Factors associated with the use of psychedelics, ketamine and MDMA among sexual and gender minority youths in Canada: a machine learning analysis.

BACKGROUND: Substance use is increasing among sexual and gender minority youth (SGMY). This increase may be due to changes in social norms and socialisation, or due to SGMY exploring the potential therapeutic value of drugs such as psychedelics. We identified predictors of psychedelics, MDMA and ketamine use. METHODS: Data were obtained from 1414 SGMY participants who completed the ongoing longitudinal 2SLGBTQ+ Tobacco Project in Canada between November 2020 to January 2021. We examined the association between 80 potential features (including sociodemographic factors, mental health-related factors and substance use-related factors) with the use of psychedelics, MDMA and ketamine in the past year. Random forest classifier was used to identify the predictors most associated with reported use of these drugs. RESULTS: 18.1% of participants have used psychedelics in the past year; 21.9% used at least one of the three drugs. Cannabis and cocaine use were the predictors most strongly associated with any of these drugs, while cannabis, but not cocaine use, was the one most associated with psychedelic use. Other mental health and 2SLGBTQ+ stigma-related factors were also associated with the use of these drugs. CONCLUSION: The use of psychedelics, MDMA and ketamine among 2SLGBTQ+ individuals appeared to be largely driven by those who used them together with other drugs. Depression scores also appeared in the top 10 factors associated with these illicit drugs, suggesting that there were individuals who may benefit from the potential therapeutic value of these drugs. These characteristics should be further investigated in future studies.

Subcutaneous Treprostinil Improves Surgical Candidacy for Next Stage Palliation in Single Ventricle Patients With High-Risk Hemodynamics.

Single ventricle (SV) patients with pulmonary vascular disease (SV-PVD) are considered poor surgical candidates for Glenn or Fontan palliation. Given limited options for Stage 1 (S1) and Stage 2 (S2) SV patients with SV-PVD, we report on the use of subcutaneous treprostinil (TRE) to treat SV-PVD in this population. This single-center, retrospective cohort study examined SV patients who were not candidates for subsequent surgical palliation due to SV-PVD and were treated with TRE. The primary outcome was ability to progress to the next surgical stage; secondary outcomes included changes in hemodynamics after TRE initiation. Between 3/2014 and 8/2021, 17 SV patients received TRE for SV-PVD: 11 after S1 and 6 after S2 (median PVR 4.1 [IQR 3.2-4.8] WU*m2 and 5.0 [IQR 1.5-6.1] WU*m2, respectively). Nine of 11 (82%) S1 progressed to S2, and 2 (18%) underwent heart transplant (HTx). Three of 6 (50%) S2 progressed to Fontan, 1 underwent HTx and 2 are awaiting Fontan on TRE. TRE significantly decreased PVR in S1 patients with median post-treatment PVR of 2.0 (IQR 1.5-2.6) WU*m2. TRE can allow for further surgical palliation in select pre-Fontan patients with SV-PVD, obviating the need for HTx. Improvement in PVR was significant in S1 patients and persisted beyond discontinuation of therapy for most patients.

Home Milrinone in Pediatric Hospice Care of Children with Heart Failure.

CONTEXT: The symptom profile of children dying from cardiac disease, especially heart failure, differs from those with cancer and other non-cardiac conditions. Treatment with vasoactive infusions at home may be a superior therapy for symptom control for these patients, rather than traditional pain and anxiety management with morphine and benzodiazepines. OBJECTIVES: We report our experience using outpatient milrinone in children receiving hospice care for end-stage heart failure. METHODS: Retrospective review of a contemporary cohort of all patients at Lucile Packard Children's Hospital, Stanford who were discharged on intravenous milrinone and hospice care between 2008 and 2021. Clinical data, including cardiac diagnosis, milrinone dose and route of administration, total milrinone days, symptoms reported, rehospitalization rates, concurrent therapies and complications were analyzed. RESULTS: Among 8 patients, median duration of home milrinone infusion was 191 (33, 572) days with the longest support duration 1,054 days. All (100%) patients were also receiving diuretics at the time of death. Five (63%) were receiving no other pain control medications until the active phase of dying. From milrinone initiation to last outpatient assessment, a reduction in the number of patients reporting respiratory discomfort, abdominal pain, weight loss/lack of appetite, and fatigue was observed. Six (75%) died at home. CONCLUSION: We used milrinone with oral diuretics effectively for symptom control in children with heart failure on palliative care. Our experience was that this combination can be used safely in the outpatient setting for long-term use without the addition of opiates, benzodiazepines, or supplemental oxygen in most cases.

Clostridium difficile: What is the risk?

INTRODUCTION: Clostridium difficile infections (CDIs) are rising among pediatric patients in the community and hospital setting. Children undergoing transplants and bowel surgery are at a higher risk, while renal surgery has a lower risk. We hypothesize children undergoing pediatric urologic procedures are uncommonly diagnosed with postoperative CDI. OBJECTIVE: To study CDI in pediatric patients undergoing urologic surgery and identify associated perioperative factors. STUDY DESIGN: The American College of Surgeons National Surgical Quality Improvement Program Pediatric data file was queried for children undergoing surgery with pediatric urology or urology between 2015 and 2017. Data points included patient demographics (age, gender, race, ASA classification), surgery performed, and perioperative outcomes (operative time, admission status, length of stay, complications, readmission, and reoperation). Students T-test and Chi-square analyses were applied to detect differences between those with CDI and those without CDI. RESULTS: Of the 27,193 patients undergoing urologic surgery, 36 (0.13%) were diagnosed with CDI. The surgeries are presented in the Summary Figure. Patients with CDI were more likely to be female (50% vs 28%, p = 0.003) than those without. There was no difference in mean age or race. Children with CDI had higher ASA classifications (p < 0.001). Their mean operative times were longer (156.1 ± 19.6 vs 105.2 ± 0.6 min, p < 0.001), as were their mean lengths of stay (4.6 ± 0.8 vs 1.3 ± 0.0 days, p < 0.001). CDI patients were more likely to have other complications (29% vs 6%, p < 0.001). Among patients with CDI, 19.4% experienced concomitant infectious complications. There was no difference in reoperation rate, but more patients with CDI required readmission (56% vs 4%, p < 0.001). A third of children with CDI had undergone vesicoureteral reflux correction, comprising 0.3% of the included procedures. Over 11% of children with CDI had undergone nephrectomy, comprising 1.1% of the included procedures for the highest rate. DISCUSSION: CDI are uncommon following pediatric urologic procedures. No patients undergoing inguinal or scrotal cases developed CDI, while only one patient developed CDI after penile surgery. Our study does have several important limitations: we are unable to provide clinical information about the exact diagnoses, CDI risk factors such as antibiotic usage or comorbid conditions, and the number of patients who were tested for CDI. CONCLUSION: While pediatric urologists are unlikely to encounter postoperative CDI, when they occur, they are associated with longer lengths of stay, increased readmission rates, and an increased rate of non-CDI complications.

Complications of rabbit anti-thymocyte globulin induction immunosuppression in HIV-infected kidney transplant recipients.

Background: Kidney transplantation in HIV-infected individuals with end-stage kidney disease is associated with improved survival compared to dialysis. Rabbit anti-thymocyte globulin (rATG) induction in HIV-infected kidney transplant recipients has been associated with a lower risk of acute rejection, but data on the rates of de novo malignancy and BK viremia in these patients is lacking. Methods: We performed a single-center retrospective cohort study of adult HIV-infected individuals who underwent kidney transplantation with rATG induction between January 2006 and December 2016. The primary outcome was the development of de novo malignancy. Secondary outcomes included the development of BK viremia, infections requiring hospitalization, HIV progression, biopsy-proven acute rejection, and patient and allograft survival. Results: Twenty-seven HIV-infected individuals with end-stage kidney disease received deceased (n=23) or living (n=4) donor kidney transplants. The cumulative rate of malignancy at five years was 29%, of whom 29% died because of advanced malignancy. BK viremia was detected in six participants (22%), of whom one had biopsy-proven BK virus-associated nephropathy and all of whom cleared the BK viremia. Five-year acute rejection rates, patient survival and death-censored allograft survival were 17%, 85% and 80% respectively. Conclusion: rATG induction in HIV-infected kidney transplant recipients was associated with a low risk of acute rejection, but a potentially higher risk of de novo malignancies and BK viremia in this cohort. Screening strategies to closely monitor for BK virus infection and malignancy post-transplantation may improve outcomes in HIV-infected kidney transplant recipients receiving rATG induction.

Syndromic Wilms tumor: a review of predisposing conditions, surveillance and treatment.

Predisposing syndromes associated with an increased risk of Wilms tumor (WT) are responsible for 9-17% of all cases of the malignancy. Due to an earlier age at WT diagnosis and an increased incidence of bilateral and metachronous disease, management of syndromic WT warrants a distinct approach from that of non-syndromic WT. This review of English-language manuscripts about WT focuses on the most common syndromes, surveillance protocols and current treatment strategies. Highlighted syndromes include those associated with WT1, such as WAGR (Wilms-Aniridia-Genitourinary-mental Retardation), Denys-Drash syndrome (DDS), and Frasier syndrome, 11p15 defects, such as Beckwith-Wiedemann syndrome (BWS), among others. General surveillance guidelines include screening renal or abdominal ultrasound every 3-4 months until the age of 5 or 7, depending on the syndrome. Further, some of the predisposing conditions also increase the risk of other malignancies, such as gonadoblastoma and hepatoblastoma. With promising results for nephron-sparing surgery in bilateral non-syndromic WT, there are increasing reports and recommendations to pursue nephron-sparing for these patients who are at greater risk of bilateral, metachronous lesions. In addition to the loss of renal parenchyma from malignancy, many patients are at risk of developing renal insufficiency as part of their syndrome. Although there may be some increase in the complication rate, recurrence free survival seems equivalent. Some conditions require specialized approaches to adjuvant therapy, as their syndrome may make them especially susceptible to side effects.

Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngeneic murine models of ovarian cancer.

BACKGROUND: New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-κB) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown. Therefore, we aimed to investigate the therapeutic potential of increasing macrophage NF-κB activity in immunocompetent mouse models of ovarian cancer. METHODS: We have generated a transgenic mouse model, termed IKFM, which allows doxycycline-inducible overexpression of a constitutively active form of IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to evaluate effects of increasing macrophage NF-κB activity in syngeneic murine TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in established tumors, and 2) during tumor implantation and early tumor growth. Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor were collected at sacrifice. Populations of macrophages and T cells within solid tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value < 0.05 was considered statistically significant. RESULTS: Increased expression of the cIKK2 transgene in TAMs from IKFM mice was confirmed at the mRNA and protein levels. Tumors from IKFM mice, regardless of the timing of doxycycline (dox) administration, demonstrated greater necrosis and immune infiltration than control tumors. Analysis of IKFM ascites and tumors showed sustained shifts in macrophage populations away from the M2 and towards the anti-tumor M1 phenotype. There were also increased tumor-infiltrating CD3+/CD8+ T cells in IKFM mice, accompanied by higher levels of CXCL9, a T cell activating factor secreted by macrophages, in IKFM ascitic fluid. CONCLUSIONS: In syngeneic ovarian cancer models, increased canonical NF-κB signaling in macrophages promoted anti-tumor TAM phenotypes and increased cytotoxic T cell infiltration, which was sufficient to limit tumor progression. This may present a novel translational approach for ovarian cancer treatment, with the potential to increase responses to T cell-directed therapy in future studies.

The epigenetic reader Brd4 is required for osteoblast differentiation.

Transcription networks and epigenetic mechanisms including DNA methylation, histone modifications, and noncoding RNAs control lineage commitment of multipotent mesenchymal progenitor cells. Proteins that read, write, and erase histone tail modifications curate and interpret the highly intricate histone code. Epigenetic reader proteins that recognize and bind histone marks provide a crucial link between histone modifications and their downstream biological effects. Here, we investigate the role of bromodomain-containing (BRD) proteins, which recognize acetylated histones, during osteogenic differentiation. Using RNA-sequencing (RNA-seq) analysis, we screened for BRD proteins (n = 40) that are robustly expressed in MC3T3 osteoblasts. We focused functional follow-up studies on Brd2 and Brd4 which are highly expressed in MC3T3 preosteoblasts and represent "bromodomain and extra terminal domain" (BET) proteins that are sensitive to pharmacological agents (BET inhibitors). We show that small interfering RNA depletion of Brd4 has stronger inhibitory effects on osteoblast differentiation than Brd2 loss as measured by osteoblast-related gene expression, extracellular matrix deposition, and alkaline phosphatase activity. Similar effects on osteoblast differentiation are seen with the BET inhibitor +JQ1, and this effect is reversible upon its removal indicating that this small molecule has no lasting effects on the differentiation capacity of MC3T3 cells. Mechanistically, we find that Brd4 binds at known Runx2 binding sites in promoters of bone-related genes. Collectively, these findings suggest that Brd4 is recruited to osteoblast-specific genes and may cooperate with bone-related transcription factors to promote osteoblast lineage commitment and maturation.

Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity.

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-XL+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-XL, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.

Affinity maturation of antibodies requires integrity of the adult thymus.

The generation of B-cell responses to proteins requires a functional thymus to produce CD4(+) T cells which helps in the activation and differentiation of B cells. Because the mature T-cell repertoire has abundant cells with the helper phenotype, one might predict that in mature individuals, the generation of B-cell memory would proceed independently of the thymus. Contrary to that prediction, we show here that the removal of the thymus after the establishment of the T-cell compartment or sham surgery without removal of the thymus impairs the affinity maturation of antibodies. Because removal or manipulation of the thymus did not decrease the frequency of mutation of the Ig variable heavy chain exons encoding antigen-specific antibodies, we conclude that the thymus controls affinity maturation of antibodies in the mature individual by facilitating the selection of B cells with high-affinity antibodies.

A review and characterization of the various perceptions of quality cancer care.

BACKGROUND: It is important to maintain high-quality cancer care while reducing spending. This requires an understanding of how stakeholders define "quality." The objective of this literature review was to understand the perceptions patients, physicians, and managed care professionals have about quality cancer care, especially chemotherapy. METHODS: A computerized literature search was conducted for articles concerning quality cancer care in patients who received chemotherapy. Among >1100 identified sources, 25 presented interviews/survey results from stakeholders. RESULTS: Patients defined quality cancer care as being treated well by providers, having multiple treatment options, and being part of the decision-making process. Waiting to see providers, having problems with referrals, going to different locations for treatment, experiencing billing inaccuracies, and navigating managed care reimbursement negatively affected patients' quality-of-care perceptions. Providers perceived quality cancer care as making decisions based on the risks-benefits of specific chemotherapy regimens and patients' health status rather than costs. Providers objected to spending substantial time interacting with payers instead of delivering care to patients. Payers must control the costs of cancer care but do not want an adversarial relationship with providers and patients. Payers' methods of managing cancer more efficiently involved working with providers to develop assessment and decision-assist tools. CONCLUSIONS: Delivering quality cancer care is increasingly difficult because of the shortage of oncologists and rising costs of chemotherapy agents, radiation therapy, and imaging tests. The definition of quality cancer care differed among stakeholders, and healthcare reform must reflect these various needs to maintain and improve quality while controlling costs.

Human metapneumovirus detection in patients with severe acute respiratory syndrome.

We used a combination approach of conventional virus isolation and molecular techniques to detect human metapneumovirus (HMPV) in patients with severe acute respiratory syndrome (SARS). Of the 48 study patients, 25 (52.1%) were infected with HMPV; 6 of these 25 patients were also infected with coronavirus, and another 5 patients (10.4%) were infected with coronavirus alone. Using this combination approach, we found that human laryngeal carcinoma (HEp-2) cells were superior to rhesus monkey kidney (LLC-MK2) cells commonly used in previous studies for isolation of HMPV. These widely available HEp-2 cells should be included in conjunction with a molecular method for cell culture followup to detect HMPV, particularly in patients with SARS.