Clinical phenotype and management of sound-induced pain: Insights from adults with pain hyperacusis.

Pain hyperacusis, also known as noxacusis, causes physical pain in response to everyday sounds that do not bother most people. How sound causes excruciating pain that can last for weeks or months in otherwise healthy individuals is not well understood, resulting in a lack of effective treatments. To address this gap, we identified the most salient physical and psychosocial consequences of debilitating sound-induced pain and reviewed the interventions that sufferers have sought for pain relief to gain insights into the underlying mechanisms of the condition. Adults (n = 32) with pain hyperacusis attended a virtual focus group to describe their sound-induced pain. They completed three surveys to identify common symptoms and themes that defined their condition and to describe their use of pharmaceutical and non-pharmaceutical therapies for pain relief. All participants endorsed negative effects of pain hyperacusis on psychosocial and physical function. Most reported sound-induced burning (80.77%), stabbing (76.92%), throbbing (73.08%), and pinching (53.85%) that occurs either in the ear or elsewhere in the body (i.e., referred pain). Participants reported using numerous pharmaceutical and non-pharmaceutical interventions to alleviate their pain with varying degrees of pain relief. Benzodiazepines and nerve blockers emerged as the most effective analgesic options while non-pharmaceutical therapies were largely ineffective. Symptoms of pain hyperacusis and therapeutic approaches are largely consistent with peripheral mechanistic theories of pain hyperacusis (e.g., trigeminal nerve involvement). An interdisciplinary approach to clinical studies and the development of animal models is needed to identify, validate, and treat the pathological mechanisms of pain hyperacusis.

A theoretical explanation of naloxone provision among primary care physicians and community pharmacists in Tennessee.

BACKGROUND: Increasing access to naloxone reduces opioid-related morbidity and mortality. Primary care and community pharmacy settings are critical access points, yet limited theoretical research has examined naloxone prescribing and dispensing behaviors. OBJECTIVES: To determine if the theory of planned behavior (TPB) combined with theoretical constructs from communication science explains intentions to co-prescribe and discuss co-dispensing naloxone among primary care physicians and community pharmacists, respectively. METHODS: This cross-sectional study surveyed cohorts of licensed primary care physicians and community pharmacists in Tennessee in 2017. Intentions were measured using profession-specific case vignettes, whereby they were asked given 10 similar patients, how many times (0-10) would they co-prescribe or discuss co-dispensing naloxone. Bivariate and multivariable analyses were used. RESULTS: The analytic sample included 295 physicians (response rate = 15.6 %) and 423 pharmacists (response rate = 19.4 %). Approximately 65 % of physicians reported never intending to co-prescribe naloxone (0 out of 10 patients), while 47 % of pharmacists reported never intending to discuss co-dispensing. All TPB constructs-attitudes (AOR = 1.32, CI = 1.16-1.50), subjective norms (AOR = 1.17, CI = 1.06-1.30), and perceived behavioral control (AOR 1.16, CI = 1.02-1.33)-were associated with an increased likelihood of pharmacists always (versus never) discussing co-dispensing. Similarly, two TPB constructs-attitudes (AOR = 1.41, CI = 1.19-1.68) and subjective norms (AOR = 1.22, CI = 1.08-1.39)-were associated with an increased likelihood of physicians always co-prescribing. Among physicians only, one communication construct-self-perceived communication competence (AOR = 1.19, CI = 1.01-1.41)-was associated with an increased likelihood of always co-prescribing. CONCLUSION: Findings support the value of theory, particularly TPB, in explaining primary care physician intentions to co-prescribe and community pharmacist intentions to discuss co-dispensing naloxone.

"Breaking Bread" With Respondents: Strategies to Increase Response Rates and Create Long-Term Cooperation With Health Clinic Administrators.

BACKGROUND AND OBJECTIVES: To fully understand the impact of unintended pregnancy, as well as to evaluate the implementation and outcomes of programs targeted at reducing unintended pregnancy, it is critical that researchers be able to collect comprehensive data from health clinics that provide these services in vulnerable communities. METHODS: Our paper details recruitment and incentive strategies, as well as the theories that guided them, which allowed us to achieve a high survey response rate among health clinic administrators in public health clinics in 2 Southeastern states-South Carolina and Alabama-both of which have high rates of unintended pregnancy. RESULTS: Grounded in organizational theory, and utilizing the Tailored Design Method, we achieved a 68% response rate utilizing paper and web survey administration with multiple contact modes. Our incentive structure comprised both traditional cash-based and food-based incentives. CONCLUSIONS: Findings indicate high response rates are achievable despite high survey burden (ie, detailed information, length of survey). We found that sample screening was critical and that food-based incentives made an impression on respondents that positively impacted the researcher-respondent relationship. Providing detailed methodology and additional literature will assist researchers working with similar populations-a gap in the applied methodological literature that was problematic at the project's onset.

Anthropometric traits and risk of multiple myeloma: differences by race, sex and diagnostic clinical features.

BACKGROUND: Obesity is an established modifiable risk factor for multiple myeloma (MM). However, associations of obesity and MM risk in Black populations, for whom obesity and MM are more common, is less clear. METHODS: Using participants enrolled in the Integrative Molecular And Genetic Epidemiology study, we evaluated the association of anthropometric traits with MM risk overall, stratified by race and sex. Among cases, we assessed the association of BMI with the presence of myeloma-defining events. RESULTS: We observed an 18% increase in MM risk for every 5 kg/m2 increase in usual adult BMI. Participants with severe obesity (BMI ≥ 40 kg/m2) had the highest risk compared to those with a normal usual adult BMI (18.5-24.9 kg/m2; OR = 1.87, 95% CI 1.25-2.80), particularly among Black men (OR = 3.94, 95% CI 0.90-17.36). Furthermore, MM cases with overweight/obesity (BMI ≥ 25 kg/m2) were more likely to present at diagnosis with low renal function (OR = 1.62, 95% CI 1.09-2.40), deletion 13q (OR = 1.73, 95% CI 1.08-2.76) and lytic lesions or compression fractures (OR = 2.39, 95% CI 0.82-7.01) and less likely to present with severe diffuse osteopenia (OR = 0.51, 95% CI 0.31-0.81). CONCLUSIONS: Findings underscore the importance of obesity as a modifiable risk factor for MM, particularly in high-risk populations, and for the clinical presentation of disease.

Surgical Field Separation in Total Laparoscopic Hysterectomy.

We aimed to study whether separating the vaginal and abdominal surgical fields during total laparoscopic hysterectomy (TLH) is associated with surgical site infection rates. This was a retrospective cohort study of all patients who underwent TLH and any concomitant procedures with two minimally invasive gynecologic surgery subspecialists between January 2016 and May 2023. Among 680 included patients, the rate of infection was 0.8% with surgical field separation and 1.3% without (3/377 vs 4/303; odds ratio 0.60, 95% CI, 0.13-2.70). There was no statistical difference between groups; however, the difference in infection rates between groups was extremely small, which led to inadequate power. Our findings suggest that rates of infection after TLH are low, with or without surgical field separation. Treating the vagina, perineum, and abdomen as a single, continuous operative field during TLH may be an acceptable practice.

Growth Patterns Between Ages 0 and 36 Months Among US Children With Orofacial Cleft: A Retrospective Cohort Study.

BACKGROUND: Little is known about how young children with orofacial cleft grow over time. OBJECTIVE: To characterize longitudinal growth patterns from ages 0 to 36 months in US children with an orofacial cleft. DESIGN: A retrospective cohort study. PARTICIPANTS/SETTING: Children with cleft lip, cleft lip and palate, or cleft palate who were younger than age 36 months at a hospital encounter between 2010 and 2019 (N = 1334) were included. The setting was a US tertiary care children's hospital with a cleft center that serves a 5-state region. MAIN OUTCOME MEASURE: Weight-for-age z scores (WAZ) and length-for-age z scores (LAZ). STATISTICAL ANALYSES PERFORMED: Longitudinal growth patterns were characterized using generalized linear mixed models to estimate mean WAZ and LAZ from age 0 to 36 months. RESULTS: Growth in infants with cleft slowed dramatically during the first 3 to 4 months of life, rebounded with catch-up growth until age 12 months for cleft lip and cleft palate and until age 36 months for cleft lip and palate. When comparing populations, children with any type of cleft demonstrated subpar growth compared with World Health Organization standards. Growth deficits were more common in those with cleft lip and palate and cleft palate compared with those with cleft lip. The intraclass coefficient showed that most of the variability in the WAZ (65%) was between individuals, whereas 35% was within an individual. The intraclass coefficient for LAZ showed that most of the variability in the LAZ (74%) was between individuals, whereas 26% was within an individual. The proportion of variance attributable to cleft type and/or comorbidities accounted for <5% of the variance for WAZ and LAZ. WAZ and LAZ were lower in children with comorbidities than those without comorbidities with cleft and World Health Organization standards. CONCLUSIONS: Infants with cleft lip and palate, cleft palate, and a cleft with comorbidities have higher rates of poor growth than peers with cleft lip and a cleft with no comorbidities, respectively.

Race, Ethnicity, and Sex Representation Trends Among Minimally Invasive Gynecologic Surgery Fellowship Trainees and Graduates.

STUDY OBJECTIVE: To study the race, ethnicity, and sex representation and annual trends of AAGL FMIGS fellows and graduates. DESIGN: A retrospective cross-sectional study. SETTING: AAMC databases were queried for demographic information between 2011 and 2023. PATIENTS/SUBJECTS: AAGL FMIGS fellows and graduates. INTERVENTIONS: N/A MEASUREMENTS AND MAIN RESULTS: Descriptive statistical analysis and the actual-to-expected (AE) ratio of each race, ethnicity, and sex were performed. AE ratio was calculated by dividing the 13-year average actual percentage of FMIGS trainees and graduates by the expected percentage based demographics of OBGYN residents and the US general population. 477 fellows graduated or were in training between 2011 and 2023; race and ethnicity information was obtained for 347 (72.7%) individuals, and sex information was available for 409 (85.7%). Representation of females ranged from 66.7% in 2017 to 93.3% in 2022. There was a significantly increasing slope for the representation of females (+1.3% per year; 95% CI 0.00-0.03; p = .027). Compared to their distribution among US OBGYN residents, White fellows' representation was lower [AE ratio, 95% CI 0.60 (0.44-0.81)] and of Asian fellows was higher [AE ratio, 95% CI 2.17 (1.47-3.21)]. Female fellows' representation was lower than expected [AE ratio, 95% CI 0.68 (0.48-0.96)] compared to their distribution among US OBGYN residents. Compared to the general US population, White fellows [AE ratio, 95% CI 0.65 (0.48-0.87)] and Hispanic fellows [AE ratio, 95% CI 0.53 (0.34-0.83)] representation was lower. Asian fellows' representation was higher compared to the general US population [AE ratio, 95% CI 5.87 (3.48-9.88)]. CONCLUSION: White and Hispanic fellows' representation was lower than expected, while Asian fellows' representation was higher in AAGL-accredited FMIGS programs. Female representation increased throughout the years, but overall, female fellows' representation was lower than expected compared to their distribution among OBGYN residents. These findings may help develop equitable recruitment strategies for FMIGS programs and reduce health disparities within complex gynecology.

Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism.

The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors.

Associations of Patient and Parent Characteristics With Parental Decision Regret in the PICU: A Secondary Analysis of the 2015-2017 Navigate Randomized Comparative Trial.

OBJECTIVES: To identify self-reported meaningful decisions made by parents in the PICU and to determine patient and parent characteristics associated with the development of parental decision regret, a measurable, self-reported outcome associated with psychologic morbidity. DESIGN: Secondary analysis of the Navigate randomized comparative trial (NCT02333396). SETTING: Two tertiary, academic PICUs. PATIENTS: Spanish- or English-speaking parents of PICU patients aged less than 18 years who were expected to remain in the PICU for greater than 24 hours from time of enrollment or who had a risk of mortality greater than 4% based on Pediatric Index of Mortality 2 score. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between April 2015 and March 2017, 233 parents of 209 patients completed a survey 3-5 weeks post-PICU discharge which included the Decision Regret Scale (DRS), a 5-item, 5-point Likert scale tool scored from 0 (no regret) to 100 (maximum regret). Two hundred nine patient/parent dyads were analyzed. The decisions parents reported as most important were categorized as: procedure, respiratory support, medical management, parent-staff interactions and communication, symptom management, fluid/electrolytes/nutrition, and no decision. Fifty-one percent of parents had some decision regret (DRS > 0) with 19% scoring in the moderate-severe range (DRS 26-100). The mean DRS score was 12.7 (sd 18.1). Multivariable analysis showed that parental Hispanic ethnicity was associated with greater odds ratio (OR 3.12 [95% CI, 1.36-7.13]; p = 0.007) of mild regret. Being parents of a patient with an increased PICU length of stay (LOS) or underlying respiratory disease was associated with greater odds of moderate-severe regret (OR 1.03 [95% CI, 1.009-1.049]; p = 0.004 and OR 2.91 [95% CI, 1.22-6.94]; p = 0.02, respectively). CONCLUSIONS: Decision regret was experienced by half of PICU parents in the 2015-2017 Navigate study. The characteristics associated with decision regret (parental ethnicity, PICU LOS, and respiratory disease) are easily identifiable. Further study is needed to understand what contributes to regret in this population and what interventions could provide support and minimize the development of regret.

Cabozantinib Plus Nivolumab in Patients with Non-Clear Cell Renal Cell Carcinoma: Updated Results from a Phase 2 Trial.

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC. PATIENT SUMMARY: We evaluated outcomes for patients with metastatic kidney cancer of the non-clear cell (NCC) type who were treated with cabozantinib + nivolumab. We found that 48% of the patients responded to the treatment, and there were no unexpected side effects. Among patients who responded to the treatment, the response lasted for a median of 17 months. We conclude that cabozantinib + nivolumab is a safe and effective treatment for NCC kidney cancer.

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

Durability of Original Monovalent mRNA Vaccine Effectiveness Against COVID-19 Omicron-Associated Hospitalization in Children and Adolescents - United States, 2021-2023.

Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered <120 days before hospitalization and 19% (95% CI = 2%-32%) if the interval was 120-364 days. VE of the original monovalent vaccine against COVID-19-related hospitalization was 31% (95% CI = 18%-43%) if the last dose was received any time within the previous year. VE against critical COVID-19-related illness, defined as receipt of noninvasive or invasive mechanical ventilation, vasoactive infusions, extracorporeal membrane oxygenation, and illness resulting in death, was 57% (95% CI = 21%-76%) when the most recent dose was received <120 days before hospitalization, 25% (95% CI = -9% to 49%) if it was received 120-364 days before hospitalization, and 38% (95% CI = 15%-55%) if the last dose was received any time within the previous year. VE was similar after excluding children and adolescents with documented immunocompromising conditions. Because of the low frequency of children who received updated COVID-19 vaccines and waning effectiveness of original monovalent doses, these data support CDC recommendations that all children and adolescents receive updated COVID-19 vaccines to protect against severe COVID-19.

Deletion of PTP4A3 phosphatase in high grade serous ovarian cancer cells decreases tumorigenicity and produces marked changes in intracellular signaling pathways and cytokine release.

The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and ERK. The objective of this study was to generate ovarian cancer cells with genetically depleted PTP4A3; to assess their tumorigenicity; to examine their cellular phenotype; and to uncover changes in their intracellular signaling pathways and cytokine release profiles. Genetic deletion of PTP4A3 using CRISPR/Cas9 enabled the generation of individual clones derived from single cells isolated from the polyclonal knockout population. We observed a >90% depletion of PTP4A3 protein levels by Western blotting in the clonal cell lines compared to the sham transfected wildtype population. The wildtype and polyclonal knockout cell lines shared similar monolayer growth rates, while the isolated clonal populations 2B4, 3C9, and 3C12 exhibited significantly lower monolayer growth characteristics consistent with their lower PTP4A3 levels. The clonal PTP4A3 knockout cell lines also had substantially lower in vitro colony formation efficiencies compared to the wildtype cells and were less tumorigenic in vivo The clonal knockout cells were markedly less responsive to IL-6-stimulated migration in a scratch wound assay compared to the wildtype cells. Antibody microarray assays documented differences in cytokine release and intracellular phosphorylation patterns in the PTP4A3 deleted clones. Bioinformatic network analyses indicated alterations in cellular signaling nodes. These biochemical changes could ultimately form the foundation for pharmacodynamic endpoints useful for emerging anti-PTP4A3 therapeutics. Significance Statement Clones of high grade serous ovarian cancer cells were isolated in which the oncogenic phosphatase PTP4A3 was deleted using CRISPR/Cas9 methodologies. The PTP4A3 null cells exhibited loss of in vitro proliferation, colony formation, and migration, and reduced in vivo tumorigenesis. Marked differences in intracellular protein phosphorylation and cytokine release were seen. The newly developed PTP4A3 knockout cells should provide useful tools to probe the role of PTP4A3 phosphatase in ovarian cancer cell survival, tumorigenicity and cell signaling.

Metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and hepatic steatosis (HS). Because dietary essential amino acid (EAA) supplementation has been shown to decrease HS in various populations, this study's objective was to determine whether supplementation would decrease HS in PCOS. METHODS: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 21 adolescents with PCOS (BMI 37.3 ± 6.5 kg/m2, age 15.6 ± 1.3 years). Liver fat, very low-density lipoprotein (VLDL) lipogenesis, and triacylglycerol (TG) metabolism were measured following each 28-day phase of placebo or EAA. RESULTS: Compared to placebo, EAA was associated with no difference in body weight (p = 0.673). Two markers of liver health improved: HS was lower (-0.8% absolute, -7.5% relative reduction, p = 0.013), as was plasma aspartate aminotransferase (AST) (-8%, p = 0.004). Plasma TG (-9%, p = 0.015) and VLDL-TG (-21%, p = 0.031) were reduced as well. VLDL-TG palmitate derived from lipogenesis was not different between the phases, nor was insulin sensitivity (p > 0.400 for both). Surprisingly, during the EAA phase, participants reported consuming fewer carbohydrates (p = 0.038) and total sugars (p = 0.046). CONCLUSIONS: Similar to studies in older adults, short-term EAA supplementation in adolescents resulted in significantly lower liver fat, AST, and plasma lipids and thus may prove to be an effective treatment in this population. Additional research is needed to elucidate the mechanisms for these effects.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Frequency of Leaks from Conical Centrifuge Tubes.

Introduction: Threaded conical centrifuge tubes are ubiquitous in biological laboratories and are frequently used for the storage/transport of potentially biohazardous samples. However, limited data are available on how frequently and from where these tubes leak. These data are valuable for laboratory biorisk management and to inform future studies on risks arising from the routine use of laboratory consumables. Methods: The frequency of leaks from threaded conical centrifuge tubes was tested using a Glo Germ solution as a tracer. Conical tubes (15 and 50 mL) from several brands were filled, inverted, and placed on their side on the benchtop. After 1 h, the presence or absence of leaks on the benchtop surface, tube threads, and exterior was recorded. Results: We observed that liquid leaked out of tubes that were apparently properly threaded in 2% of 15 mL tubes (confidence interval [95% CI] 1.4-2.6) and 1.4% of 50 mL tubes (95% CI 0.2-1.5). After opening, liquid was found on the threads on the outside of the tube in 20% of 15 mL tubes (95% CI 10-31) and 14% of 50 mL tubes (95% CI 1-28). We did not find sufficient evidence that differences in leak rates among brands were practically significant. Conclusions: The fact that leaks were not uncommonly observed from conical centrifuge tubes suggests that mitigations for any hazard posed by a leak should be a component of every biorisk management strategy for protocols involving the manipulation of hazardous substances in these tubes. Further research should be conducted on other activities that could cause tubes to leak (such as centrifugation or vortexing) and should be completed to understand the risks associated with this consumable. Research into the costs and benefits of mitigating the risk of leaks from conical tubes is recommended.

Trauma resident exposure in Canada and operative numbers (TraumaRECON): a national multicentre retrospective review of operative and nonoperative trauma teaching.

BACKGROUND: General surgeons play an important role in the provision of trauma care in Canada and the current extent of their trauma experience during training is unknown. We sought to quantify the operative and nonoperative educational experiences among Canadian general surgery trainees. METHODS: We conducted a multicentre retrospective study of major operative exposures experienced by general surgery residents, as identified using institutional trauma registries and subsequent chart-level review, for 2008-2018. We also conducted a site survey on trauma education and structure. RESULTS: We collected data on operative exposure for general surgery residents from 7 programs and survey data from 10 programs. Operations predominantly occurred after hours (73% after 1700 or on weekends) and general surgery residents were absent from a substantial proportion (25%) of relevant trauma operations. The structure of trauma education was heterogeneous among programs, with considerable site-specific variability in the involvement of surgical specialties in trauma care. During their training, graduating general surgery residents each experienced around 4 index trauma laparotomies, 1 splenectomy, 1 thoracotomy, and 0 neck explorations for trauma. CONCLUSION: General surgery residents who train in Canada receive variable and limited exposure to operative and nonoperative trauma care. These data can be used as a baseline to inform the application of competency-based medical education in trauma care for general surgery training in Canada.

ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype.

We have previously demonstrated synergy between ICOS costimulation (IVAX; ICOSL-transduced B16-F10 cellular vaccine) and CTLA-4 blockade in antitumor therapy. In this study, we employed CyTOF and single-cell RNA sequencing and observed significant remodeling of the lymphoid and myeloid compartments in combination therapy. Compared with anti-CTLA-4 monotherapy, the combination therapy enriched Th1 CD4 T cells, effector CD8 T cells, and M1-like antitumor proinflammatory macrophages. These macrophages were critical to the therapeutic efficacy of anti-CTLA-4 combined with IVAX or anti-PD-1. Macrophage depletion with clodronate reduced the tumor-infiltrating effector CD4 and CD8 T cells, impairing their antitumor functions. Furthermore, the recruitment and polarization of M1-like macrophages required IFN-γ. Therefore, in this study, we show that there is a positive feedback loop between intratumoral effector T cells and tumor-associated macrophages (TAMs), in which the IFN-γ produced by the T cells polarizes the TAMs into M1-like phenotype, and the TAMs, in turn, reshape the tumor microenvironment to facilitate T cell infiltration, immune function, and tumor rejection.

Differential cognitive and behavioral development from 6 to 24 months in autism and fragile X syndrome.

BACKGROUND: Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. METHODS: The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. RESULTS: Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. CONCLUSIONS: Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.