (IQR 3-13). 38 % were male. Median BMI-for-age-percentile was 80.8 (IQR 50.3-98.3). When comparing individual variables to KUB in bivariate analyses, it was found that RD on ultrasound is predictive of significant stool burden on KUB (p = 0.03). No other individual variables were predictive. In the multivariate analyses, no combination of tests was found to be predictive of KUB. DISCUSSION: We compared the effectiveness of four commonly used diagnostic tests in children with BBD to validate the use of KUB. In conclusion, our results support the use of RD on ultrasound as a non-radiating alternative to KUB to assess stool burden. Data also suggest that KUB for fecal load does not correlate with urinary (DVSS) or bowel (Rome IV, BSFS) symptoms in BBD, and that symptoms scores should still be used independently for diagnosis and monitoring of treatment response. CONCLUSION: In conclusion, KUB has a limited role in the diagnosis of BBD.

Using Academic Consultation-Liaison Telepsychiatry to Meet the Mental Health Needs of Complex, Medically Ill Patients in Underserved Areas: A Case Report.

Background: The nationwide shortage of mental health resources often disproportionately affects rural areas. As innovative strategies are required to address mental health resource shortages in rural areas, telepsychiatry consultation (TPC) may represent a population health-oriented approach to bridge this gap. In this case report, we examine the use of TPC from an academic consultation-liaison psychiatry service to a rural community hospital. Case Report: We describe the case of a woman with Wernicke encephalopathy seeking to leave the hospital against medical advice and the role that the TPC service played in the patient's evaluation and management, including assessing decision-making capacity. Discussion: We then examine benefits and limitations of the service, including a narrative review of the relevant, but limited, available literature as well as suggestions for how the service may be improved and incorporated into psychiatry residency and fellowship training in the future.

The Evaluation of Gastric Emptying Using Nuclear Scintigraphy Compared to Three-Dimensional Multi-detector Computed Tomography (3D-MDCT) Gastric Volumetry in the Assessment of Poor Weight Loss Following Sleeve Gastrectomy.

BACKGROUND: Poor weight loss and weight regain are principal challenges following laparoscopic sleeve gastrectomy (LSG). There is a lack of standardised assessments and diagnostic tests to stratify the status post-LSG and determine whether anatomical or physiological problem exists. We aimed to compare nuclear scintigraphy gastric emptying with CT volumetric analysis of sleeve anatomy and determine the impact of anatomy on physiological function and its correlation with weight loss. MATERIALS AND METHODS: Patients greater than 12 months post-LSG were categorised into optimal weight loss (OWL) (n = 29) and poor weight loss groups (PWL) (n = 50). All patients underwent a protocolised nuclear scintigraphy and three-dimensional multi-detector computed tomography (3D-MDCT) gastric volumetry imaging. RESULTS: Post-operative % total weight loss in OWL was 26.2 ± 10.5% vs. 14.2 ± 10.7% in the PWL group (p value < 0.0001). The PWL group had significantly more delayed gastric emptying half-time than OWL (34.1 ± 18.8 vs. 19.5 ± 4.7, p value < 0.0001). Gastric emptying half-time showed statistically significant correlations with weight loss parameters (BMI; r = 0.215, p value 0.048, %EWL; r = - 0.336, p value 0.002 and %TWL; r = - 0.379, p value < 0.001). The median gastric volume on 3D-MDCT did not differ between the OWL (246 (IQR 50) ml) and PWL group (262 (IQR 129.5) ml), p value 0.515. Nuclear scintigraphy gastric emptying half-time was the most highly discriminant measure. A threshold of 21.2 min distinguished OWL from PWL patients with 86.4% sensitivity and 68.4% specificity. CONCLUSION: Nuclear scintigraphy is a potentially highly accurate tool in the functional assessment of sleeve gastrectomy physiology. It appears to perform better as a diagnostic test than volumetric assessment. Gastric volume did not correlate with weight loss outcomes. We have established diagnostic criteria of greater than 21 min to assess sleeve failure, which is linked to suboptimal weight loss outcomes.

Dynamic Evolution of Catatonia in the Context of Cerebral Venous Sinus Thrombosis.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2023;25(4):22f03471. Author affiliations are listed at the end of this article.

Collaborative Care Model Education Opportunities for Psychiatry Trainees: A Narrative Review.

Importance: The Collaborative Care Model (CoCM) is an evidence-based methodology meant to improve access to mental health care, especially in primary care settings. While evidence about the efficacy of CoCM is abundant, literature regarding how CoCM is taught to psychiatry trainees appears to be more limited. As psychiatrists play a key role within the CoCM framework, psychiatry trainee exposure to CoCM skills and concepts is imperative for growth of these services. As psychiatry trainees may one day practice CoCM, we aimed to examine available literature about educational opportunities in CoCM for psychiatry trainees.Observations: While literature was indeed sparse, we identified that CoCM is taught to psychiatry trainees in the form of clinical rotations, didactics, and leadership experiences. Future opportunities are abundant to increase educational opportunities in CoCM for psychiatry trainees.Conclusions and Relevance: Potential future studies should make use of innovative technologies (such as telehealth), should be process-oriented, and should focus more on team dynamics and opportunities for further collaboration with primary care practices within the CoCM framework.

Proactive use of QI methodology in consultation-liaison psychiatry to support the opening of a new COVID+ behavioral health inpatient unit during the omicron surge.

Inpatient consultation-liaison (CL) psychiatry teams routinely facilitate the transfer of medically stable patients in behavioral health crisis from the general hospital to inpatient psychiatric units. The COVID-19 pandemic had a significant impact on this process when inpatient psychiatric units were unable to provide care for patients with asymptomatic COVID-19 infection because of infection control concerns in units unable to accommodate isolation precautions. Similar to other disrupted hospital workflows, these clinical handoffs became more complicated by requiring COVID exposed or COVID+ patients in the midst of behavioral health crisis to quarantine or isolate on general hospital units if not otherwise stable for discharge to the community. To better respond to the growing number of patients isolating in the general hospital during the 2022 Omicron surge, we used quality improvement (QI) methodology to illustrate the need to create a COVID+ unit in the inpatient psychiatric hospital to care for the growing cohort of COVID+ patients in psychiatric crisis who were otherwise unable to access traditional psychiatric hospital care because of their isolation status.

Factors that influence preference for male or female urologist among underserved patients in New York City.

Objective: To examine the prevalence of patient preference for male or female urologic provider and explore which patient characteristics influence this preference. Materials and Methods: After obtaining hospital Institutional Review Board approval, a 14-question survey in English and Spanish was administered across four general urology clinic sites in a single hospital system in New York City. The survey asked demographic questions and preference for a male or a female urologist. The survey included questions pertaining to the nature of the clinic visit and subsequent provider preference as well. Statistics were performed using Stata 16 (StataCorp, College Station, TX). Results: A total of 540 patients completed the 14-question survey. The vast majority of survey respondents identified as male (90%). The largest proportion demographic groups were those aged 41-60 (47%), Hispanic or Latino (43%), Catholic (47%), unemployed (40%) and those with a high school level of education (34%). Most patients (60%) did not have a preference for a specific gender provider, whereas 37% preferred a male provider, and 3% preferred a female provider. On univariate analysis, patient age 25-40, less than high school education level and lack of employment were significant predictors of provider gender preference (p < 0.05), with most patients indicating a male provider preference. On multivariate analysis of gender, age, education level and employment status, gender and education level were not significant predictors of preference, whereas age 25-40 and being unemployed were significant predictors (p < 0.05). Conclusion: Patient gender, race and religion do not appear to influence their preference to be seen by a male or a female urologist in the clinic setting. However, patient age, unemployment and potentially educational attainment were significantly associated with a provider gender preference.

The MMAAS Project: An Observational Human Study Investigating the Effect of Anabolic Androgenic Steroid Use on Gene Expression and the Molecular Mechanism of Muscle Memory.

OBJECTIVE: It remains unknown whether myonuclei remain elevated post anabolic-androgenic steroid (AAS) usage in humans. Limited data exist on AAS-induced changes in gene expression. DESIGN: Cross-sectional/longitudinal. SETTING: University. PARTICIPANTS: Fifty-six men aged 20 to 42 years. INDEPENDENT VARIABLES: Non-resistance-trained (C) or resistance-trained (RT), RT currently using AAS (RT-AS), of which if AAS usage ceased for ≥18 weeks resampled as Returning Participants (RP) or RT previously using AAS (PREV). MAIN OUTCOME MEASURES: Myonuclei per fiber and cross-sectional area (CSA) of trapezius muscle fibers. RESULTS: There were no significant differences between C (n = 5), RT (n = 15), RT-AS (n = 17), and PREV (n = 6) for myonuclei per fiber. Three of 5 returning participants (RP1-3) were biopsied twice. Before visit 1, RP1 ceased AAS usage 34 weeks before, RP2 and RP3 ceased AAS usage ≤2 weeks before, and all had 28 weeks between visits. Fiber CSA decreased for RP1 and RP2 between visits (7566 vs 6629 µm 2 ; 7854 vs 5677 µm 2 ) while myonuclei per fiber remained similar (3.5 vs 3.4; 2.5 vs 2.6). Respectively, these values increased for RP3 between visits (7167 vs 7889 µm 2 ; 2.6 vs 3.3). CONCLUSIONS: This cohort of past AAS users did not have elevated myonuclei per fiber values, unlike previous research, but reported AAS usage was much lower. Training and AAS usage history also varied widely among participants. Comparable myonuclei per fiber numbers despite decrements in fiber CSA postexposure adheres with the muscle memory mechanism, but there is variation in usage relative to sampling date and low numbers of returning participants.

Paradoxical pulmonary artery systolic pressure response with catheter-directed therapies for pulmonary embolism.

Background: Early data on use of catheter-directed therapies (CDT) for treatment of Intermediate or High-Risk pulmonary embolism (PE) show improvement in pulmonary artery systolic pressures (PAsP) and RV/LV ratios. Occasionally a paradoxical rise in PAsP was observed with CDT utilizing ultrasound-assisted thrombolysis (USAT). It is unclear whether this pattern is seen with CDT utilizing mechanical aspiration. Objectives: To investigate and compare the changes in PAsP between those who underwent CDT with USAT to those with mechanical aspiration. Methods: A retrospective analysis of those diagnosed with Intermediate or High-Risk PE who underwent CDT using USAT or mechanical aspiration from 7/2013 to 3/2023. The primary outcome was comparison of PAsP changes between the two modalities. Secondary outcomes include length of stay, mortality, and bleeding complications. Results: A total of 142 patients were analyzed, of which 93 underwent USAT and 49 underwent mechanical thrombectomy. The mechanical thrombectomy group had significantly lower post-intervention PAsP than the USAT group (42.2 ± 13.4 mmHg vs 54.5 ± 15.2 mmHg, p < 0.0001) and a greater adjusted mean reduction (-16.5 ± 2.7 vs. -7.7 ± 3.2 mmHg. p < 0.0001). A higher frequency of a paradoxical rise in PAsP was observed in the USAT group (22 % vs 4.1 %, p < 0.001). Conclusions: CDT utilizing mechanical thrombectomy was associated with lower post-interventional PAsP and greater mean negative change compared to USAT. Occasional paradoxical rises in PAsP were observed with both types of CDT, but they were more frequent with USAT. Hemodynamic monitoring should be considered after CDT. Condensed unstructured abstract: We report a retrospective comparison of changes to pulmonary artery systolic pressures (PAsPs) between catheter-directed ultrasound-assisted thrombolysis (USAT) and catheter-directed mechanical thrombectomy in Intermediate and High-Risk pulmonary embolism. Those treated with mechanical thrombectomy compared to USAT had significantly lower post-interventional PAsP (42.2 ± 13.4 mmHg vs 54.5 ± 15.2 mmHg, p < 0.0001) and a greater adjusted mean reduction (-16.2 ± 2.7 vs. -7.5 ± 3.2 mmHg, p < 0.0001). A paradoxical rise in PAsP was observed more frequently in the USAT group than the mechanical thrombectomy group (22 % vs 4.1 %, p < 0.001).

Midline submuscular penile prosthesis reservoir placement for patients with bilateral inaccessible inguinal rings: technique and outcomes.

Introduction: One of the most challenging aspects of inflatable penile prosthesis (IPP) surgery is reservoir placement. The traditional space of Retzius (SOR) is not suitable for all patients. For example, radical cystectomy or prostatectomy may alter the anatomical SOR. Hence, traditional placement of the reservoir in this space increases the risk of bowel or vascular injury. Also, patients with bilateral inguinal hernias repaired with mesh, or those with previous reservoirs that have been retained, are not eligible for a Retzius reservoir. Our study reports on the use of midline sub-rectus muscle placement of a penile prosthesis reservoir in these patients as an alternative to high submuscular placement commonly used. Methods: A retrospective chart review of male patients who underwent IPP surgery between June 2017 and 2021 was conducted. Patients were divided into two groups based on the location of the reservoir: SOR versus Midline Submuscular Reservoir (MSMR). Complication rates were compared, including herniated reservoirs, infections, bowel injuries, and vascular injuries. Results: Our cohort included 461 patients who underwent IPP surgery between June 2017 and 2021 in one tertiary center. SOR was used in 89% of patients and MSMR in 11% of patients (n = 413 and 48, respectively). Median follow-up for all patients was 28 months. The mean age was 67 ± 8 years. There was no statistically significant difference between the two groups regarding age or comorbidities (BMI, diabetes mellitus, hypertension, hyperlipidemia, and coronary artery disease). The complication rate was low in both the SOR and MSMR groups, with device malfunction being the most common (2% versus 4%, respectively; p = 0.32). The infection rate was 0.5% in the SOR group with no infections in the MSMR group (NS). There was only one case of herniation requiring surgical revision in the SOR group and no cases of bowel or vascular injury. Conclusion: Placement of a penile prosthesis reservoir within a midline rectus submuscular space is a safe and effective technique when the SOR is compromised by previous surgery or bilateral inguinal canals are not accessible.

The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis.

BACKGROUND: Parkinson's disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. METHODS: We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)-DA pathway. RESULTS: We demonstrated that PD-linked LRRK2 mutations were able to modulate TH-DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH-DA pathway. CONCLUSIONS: Our findings highlight the vital role of the TH-DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH-DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH-DA pathway inhibitors in early or prodromic PD.

Anti-HLA-A2-CAR Tregs prolong vascularized mouse heterotopic heart allograft survival.

Alloantigen-specific regulatory T cell (Treg) therapy is a promising approach for suppressing alloimmune responses and minimizing immunosuppression after solid organ transplantation. Chimeric antigen receptor (CAR) targeting donor alloantigens can confer donor reactivity to Tregs. However, CAR Treg therapy has not been evaluated in vascularized transplant or multi-MHC mismatched models. Here, we evaluated the ability of CAR Tregs targeting HLA-A2 (A2-CAR) to prolong the survival of heterotopic heart transplants in mice. After verifying the in vitro activation, proliferation, and enhanced suppressive function of A2-CAR Tregs in the presence of A2-antigen, we analyzed the in vivo function of Tregs in C57BL/6 (B6) mice receiving A2-expressing heart allografts. A2-CAR Treg infusion increased the median survival of grafts from B6.HLA-A2 transgenic donors from 23 to 99 days, whereas median survival with polyclonal Treg infusion was 35 days. In a more stringent model of haplo-mismatched hearts from BALB/cxB6.HLA-A2 F1 donors, A2-CAR Tregs slightly increased median graft survival from 11 to 14 days, which was further extended to >100 days when combined with a 9-day course of rapamycin treatment. These findings demonstrate the efficacy of CAR Tregs, alone or in combination with immunosuppressive agents, toward protecting vascularized grafts in fully immunocompetent recipients.

The effect of tumor grade heterogeneity on recurrence in non-muscle invasive bladder cancer.

OBJECTIVE: To investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance. METHODS: We identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy. RESULTS: Two hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence. CONCLUSIONS: The prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.

Non-Alcohol-Related Wernicke's Encephalopathy: Diagnosis and Treatment.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

Precision Engineering of an Anti-HLA-A2 Chimeric Antigen Receptor in Regulatory T Cells for Transplant Immune Tolerance.

Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-ζ signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR+TCRdeficient human Tregs maintained both Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR+TCRdeficient Tregs did not impair the function of these HLA-A2+ islets, whereas similarly engineered A2-CAR+TCRdeficientCD4+ conventional T cells rejected the islets in less than 2 weeks. A2-CAR+TCRdeficient Tregs delayed graft-versus-host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.