HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.

SARS-CoV-2 breakthrough infection induces rapid memory and de novo T cell responses.

Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.

Cross talk between Paneth and tuft cells drives dysbiosis and inflammation in the gut mucosa.

Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.

Phosphoinositide species and filamentous actin formation mediate engulfment by senescent tumor cells.

Cancer cells survive chemotherapy and cause lethal relapse by entering a senescent state that facilitates expression of many phagocytosis/macrophage-related genes that engender a novel cannibalism phenotype. We used biosensors and live-cell imaging to reveal the basic steps and mechanisms of engulfment by senescent human and mouse tumor cells. We show filamentous actin in predator cells was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species revealed increased concentration and distinct localization of predator PI(4) P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a transient burst of PI(3) P before and following internalization. PIK3C2B, the kinase responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, our data reveal the most fundamental cellular processes of senescent cell engulfment, including the precise localizations and dynamics of actin and PI species throughout the entire process.

Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study.

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.

The Importance of Photoaging Prevention in All Skin Types: An Update on Current Advancements.

Light from across the electromagnetic spectrum, including ultraviolet, visible, and infrared light, can cause detrimental cutaneous effects including photocarcinogenesis and photoaging. Traditional and broad-spectrum sunscreens offer protection against ultraviolet radiation. However, visible and infrared light may not always be covered by traditional sunscreens. These forms of solar radiation have been shown to cause photodamage and may have particular importance in the effects induced in skin of color. This article aims to review the mechanisms of photoaging from various light forms, the implications of these damaging effects on skin of color, and innovative approaches that can advance the way patients practice photoprotection. We will expand upon the latest innovations in photoprotection that hold the potential to increase patient adherence and improve skin health across all skin types. J Drugs Dermatol. 2024;23(1):1306-1310.   doi:10.36849/JDD.7255.

Updates on the Molecular Basis of Photoaging in All Skin Types.

Photoaging is a complex, ongoing process that clinically manifests as cutaneous rhytides, atrophy, laxity, dyspigmentation, telangiectasias, roughness, and mottled appearance of the skin. There is an abundance of research establishing the mechanism of ultraviolet (UV) - induced photodamage as it is a significant source of photoaging and skin cancers. While UV damage is known to induce photoaging, it is important to understand how other forms of light radiation also contribute to this process. UV only constitutes 5 to 10% of solar radiation that reaches the earth's surface. The remaining nearly 90% is evenly split between infrared and visible light radiation. Early research shows that varied skin types may elicit different photobiologic responses to light. This article presents the mechanisms and biomarkers of photodamage induced by light from across the spectrum, including UV, visible light, and infrared to better prevent and reverse the damage of photoaging in all skin types.J Drugs Dermatol. 2024;23(7):504-509.  doi:10.36849/JDD.7438.

Gender and Racial Diversity Among Obstetrics and Gynecology Departments and Gynecologic Oncology Divisions in Canada: Are We There Yet?

OBJECTIVES: Gender and racial diversity in academic Canadian departments of obstetrics and gynecology (OBGYN) have not been previously described. We examined gender representation in leadership in academic OBGYN departments and gynecologic oncology (GO) divisions, and determined factors predictive of leadership and promotion including racialized status. METHODS: This cross-sectional study of Canadian residency-affiliated academic OBGYN departments queried institutional websites in January 2021 to compile a list of academic faculty. Subjective gender was assessed using photographs and pronouns, and racialized status was determined using photographs. Logistic regression analyses determined predictive factors for leadership roles. Fassiotto et al. rank equity indices (REI) and Hofler et al. representation ratios were calculated. RESULTS: Within 16 Canadian institutions there were 354 (33.6%) men and 699 (66.4%) women, with 18.3% racialized faculty. Men were more likely to reach full professorship (P < 0.00001) and leadership positions of department chair, vice-chair or division head (P = 0.01). Representation ratios for women in OBGYN were <1 for all administrative leadership positions, and pairwise comparisons of the probability of promotion for women OBGYNs using REI reveal significant disparities between senior and junior administrative leadership and professorial ranks. Racialized physicians were less likely to have attained full professorship (P = 0.002). Ninety-seven academic GOs were identified: 68 (70.1%) were women, 17 (17.5%) racialized. Seven GO divisions (44%) had no racialized members. On multivariate analysis, only year of completion of fellowship was predictive of leadership. CONCLUSION: In academic Canadian OBGYN departments women are underrepresented in leadership and full professor positions. Racialized faculty are underrepresented in full professorship.

Postoperative Cognitive Decline in Patients Undergoing Major Gynecologic Oncology Surgery: A Pilot Prospective Study.

OBJECTIVES: Postoperative cognitive decline (POCD) is characterised by deficits in attention, memory, executive function, and information processing that persist beyond the early postoperative period. Its incidence ranges from 10%-25% after noncardiac surgery. Limited literature exists on POCD after gynecologic oncology surgery. Our primary objective was to identify the incidence of POCD among patients 55 years or older undergoing major gynecologic oncology surgery. METHODS: This mixed-methods, prospective, observational cohort study followed patients 55 years or older who underwent surgery for gynecologic malignancies between February and July 2022. Semi-structured interviews and the Mini-Mental State Exam (MMSE) were administered before surgery as well as 1 and 3 months after. Assessments were delivered virtually and in-person in the context of the COVID-19 pandemic. POCD was defined as ≥2-point decline from baseline MMSE score. RESULTS: Twenty-four patients participated; 19 completed the 1-month follow-up, and 15 completed the 3-month follow-up. The average age was 64 (range: 56-90). The mean preoperative MMSE score was 16.6 out of 17 (virtual) and 12.9 out of 13 (in-person). Two patients had a 1-point decline in their 1-month MMSE score; both recovered by 3 months. One patient had a 1-point decline in their 3-month MMSE score. Semi-structured interviews revealed common themes of "brain fog" at the 1-month follow-up and mild, persistent attention and word-finding deficits at 3 months postoperatively. CONCLUSIONS: This study's qualitative component captured subtle subjective findings suggestive of potential POCD. Larger studies are required, and a more extensive neuropsychological test battery may be required to elicit subtle findings not clearly reflected by MMSE scores.

Incidence and Management of Neonatal Pneumothorax in a 10-Hospital Regional Perinatal Network in Switzerland: A Retrospective Observational Study.

OBJECTIVE: Pneumothorax (PTX) is a potentially life-threatening condition that affects neonates, with an incidence of 0.05 to 2%. Its management includes conservative treatment, chest tube (CT) drainage, and needle aspiration (NA). Aims were to evaluate the incidence of PTX in a 10-hospital perinatal network, its clinical characteristics and risk factors, and to compare the different treatment options. STUDY DESIGN: All neonates diagnosed with PTX and hospitalized in the network were included in this retrospective observational trial over a period of 30 months. Primary outcome was the incidence of PTX. Secondary outcomes were the treatment modality, the length of stay (LOS), and the number of chest X-rays. RESULTS: Among the 173 neonates included, the overall incidence of PTX was 0.56 per 100 births with a large range among the hospitals (0.12-1.24). Thirty-nine percent of pneumothoraces were treated conservatively, 41% by CT drainage, 13% by NA, and 7% by combined treatment. Failure rate was higher for NA (37%) than for CT drainage (9%). However, the number of X-rays was lower for patients treated by NA, with a median of 6 (interquartile range [IQR] 4-6.25), than by CT drainage, with a median of 9 (IQR 7-12). LOS was shorter for NA than for CT drainage, with a median of 2 (IQR 1-4.25) and 6 days (IQR 3-15), respectively. Complications, including apnea and urinary retention, occurred in 28% of patients managed with CT drainage, whereas none was observed with NA. CONCLUSION: High variability of PTX incidence was observed among the hospitals within the network, but these values correspond to the literature. NA showed to reduce the number of X-rays, the LOS, and complications compared with CT drainage, but it carries a high failure rate. This study helped provide a new decisional management algorithm to harmonize and improve PTX treatment within our network. KEY POINTS: · Neonatal PTX is a frequent pathology with a high incidence requiring urgent management.. · We report a large variability of PTX incidence between different hospitals of the same network.. · Needle aspiration carries higher failure rate, shorter hospital stay duration without complications reported..

Effect of different lung recruitment strategies and airway device on oscillatory mechanics in children under general anaesthesia.

BACKGROUND: Atelectasis has been reported in 68 to 100% of children undergoing general anaesthesia, a phenomenon that persists into the recovery period. Children receiving recruitment manoeuvres have less atelectasis and fewer episodes of oxygen desaturation during emergence. The optimal type of recruitment manoeuvre is unclear and may be influenced by the airway device chosen. OBJECTIVE: We aimed to investigate the different effects on lung mechanics as assessed by the forced oscillation technique (FOT) utilising different recruitment strategies: repeated inflations vs. one sustained inflation and different airway devices, a supraglottic airway device vs. a cuffed tracheal tube. DESIGN: Pragmatic enrolment with randomisation to the recruitment strategy. SETTING: We conducted this single-centre trial between February 2020 and March 2022. PARTICIPANTS: Seventy healthy patients (53 boys) aged between 2 and 16 years undergoing general anaesthesia were included. INTERVENTIONS: Forced oscillations (5 Hz) were superimposed on the ventilator waveform using a customised system connected to the anaesthesia machine. Pressure and flow were measured at the inlet of the airway device and used to compute respiratory system resistance and reactance. Measurements were taken before and after recruitment, and again at the end of surgery. MAIN OUTCOME MEASURES: The primary endpoint measured is the change in respiratory reactance. RESULTS: Statistical analysis (linear model with recruitment strategy and airway device as factors) did not show any significant difference in resistance and reactance between before and after recruitment. Baseline reactance was the strongest predictor for a change in reactance after recruitment: prerecruitment Xrs decreased by mean (standard error) of 0.25 (0.068) cmH 2 O s l -1 per  1 cmH 2 O -1  s l -1 increase in baseline Xrs ( P  < 0.001). After correcting for baseline reactance, the change in reactance after recruitment was significantly lower for sustained inflation compared with repeated inflation by mean (standard error) 0.25 (0.101) cmH 2 O ( P  = 0.0166). CONCLUSION: Although there was no significant difference between airway devices, this study demonstrated more effective recruitment via repeated inflations than sustained inflation in anaesthetised children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12619001434189.

An Exploratory Study of the Perceived Need for and Acceptability of a Healthy Frozen Meal Product Among Rural Corner Store Customers in North Carolina.

This pilot study assesses barriers to obtaining healthy affordable food and the early-stage acceptability of a novel subsidized healthy frozen meal product designed to address food insecurity and nutritional status among corner store customers in rural North Carolina. A convenience sample of 50 customers were surveyed to examine the perceived availability of healthy food options, barriers to maintaining healthy diets, food shopping and consumption habits, and reception of the product. Findings confirmed barriers to obtaining healthy foods that the product seeks to address, the validity of corner stores as the intervention site, and approval of the product's taste and concept.

Geometric tumor embolic budding characterizes inflammatory breast cancer.

PURPOSE: Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery. METHODS: This study combines experimental studies with two different IBC xenografts with image algorithmic studies utilizing human tissue microarrays (TMAs) of IBC vs non-IBC cases to support a novel hypothesis to explain IBC's sina qua non signature of florid lymphovascular emboli. RESULTS: In the human TMAs, compared to tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which show that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really sets IBC apart is the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers indicate geometric or exponential differences between IBC and non-IBC. In the experimental xenograft studies, Mary-X gives rise to tight spheroids in vitro which exhibit dynamic budding into smaller daughter spheroids whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into smaller daughter emboli in vivo. The mechanism that regulates this involves the generation of E-cad/NTF1, a calpain-mediated cleavage 100 kDa product of 120 kDa full length membrane E-cadherin. Inhibiting this calpain-mediated cleavage of E-cadherin by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides that both penetrate the cell membrane and mimic either the cleavage site or the binding site on E-cadherin, inhibits the generation of E-cad/NTF1 in a dose-dependent manner, reduces spheroid compactness and decreases budding. CONCLUSION: Since E-cad/NFT1 retains the p120ctn binding site but loses the α-and ß-catenin sites, promoting its 360° distribution around the cell's membrane, the vacilating levels of this molecule trigger budding of both the spheroids as well as the emboli. Recurrent and geometric budding of parental emboli into daughter emboli then would account for the plethora of emboli seen in IBC.

Hematologic disorder-associated Cxcr4 gain-of-function mutation leads to uncontrolled extrafollicular immune response.

The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies during infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling caused by defective receptor desensitization leads to exacerbated extrafollicular B-cell response. Using a mouse model bearing a gain-of-function mutation of Cxcr4 described in 2 human hematologic disorders, warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and Waldenström macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mechanistic target of rapamycin signaling, cycled more, and differentiated more potently into plasma cells than wild-type B cells after Toll-like receptor (TLR) stimulation. Moreover, Cxcr4 gain of function promoted enhanced homing and persistence of immature plasma cells in the bone marrow, a phenomenon recapitulated in WHIM syndrome patient samples. This translated in increased and more sustained production of antibodies after T-independent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response.

A double-blinded, randomized trial comparing surgeon-administered transversus abdominis plane block with placebo after midline laparotomy in gynecologic oncology surgery.

BACKGROUND: Surgeon-administered transversus abdominis plane block is a contemporary approach to providing postoperative analgesia, and this approach is performed by transperitoneally administering local anesthetic in the plane between the internal oblique and transversus abdominis muscles to target the sensory nerves of the anterolateral abdominal wall. Although this technique is used in many centers, it has not been studied prospectively in patients undergoing a midline laparotomy. OBJECTIVE: This study aimed to evaluate whether surgeon-administered transversus abdominis plane block reduces postoperative opioid requirements and improves clinical outcomes. STUDY DESIGN: In this double-blind, randomized, placebo-controlled trial, patients with a suspected or proven gynecologic malignancy undergoing surgery through a midline laparotomy at 1 Canadian tertiary academic center were randomized to either the bupivacaine group (surgeon-administered transversus abdominis plane blocks with 40 mL of 0.25% bupivacaine) or the placebo group (surgeon-administered transversus abdominis plane blocks with 40 mL of normal saline solution) before fascial closure. The primary outcome was the total dose of opioids (in morphine milligram equivalents) received in the first 24 hours after surgery. The secondary outcomes included opioid doses between 24 and 48 hours, pain scores, postoperative nausea and vomiting, incidence of clinical ileus, time to flatus, and hospital length of stay. The exclusion criteria included contraindications to study medication, history of chronic opioid use, significant adhesions on the anterior abdominal wall preventing access to the injection site, concurrent nonabdominal surgical procedure, and the planned use of neuraxial anesthesia or analgesia. To detect a 20% decrease in opioid requirements with a 2-sided type 1 error of 5% and power of 80%, a sample size of 36 patients per group was calculated. RESULTS: From October 2020 to November 2021, 38 patients were randomized to the bupivacaine arm, and 41 patients were randomized to the placebo arm. The mean age was 60 years, and the mean body mass index was 29.3. A supraumbilical incision was used in 30 of 79 cases (38.0%), and bowel resection was performed in 10 of 79 cases (12.7%). Patient and surgical characteristics were evenly distributed. The patients in the bupivacaine group required 98.0±59.2 morphine milligram equivalents in the first 24 hours after surgery, whereas the patients in the placebo group required 100.8±44.0 morphine milligram equivalents (P=.85). The mean pain score at 4 hours after surgery was 3.1±2.4 (0-10 scale) in the intervention group vs 3.1±2.0 in the placebo group (P=.93). Clinically significant nausea or vomiting was reported in 1 of 38 patients (2.6%) in the intervention group vs 1 of 41 patients (2.4%) in the placebo group (P=.95). Time to first flatus, rates of clinical ileus, and length of stay were similar between groups. Subgroup analysis of patients with a body mass index of <25 and patients who received an infraumbilical incision showed similarly comparable outcomes. CONCLUSION: Surgeon-administered transversus abdominis plane block with bupivacaine was not found to be superior to the placebo intervention in reducing postoperative opioid requirements or improving other postoperative outcomes for patients undergoing a midline laparotomy. These results differed from previous reports evaluating the ultrasound-guided transversus abdominis plane block approach. Surgeon-administered transversus abdominis plane block should not be considered standard of care in postoperative multimodal analgesia.

Antibiotic resistance, heteroresistance, and eradication success of Helicobacter pylori infection in children.

BACKGROUND: Antibiotic resistance is a well-known factor of Helicobacter pylori eradication failure. Heteroresistance indicates the coexistence of resistant and susceptible strains and might lead to underestimating antimicrobial resistance. This study aims to evaluate the susceptibility profile, the frequency of heteroresistance of H. pylori strains, and their effect on eradication success in a pediatric population. MATERIALS AND METHODS: Children aged 2-17 years who underwent an upper gastrointestinal endoscopy from 2011 to 2019 with positive H. pylori status were included. Susceptibility was measured by disk diffusion and E-test. The difference in susceptibility profiles between isolates from the antrum and the corpus was used to detect heteroresistance. For those who received eradication treatment, we evaluated eradication rate and factors affecting treatment success. RESULTS: Inclusion criteria were met by 565 children. Strains susceptible to all antibiotics were detected in 64.2%. Primary resistance rates for clarithromycin (CLA), metronidazole (MET), levofloxacin (LEV), tetracyclin (TET), and amoxicillin (AMO) were 11%, 22.9%, 6.9%, 0.4%, and 0% and secondary resistance rates were 20.4%, 29.4%, 9.3%, 0%, and 0%. Heteroresistance was present in untreated children in 2%, 7.1%, 0.7%, 0.7%, and 0% for CLA, MET, LEV, TET, and AMO. First-line eradication rates were 78.5% in intention-to-treat (ITT), 88.3% in full-analysis-set (FAS), and 94.1% in per-protocol (PP). Factors affecting eradication success were the duration of treatment when the triple-tailored treatment was used, the number of daily doses of amoxicillin administered, and the patient's adherence to treatment. CONCLUSIONS: This study shows the presence of relatively low primary resistance rates for H. pylori isolates but demonstrates the presence of heteroresistance in our population. Routine biopsies from the antrum and corpus must be considered for susceptibility testing to allow tailored treatments and increase eradication rates. Treatment success is affected by treatment choice, correct dosing of medications, and adherence. All these factors should be considered when evaluating the efficacy of an eradication regimen.

Racial and ethnic underrepresentation in dermatology clinical trials.

BACKGROUND: Including participants of diverse racial and ethnic populations in clinical trials is important to reduce disparities and promote health care equity. OBJECTIVE: To evaluate racial and ethnic representation in dermatology clinical trials. METHODS: Participant data from dermatology trials completed in the United States from 2017 to 2021 from ClinicalTrials.gov were compared to census data to determine if minority groups were represented at rates that reflect population demographics. Participation was compared with prevalence rates for the most underrepresented racial group. RESULTS: Of 246 trials that met inclusion criteria, 87.4% (215) reported racial data. Compared to census data, Black/African American, American Indian/Alaskan Native, and 2 or more races were underrepresented. Hispanic or Latinos were an underrepresented ethnic group. LIMITATIONS: The search was limited to ClinicalTrials.gov registered studies that fell within search parameters. Race reporting methods were not specified. Detailed analysis was only performed for the most underrepresented racial group. CONCLUSION: Certain minority groups were underrepresented in dermatology trials. Black/African Americans were most underrepresented and underrepresented even when accounting for prevalence rates. Trial representation that accurately reflects population demographics and subgroup prevalence rates can help reduce health inequity, improve clinical understanding, and enhance treatment access for the growing diverse population.

Predicting obstructive sleep apnoea and perioperative respiratory adverse events in children: role of upper airway collapsibility measurements.

BACKGROUND: Obstructive sleep apnoea (OSA) and perioperative respiratory adverse events are significant risks for anaesthesia in children undergoing adenotonsillectomy. Upper airway collapse is a crucial feature of OSA that contributes to respiratory adverse events. A measure of upper airway collapsibility to identify undiagnosed OSA can help guide perioperative management. We investigated the utility of pharyngeal closing pressure (PCLOSE) for predicting OSA and respiratory adverse events. METHODS: Children scheduled for elective adenotonsillectomy underwent in-laboratory polysomnography 2-12 weeks before surgery. PCLOSE measurements were obtained while the child was anaesthetised and breathing spontaneously just before surgery. Logistic regression was used to assess the predictive performance of PCLOSE for detecting OSA and perioperative respiratory adverse events after adjusting for potential covariates. RESULTS: In 52 children (age, mean [standard deviation] 5.7 [1.8] yr; 20 [38%] females), airway collapse during PCLOSE was observed in 42 (81%). Of these, 19 of 42 (45%) patients did not have OSA, 15 (36%) had mild OSA, and eight (19%) had moderate-to-severe OSA. All 10 children with no evidence of airway collapse during the PCLOSE measurements did not have OSA. PCLOSE predicted moderate-to-severe OSA (odds ratio [OR] 1.71; 95% confidence interval [CI]: 1.2-2.8; P=0.011). All children with moderate-to-severe OSA could be identified at a PCLOSE threshold of -4.0 cm H2O (100% sensitivity), and most with no or mild OSA were ruled out (64.7% specificity; receiver operating characteristic/area under the curve=0.857). However, there was no significant association between respiratory adverse events and PCLOSE (OR 1.0; 95% CI: 0.8-1.1; P=0.641). CONCLUSIONS: Measurement of PCLOSE after induction of anaesthesia can reliably identify moderate or severe OSA but not perioperative respiratory adverse events in children before adenotonsillectomy. CLINICAL TRIAL REGISTRATION: ANZCTR ACTRN 12617001503314.

Conceptualizing Community Mental Health Service Utilization for BIPOC Youth.

Historically, children and adolescents who identify as Black, Indigenous, and other people of Color (BIPOC) have had inequitable access to mental healthcare, and research shows that they are significantly less likely than their white American counterparts to utilize available services. Research identifies barriers that disproportionately impact racially minoritized youth; however, a need remains to examine and change systems and processes that create and maintain racial inequities in mental health service utilization. The current manuscript critically reviews the literature and provides an ecologically based conceptual model synthesizing previous literature relating to BIPOC youth barriers for service utilization. The review emphasizes client (e.g. stigma, system mistrust, childcare needs, help seeking attitudes), provider (e.g. implicit bias, cultural humility, clinician efficacy), structural/organizational (clinic location/proximity to public transportation, hours of operation, wraparound services, accepting Medicaid and other insurance-related issues), and community (e.g. improving experiences in education, the juvenile criminal-legal system, medical, and social service systems) factors that serve as barriers and facilitators contributing to disparities in community mental health service utilization for BIPOC youth. Importantly, we conclude with suggestions for dismantling inequitable systems, increasing accessibility, availability, appropriateness, and acceptability of services, and ultimately reducing disparities in efficacious mental health service utilization for BIPOC youth.

Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons.

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.