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Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV.In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594.Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling).Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs.Gilead Sciences.

Linking clinical services to community-based resources is a promising strategy for assisting patients with chronic disease prevention and management. However, there remains a gap in understanding how to effectively develop and implement community–clinical linkages (CCLs), especially in communities of color. The Healthy Here initiative used Stage Theory of organizational change to implement a centralized wellness referral system, linking primary care clinics to community organizations in majority Hispanic/Latinx and Native American communities. Data were collected using a standardized referral form. Facilitators and challenges were identified through semi-structured discussions with partner organizations. Between 2016 and 2021, 43 clinics and 497 health care providers made 7,465 referrals, the majority of which were from the focus populations. The average proportion of patients referred by clinic champions decreased significantly over time, reflecting diffusion of the intervention within clinics. Facilitators to system success included building on existing networked partnerships, utilizing a centralized referral center, leveraging funding, sharing data, addressing challenges collectively, incorporating multilevel leadership, and co-developing and testing a standardized referral form and process with a single clinic and provider before scaling up. Challenges included funding restrictions, decreasing referrals within clinics over time, changing availability of resources and programs, and the COVID-19 pandemic. This innovative initiative demonstrates that CCLs can be developed and implemented to successfully reach Hispanic/Latinx and Native American communities and provides strategies for overcoming challenges.

The aim of this study was to evaluate the Social Vulnerability Index (SVI) as a predictor of long-term outcomes after injury.The SVI is a measure used in emergency preparedness to identify need for resources in the event of a disaster or hazardous event, ranking each census tract on 15 demographic/social factors.Moderate-severely injured adult patients treated at 1 of 3 level-1 trauma centers were prospectively followed 6 to 14 months post-injury. These data were matched at the census tract level with overall SVI percentile rankings. Patients were stratified based on SVI quartiles, with the lowest quartile designated as low SVI, the middle 2 quartiles as average SVI, and the highest quartile as high SVI. Multivariable adjusted regression models were used to assess whether SVI was associated with long-term outcomes after injury.A total of 3153 patients were included [54% male, mean age 61.6 (SD = 21.6)]. The median overall SVI percentile rank was 35th (IQR: 16th-65th). compared to low SVI patients, high SVI patients were more likely to have new functional limitations [odds ratio (OR), 1.51; 95% confidence interval (CI), 1.19-1.92), to not have returned to work (OR, 2.01; 95% CI, 1.40-2.89), and to screen positive for post-traumatic stress disorder (OR, 1.56; 95% CI, 1.12-2.17). Similar results were obtained when comparing average with low SVI patients, with average SVI patients having significantly worse outcomes.The SVI has potential utility in predicting individuals at higher risk for adverse long-term outcomes after injury. This measure may be a useful needs assessment tool for clinicians and researchers in identifying communities that may benefit most from targeted prevention and intervention efforts.

BACKGROUND: Although dietary guidelines recommend that vegetables and fruits make up half the diet, it is unclear whether serving vegetables and fruits in larger portions will have sustained effects on children's intake over multiple days. OBJECTIVES: This study tested the effects on children's intake of 2 strategies for increasing the proportion of vegetables and fruits: either adding or substituting extra portions as side dishes at meals and snacks over 5 d. METHODS: In a cluster-randomized crossover design with 3 periods, we provided all meals and snacks for 5 d to 53 children aged 3–5 y in classrooms in their childcare centers. In the Control condition, we served typical portions for all food groups. In the Addition condition we increased portions of low-energy-dense vegetables and fruits by 50%, and in the Substitution condition we increased portions of vegetables and fruits by 50% and also reduced portions of other foods by an equivalent weight. RESULTS: For vegetables, the Addition strategy increased daily intake compared with Control by 24% (mean ± SEM = 12 ± 3 g/d; P = 0.0002), and the Substitution strategy increased intake compared with Control by 41% (22 ± 3 g/d; P < 0.0001). For fruits, consumption increased by similar amounts: Addition by 33% (60 ± 6 g/d) and Substitution by 38% (69 ± 8 g/d; both P < 0.0001). Both strategies increased vegetable and fruit intakes compared with Control across all 5 days (all P < 0.004), although the increase in fruit consumption with Addition declined over time (P < 0.0001). Daily energy intake compared with Control increased by 5% with Addition (57 ± 17 kcal; P = 0.001) but decreased by 6% with Substitution (−64 ± 21 kcal; P = 0.004). CONCLUSIONS: Both the Addition and Substitution strategies promoted increases in vegetable and fruit intake over 5 d in preschool children. When excess energy intake is a concern, substituting vegetables and fruits for other foods is a better option than simply serving more. This trial was registered at http://www.clinicaltrials.gov as NCT03242863 (https://clinicaltrials.gov/ct2/show/NCT03242863), where the protocol is available.

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

Background: Routine genome-wide screening for cardiovascular disease risk may inform clinical decision-making. However, little is known about whether clinicians and patients would find such testing useful or acceptable within the context of a genomics-enabled learning health system. Methods: We conducted surveys with patients and their clinicians who were participating in the HeartCare Study, a precision cardiology care project that returned results from a next-generation sequencing panel of 158 genes associated with cardiovascular disease risk. Six weeks after return of results, we assessed patients’ and clinicians’ perceived utility and disutility of HeartCare, the effect of the test on clinical recommendations, and patients’ attitudes toward integration of research and clinical care. Results: Among 666 HeartCare patients with a result returned during the survey study period, 42.0% completed a full or partial survey. Patient-participants who completed a full survey (n=224) generally had positive perceptions of HeartCare independent of whether they received a positive or negative result. Most patient-participants considered genetic testing for cardiovascular disease risk to have more benefit than risk (88.3%) and agreed that it provided information that they wanted to know (81.2%), while most disagreed that the test caused them to feel confused (77.7%) or overwhelmed (78.0%). For 122 of their patients with positive results, clinicians (n=13) reported making changes in clinical care for 66.4% of patients, recommending changes in health behaviors for 36.9% of patients, and recommending to 33.6% of patients that their family members have clinical testing. Conclusions: Both patients and clinicians thought the HeartCare panel screen for cardiovascular disease risk provided information that was useful in terms of personal or health benefits to the patient and that informed clinical care without causing patients to be confused or overwhelmed. Further research is needed to assess perceptions of genome-wide screening among the US cardiology clinic population.

Background Refractory obsessive-compulsive disorder (OCD) among adults is the first psychiatric indication of deep brain stimulation (DBS) to receive an FDA Humanitarian Device Exemption (HDE). Given the HDE approval and encouraging evidence that has since emerged, exploration of DBS for OCD may expand to adolescents in the future. More than 100,000 adolescents in the U.S. suffer from refractory OCD, and there is already a precedent for the transition of DBS in adults to children in the case of dystonia. However, the risk-benefit analysis of pediatric DBS for OCD may be more complex and raise different ethical questions compared to pediatric DBS for dystonia. Objective This study aimed to gain insight into pressing ethical issues related to using DBS in adolescents with OCD. Methods Semi-structured interviews were conducted with clinicians (n = 25) caring for pediatric patients with refractory OCD. Interview transcripts were coded with MAXQDA 2018 software and analyzed using thematic content analysis to identify emergent themes. Results Five central themes were identified in clinician responses, three of which were exacerbated in the pediatric DBS setting. Clinicians expressed concerns related to conditions of decision-making including adolescents' capacity to assent (80%), the lack of evidence about the outcomes and potential unknown effects of using DBS in adolescents with OCD (68%), and the importance of exhausting other treatment options before considering DBS (20%). Conclusions Strategies to address clinician concerns include implementation of validated decision support tools and further research into the outcomes of pediatric DBS for OCD to establish clear guidelines for patient selection.

Blood blister aneurysms are small, thin-walled, rapidly growing side-wall aneurysms that have proved particularly difficult to treat, and evidence-based guidance for treatment strategies is lacking. A systematic review and meta-analysis was performed to aggregate the available data and compare the 3 primary treatment modalities.We performed a comprehensive literature search according to PRISMA guidelines followed by an indirect meta-analysis that compares the safety and efficacy of surgical, flow-diverting stents (FDS), and other endovascular approaches for the treatment of ruptured blood blister aneurysms.A total of 102 studies were included for quantitative synthesis, with sample sizes of 687 treated surgically, 704 treated endovascularly without FDS, and 125 treated via flow diversion. Comparatively, FDS achieved significantly reduced rates of perioperative retreatment compared with both surgical (P = 0.025) and non-FDS endovascular (P0.001). The FDS subgroup also achieved a significantly lower incidence of perioperative rebleed (P 0.001), perioperative hydrocephalus (P = 0.012), postoperative infarction (P = 0.002), postoperative hydrocephalus (P0.001), and postoperative vasospasm (P = 0.002) compared with those patients in the open surgical subgroup. Although no significant differences were found among groups on the basis of functional outcomes, angiographic outcomes detailed by rates of radiographic complete occlusion were highest for surgical (90.7%, 262/289) and FDS (89.1%, 98/110) subgroups versus the non-FDS endovascular subgroup (82.7%, 268/324).Flow diversion seems to be an effective treatment strategy for ruptured blood blister aneurysms, with lower rates of perioperative complications compared with surgical and other endovascular techniques, but studies investigating long-term outcomes after flow diversion warrant further study.

Many medical students hold negative perceptions about the surgical field that deter them from pursuing surgical training. We hypothesize that these perceptions can be sustainably changed with preclinical surgical education.Students were administered a 10-question survey before the educational experience, immediately after completing the experience, and 1-3 years later. Survey questions focused on perceptions about surgery. Changes in responses over time were measured and analyzed.The study was performed in the setting of a voluntary preclinical surgical education experience.Surveys were administered to 217 first-year medical students who all participated in the preclinical surgical education experience from 2017 to 2019. Follow-up surveys were administered to all cohorts simultaneously and anonymously via email.Nine of the ten questions demonstrated statistically significant changes in perceptions from pre-experience to immediately post-experience (p0.048). Though attenuation was seen over time, changes in perception regarding the workload and time investment of surgical training, the role of women in surgery, and the relationships between surgeons and their patients were sustained over time (p0.044).The results indicated that our model of surgical education could effect long-term changes in negative perceptions about the surgical field. Many of these negative perceptions are highly concerning to medical students. As such, success in changing perceptions about length and difficulty of training, gender inclusivity, and patient-centered care in surgery is important in increasing student interest in the surgical field. This becomes relevant in the current climate of a nationwide shortage of surgeons and the need to better attract students to this profession.

bgelaye@hsph.harvard.edu Article Objective: To examine the independent and joint relationships of poor subjective sleep quality and antepartum depression with suicidal ideation among pregnant women. Methods: A cross-sectional study was conducted among 641 pregnant women attending prenatal care clinics in Lima, Peru. Antepartumdepression and suicidal ideationwere assessed using the Patient Health Questionnaire-9 scale. Antepartumsubjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Logistic regression procedures were performed to estimate odds ratios (aOR) and 95% confidence intervals (95% CI) adjusted for confounders. Results: Overall, the prevalence of suicidal ideation in this cohort was 16.8% and poor subjective sleep qualitywas more common among women endorsing suicidal ideation as compared to their counterpartswho did not (47.2% vs. 24.8%, Pb.001). After adjustment for confounders including maternal depression, poor subjective sleep quality (defined using the recommended criteria of PSQI global score of N5 vs. ≤5) was associated with a 1.7-fold increased odds of suicidal ideation (aOR=1.67; 95% CI 1.02–2.71). When assessed as a continuous variable, each 1-unit increase in the global PSQI score resulted in an 18% increase in odds for suicidal ideation, even after adjusting for depression (aOR=1.18; 95% CI 1.08–1.28). Women with both poor subjective sleep quality and depression had a 3.5-fold increased odds of suicidal ideation (aOR=3.48; 95% CI 1.96–6.18) as compared with those who had neither risk factor. Conclusion: Poor subjective sleep quality was associated with increased odds of suicidal ideation. Replication of these findings may promote investments in studies designed to examine the efficacy of sleep-focused interventions to treat pregnant women with sleep disorders and suicidal ideation. This research was supported by an award fromtheNational Institutes of Health (NIH; R01-HD-059835, T37-MD000149 and K01MH100428). The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The authors wish to thank the dedicated staff members of Asociacion Civil Proyectos en Salud (PROESA), Peru and Instituto Especializado Materno Perinatal, Peru, for their expert technical assistance with this research. Revisión por pares

In the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs.To assess the use and safety of outpatient management of acute appendicitis.This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25 US hospitals from May 1, 2016, to February 28, 2020.Participants randomized to antibiotics (intravenous then oral) could be discharged from the emergency department based on clinician judgment and prespecified criteria (hemodynamically stable, afebrile, oral intake tolerated, pain controlled, and follow-up confirmed). Outpatient management and hospitalization were defined as discharge within or after 24 hours, respectively.Outcomes compared among patients receiving outpatient vs inpatient care included serious adverse events (SAEs), appendectomies, health care encounters, satisfaction, missed workdays at 7 days, and EuroQol 5-dimension (EQ-5D) score at 30 days. In addition, appendectomy incidence among outpatients and inpatients, unadjusted and adjusted for illness severity, was compared.Among 776 antibiotic-randomized participants, 42 (5.4%) underwent appendectomy within 24 hours and 8 (1.0%) did not receive their first antibiotic dose within 24 hours, leaving 726 (93.6%) comprising the study population (median age, 36 years; range, 18-86 years; 462 [63.6%] male; 437 [60.2%] White). Of these participants, 335 (46.1%; site range, 0-89.2%) were discharged within 24 hours, and 391 (53.9%) were discharged after 24 hours. Over 7 days, SAEs occurred in 0.9 (95% CI, 0.2-2.6) per 100 outpatients and 1.3 (95% CI, 0.4-2.9) per 100 inpatients; in the appendicolith subgroup, SAEs occurred in 2.3 (95% CI, 0.3-8.2) per 100 outpatients vs 2.8 (95% CI, 0.6-7.9) per 100 inpatients. During this period, appendectomy occurred in 9.9% (95% CI, 6.9%-13.7%) of outpatients and 14.1% (95% CI, 10.8%-18.0%) of inpatients; adjusted analysis demonstrated a similar difference in incidence (-4.0 percentage points; 95% CI, -8.7 to 0.6). At 30 days, appendectomies occurred in 12.6% (95% CI, 9.1%-16.7%) of outpatients and 19.0% (95% CI, 15.1%-23.4%) of inpatients. Outpatients missed fewer workdays (2.6 days; 95% CI, 2.3-2.9 days) than did inpatients (3.8 days; 95% CI, 3.4-4.3 days) and had similar frequency of return health care visits and high satisfaction and EQ-5D scores.These findings support that outpatient antibiotic management is safe for selected adults with acute appendicitis, with no greater risk of complications or appendectomy than hospital care, and should be included in shared decision-making discussions of patient preferences for outcomes associated with nonoperative and operative care.ClinicalTrials.gov Identifier: NCT02800785.

PURPOSE Violence continues to be a significant public health burden, but little is known about the long-term outcomes of these patients. Our goal was to determine the impact of violence-related trauma on long-term functional and psychosocial outcomes. METHODS We identified trauma patients with moderate to severe injuries (Injury Severity Score, ≥9) treated at one of three level 1 trauma centers. These patients were asked to complete a survey over the phone between 6 and 12 months after injury evaluating both functional and psychosocial outcomes (12-item Short Form Survey, Trauma Quality of Life, posttraumatic stress disorder [PTSD] screen, chronic pain, return to work). Patients were classified as having suffered a violent injury if the mechanism of injury was a stab, gunshot, or assault. Self-inflicted wounds were excluded. Adjusted logistic regression models were built to determine the association between a violent mechanism of injury and long-term outcomes. RESULTS A total of 1,050 moderate to severely injured patients were successfully followed, of whom 176 (16.8%) were victims of violence. For the victims of violence, mean age was 34.4 years (SD, 12.5 years), 85% were male, and 57.5% were Black; 30.7% reported newly needing help with at least one activity of daily living after the violence-related event. Fifty-nine (49.2%) of 120 patients who were working before their injury had not yet returned to work; 47.1% screened positive for PTSD, and 52.3% reported chronic pain. On multivariate analysis, a violent mechanism was significantly associated with PTSD (odds ratio, 2.57; 95% confidence interval, 1.59-4.17; p < 0.001) but not associated with chronic pain, return to work, or functional outcomes. CONCLUSION The physical and mental health burden after violence-related trauma is not insignificant. Further work is needed to identify intervention strategies and social support systems that may be beneficial to reduce this burden. LEVEL OF EVIDENCE Prognostic and epidemiological, level III.

Background The coronavirus disease 2019 pandemic restricted movement of individuals and altered provision of health care, abruptly transforming health care-use behaviors. It serves as a natural experiment to explore changes in presentations for surgical diseases including acute appendicitis. The objective was to determine if the pandemic was associated with changes in incidence of acute appendicitis compared to a historical control and to determine if there were associated changes in disease severity. Methods The study is a retrospective, multicenter cohort study of adults (N = 956) presenting with appendicitis in nonpandemic versus pandemic time periods (December 1, 2019–March 10, 2020 versus March 11, 2020–May 16, 2020). Corresponding time periods in 2018 and 2019 composed the historical control. Primary outcome was mean biweekly counts of all appendicitis presentations, then stratified by complicated (n = 209) and uncomplicated (n = 747) disease. Trends in presentations were compared using difference-in-differences methodology. Changes in odds of presenting with complicated disease were assessed via clustered multivariable logistic regression. Results There was a 29% decrease in mean biweekly appendicitis presentations from 5.4 to 3.8 (rate ratio = 0.71 [0.51, 0.98]) after the pandemic declaration, with a significant difference in differences compared with historical control (P = .003). Stratified by severity, the decrease was significant for uncomplicated appendicitis (rate ratio = 0.65 [95% confidence interval 0.47–0.91]) when compared with historical control (P = .03) but not for complicated appendicitis (rate ratio = 0.89 [95% confidence interval 0.52–1.52]); (P = .49). The odds of presenting with complicated disease did not change (adjusted odds ratio 1.36 [95% confidence interval 0.83–2.25]). Conclusion The pandemic was associated with decreased incidence of uncomplicated appendicitis without an accompanying increase in complicated disease. Changes in individual health care–use behaviors may underlie these differences, suggesting that some cases of uncomplicated appendicitis may resolve without progression to complicated disease.

Pannexin 1 (PANX1) is a glycoprotein that forms large pore channels capable of passing ions and metabolites such as ATP for cellular communication. PANX1 has been implicated in many diseases including breast cancer and melanoma, where inhibition or deletion of PANX1 reduced the tumorigenic and metastatic properties of the cancer cells. We interrogated the effect of single amino acid changes in various PANX1 domains using naturally occurring variants reported in cancer patient tumors. We found that a previously reported variant (Q5H) is present in cancer cells, but was not different from the wild type (Q5) in glycosylation, trafficking, or channel function and did not affect cellular properties. We discovered that the Q5H variant is in fact the highly conserved ancestral allele of PANX1 with 89% of humans carrying at least one Q5H allele. Another mutated form Y150F, found in a melanoma patient tumor, prevented phosphorylation at Y150 as well as complex N-glycosylation while increasing intracellular localization. Sarcoma (SRC) is the predicted kinase to phosphorylate the Y150 residue, and its phosphorylation is not likely to be constitutive, but rather dynamically regulated. The Y150 phosphorylation site is the first one reported to play a role in regulating posttranslational modifications and trafficking of PANX1, with potential consequences on its large-pore channel structure and function in melanoma cells.

The influence of patient-level factors on palliative and hospice care is unclear. We conducted a retrospective review of 2321 patients aged ≥18 that died within 6 months of admission to our institution between 2012 and 2017. Patients were included for analysis if their chart was complete, their length of stay was ≥48 hours, and if based on their diagnoses, they would have benefited from palliative care consultation (PCC). Bayesian regression with a weakly informative prior was used to find the odds ratio (OR) and 99% credible interval (CrI) of receiving PCC based on race/ethnicity, education, language, insurance status, and income. 730 patients fit our inclusion criteria and 30% (n = 211) received PCC. The OR of receiving PCC was 1.26 (99% CrI, 0.73-2.12) for Blacks, 0.81 (99% CrI, 0.31-1.86) for Hispanics, and 0.69 (99% CrI, 0.19-2.46) for other minorities. Less than high school education was associated with greater odds of PCC (OR 2.28, 99% CrI, 1.09-4.93) compared to no schooling. Compared to English speakers, non-English speakers had higher odds of receiving PCC when cared for by medical services (OR 3.01 [99% CrI, 1.44-5.32]) but lower odds of PCC when cared for by surgical services (0.22 [99% CrI

Background: Following left atrial appendage (LAA) electrical isolation, the decision on whether to continue oral anticoagulation after successful atrial fibrillation ablation is based on the study of its mechanical function on transesophageal echocardiography (TEE). In this cohort, LAA contraction is absent and the incorrect interpretation of emptying flow velocities can lead to unwanted clinical sequelae. Methods: One hundred and sixty consecutive TEE exams performed to evaluate the LAA mechanical function following its electrical isolation were reviewed by an experienced operator blinded to the original diagnosis of LAA dysfunction. The rate of diagnostic discrepancy in the assessment LAA dysfunction and its clinical implications were evaluated. Results: Diagnostic discrepancy with misclassification of the LAA mechanical function occurred 36% (58/160) of TEE exams. In most cases (57/58), such discrepancy was observed in the setting of an incorrect original diagnosis of a normal LAA mechanical function despite absent/reduced or inconsistent LAA contraction. This main source of this wrong diagnosis was the wrong interpretation of passive LAA flows (34/57; 60%), followed by failure to identify dissociated firing (15/57; 26%). In rare cases (8/57; 14%), velocities of surrounding structures were interpreted as LAA flow due to misplacement of the pulsed-wave Doppler sample volume. Following LAA isolation, the proportion of patients who experienced a cerebrovascular event while off oral anticoagulation due to the misclassification of their LAA mechanical function was 70% (7/10 [95% CI, 40%–89%]). Conclusions: Underdiagnosis of LAA mechanical dysfunction is common in TEEs performed following LAA electrical isolation, and it is associated with an increased risk of cerebrovascular events owing to oral anticoagulation discontinuation despite absent/reduced LAA contraction. Careful review of the TEE exam by an operator with specific expertise in LAA imaging and familiar with the functional implications of LAA isolation is necessary before interrupting oral anticoagulation in this cohort.

Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma.We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish).Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAFWe unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

ObjectivePsychiatric polygenic risk scores (PRS) have the potential to transform aspects of psychiatric care and prevention, but there are concerns about their implementation. We sought to assess child and adolescent psychiatrists’ (CAP) experiences, perspectives, and potential uses of psychiatric PRS.MethodsA survey of 960 US-based practicing CAP.ResultsMost respondents (54%) believed psychiatric PRS are currently at least slightly useful and 87% believed they will be so in five years. Yet, 77% rated their knowledge of PRS as poor or very poor. Ten percent have had a patient/family bring PRS to them, and 25% would request PRS if a patient/caregiver asked. Respondents endorsed different actions in response to a hypothetical child with a top 5th percentile psychiatric PRS but no diagnosis: 48% would increase prospective monitoring of symptoms, 42% would evaluate for current symptoms, and 4% would prescribe medications. Most respondents were concerned that high PRS results could lead to overtreatment and negatively impact patients’ emotional well-being.ConclusionFindings indicate emerging use of psychiatric PRS within child and adolescent psychiatry in the US. Thus, it is critical to examine the ethical and clinical challenges that PRS may generate and begin efforts to promote their informed and responsible use.

The volume of calls for governments and public health officials to take concerted action on climate change has become almost deafening. Public health researchers and practitioners need to look beyond what we know about the health impacts of climate change, to what we are doing as our part in contributing to holding global temperature rise to under 1.5°C. This commentary reflects on the common threads across the articles of a special section in this issue of the Canadian Journal of Public Health, "Moving on IPCC 1.5°C", which sought examples of bold research and action advancing climate change mitigation and adaptation. Among the articles, there are signs that the public health community is gaining momentum in confronting the climate crisis. Three critical lessons emerged: the need for institutional change from the top of public health, the essential power of community in intersectoral action on climate change preparedness, and the importance of centring Indigenous wisdom to decolonize colonial legacy systems. We encourage readers to move public health research and practice from an instrumental relationship with nature to one of reverence and sacred reciprocity.RéSUMé: Le volume des appels aux gouvernements et aux autorités de santé publique à agir de concert face aux changements climatiques devient assourdissant. Au-delà de ce que nous savons des effets des changements climatiques sur la santé, les chercheurs et les praticiens en santé publique doivent examiner ce que nous faisons pour maintenir la hausse de la température mondiale en deçà de 1,5 °C. Dans ce commentaire, nous réfléchissons à la trame commune des articles d’une rubrique spéciale dans ce numéro de la Revue canadienne de santé publique, « Réaction au cri d’alarme du GIEC », qui sollicitait des exemples d’études et de mesures audacieuses pour faire progresser l’atténuation des changements climatiques et l’adaptation à ces changements. Dans les articles de la rubrique, il y a des signes que la communauté de la santé publique se mobilise pour faire face à la crise climatique. Trois leçons essentielles s’en dégagent : la nécessité d’un changement institutionnel au sommet de la santé publique, le pouvoir essentiel de la communauté dans l’action intersectorielle de préparation aux changements climatiques, et l’importance de miser sur la sagesse autochtone pour décoloniser les systèmes hérités du colonialisme. Nous encourageons nos lecteurs à faire passer la recherche et la pratique en santé publique d’une relation instrumentale avec la nature à une relation de révérence et de réciprocité sacrée.

Previous geographically limited studies have shown differential impact of COVID-19 on Hispanic individuals. Data were obtained from the Centers for Disease Control and Prevention. We performed multivariate Poisson regression assessing risk of hospitalization and death in Hispanic White (HW), Hispanic Black (HB), and Hispanic Multiracial/Other (HM) groups compared to non-Hispanic Whites (NHW). The relative risk of hospitalization was 1.35, 1.58, and 1.50 (p

BACKGROUND: Chronic hypothalamic-pituitary-adrenal (HPA) axis activity role in the pathogenesis of preterm birth (PTB) remains unclear due to inconsistent measures with limited ability to monitor long-term cortisol concentrations. We explored this relationship using the novel method of assessing cortisol in hair, which is a valid and reliable measure of chronic HPA axis activity. METHODS: 137 participants (40 PTB cases and 97 controls from a birth cohort of pregnant women in Peru) were interviewed and invited to provide a 9-cm hair sample from the posterior vertex position of the scalp (mean = 13 weeks gestation). Hair cortisol concentration (HCC) was determined using luminescence immunoassay and values were natural-log transformed. PTB cases were defined as women who delivered before 37 gestational weeks. Case-control differences were assessed using multivariable linear and logistic regressions. RESULTS: Overall, combined pre-conception and first-trimester HCC was 13% lower among cases as compared with controls (p-value = 0.01). Compared with controls, maternal HCC among PTB cases were 14% (p = 0.11), 10% (p = 0.22) and 14% (p = 0.08) lower for 3–6 months pre-conception, 0–3 months pre-conception, and first trimester, respectively. After adjusting for putative confounders, a 1-unit increase in HCC was associated with 55% reduced odds of PTB (aOR = 0.45; 95% CI: 0.17–1.17). For a 1-unit increase in HCC in the scalp-intermediate and scalp-distal segments (representing HCC concentrations in 0–3 months pre-conception and first trimester), the corresponding odds for PTB were 0.53 (95% CI: 0.19–1.48) and 0.39 (95% CI: 0.13–1.13), respectively. CONCLUSIONS: Women who deliver preterm, as compared with those who deliver at term, have lower preconception and first trimester HCC. Our findings suggest that HPA axis activation, integral to the adaptive stress-response system, may be chronically dysregulated in women at increased risk of PTB.

Objective Assess the prevalence of anxiety, depression, and posttraumatic stress disorder (PTSD) after injury and their association with long-term functional outcomes. Background Mental health disorders (MHD) after injury have been associated with worse long-term outcomes. However, prior studies almost exclusively focused on PTSD. Methods Trauma patients with an injury severity score ≥9 treated at 3 Level-I trauma centers were contacted 6-12 months post-injury to screen for anxiety (generalized anxiety disorder-7), depression (patient health questionnaire-8), PTSD (8Q-PCL-5), pain, and functional outcomes (trauma quality of life instrument, and short-form health survey)). Associations between mental and physical outcomes were established using adjusted multivariable logistic regression models. Results Of the 531 patients followed, 108 (20%) screened positive for any MHD: of those who screened positive for PTSD (7.9%, N = 42), all had co-morbid depression and/or anxiety. In contrast, 66 patients (12.4%) screened negative for PTSD but positive for depression and/or anxiety. Compared to patients with no MHD, patients who screened positive for PTSD were more likely to have chronic pain {odds ratio (OR): 8.79 [95% confidence interval (CI): 3.21, 24.08]}, functional limitations [OR: 7.99 (95% CI: 3.50, 18.25)] and reduced physical health [β: -9.3 (95% CI: -13.2, -5.3)]. Similarly, patients who screened positive for depression/anxiety (without PTSD) were more likely to have chronic pain [OR: 5.06 (95% CI: 2.49, 10.46)], functional limitations [OR: 2.20 (95% CI: 1.12, 4.32)] and reduced physical health [β: -5.1 (95% CI: -8.2, -2.0)] compared to those with no MHD. Conclusions The mental health burden after injury is significant and not limited to PTSD. Distinguishing among MHD and identifying symptom-clusters that overlap among these diagnoses, may help stratify risk of poor outcomes, and provide opportunities for more focused screening and treatment interventions.

Mounting evidence supports several naturalistic developmental behavioral interventions (NDBI) for toddlers and preschoolers within inclusive childcare centers and preschools. However, these interventions pose many barriers to community implementation. As part of a larger project to create an adapted NDBI for early educators in childcare centers, we surveyed 101 early interventionists who had worked with a toddler with autism within the last 12 months. Early interventionists rated 22-of-31 NDBI strategies to be significantly more effective for All Toddlers versus Toddlers with Autism. However, when comparing the top 10 rated strategies between groups, there was a large degree of overlap. Moreover, many of these highly rated NDBI strategies are consistent with best practice accreditation and early education standards within the United States.

Background Low- and middle-income countries bear a disproportionate burden of preterm birth (PTB) and low infant birth weight (LBW) complications where affective and anxiety disorders are more common in the antepartum period than in industrialized countries. Objective To evaluate the extent to which early pregnancy antepartum depression, generalized anxiety disorder, and posttraumatic stress disorder (PTSD) are associated with infant birth weight and gestational age at delivery among a cohort of pregnant women in Peru. Methods Our prospective cohort study consisted of 4408 pregnant women. Antepartum depression, generalized anxiety, and PTSD were assessed in early pregnancy using the Patient Health Questionnaire-9, Generalized Anxiety Disorder Scale-7 and PTSD Checklist – Civilian Version, respectively. Pregnancy outcome data were obtained from medical records. Multivariable linear and logistic regression procedures were used to estimate adjusted measures of association (β coefficients and odds ratios) and 95% confidence intervals (CI). Results After adjusting for confounders, women with antepartum generalized anxiety (32.6% prevalence) had higher odds of LBW (adjusted odds ratio (OR)=1.47; 95%CI: 1.10–1.95) and were more likely to deliver small for gestational age (OR = 1.39; 95%CI: 1.01–1.92) infants compared to those without anxiety. Compared to those without PTSD, women with PTSD (34.5%) had higher odds of delivering preterm (OR = 1.28; 95%CI: 1.00–1.65) yet PTSD was not associated with LBW nor gestational age at delivery. Women with antepartum depression (26.2%) were at no increased risk of delivering a preterm, low-birth-weight or small-for-gestational-age infant. Limitations Our ability to make casual inferences from this observational study is limited; however, these findings are consistent with prior studies. Conclusion Generalized anxiety disorder during pregnancy appeared to increase odds of delivering a low-birth-weight or small-for-gestational-age infant, while PTSD was associated with increased odds of delivering preterm. Our findings, and those of others, suggest antenatal care should be tailored to screen for and provide additional mental health services to patients.

Study purpose The purpose of this study is to evaluate the relevancy and fit of a proposed group-based, peer-mentored intervention, based on the principles of Self-Determination Theory (SDT), to facilitate the development of health self-management skills needed to transition from pediatric to adult-based healthcare. Design and methods Individual in-depth interviews with 28 transition-age youth (TAY) ages 17–22 and 24 caregivers (parents) from Gastroenterology, Renal and Rheumatology clinical services assessed interests in and preferred content, timing of and format for an intervention to help youth build self-management skills. Descriptive statistics were used for short answer questions and rating scales. Thematic analysis was used to analyze transcripts. Results >90% of TAY and all caregivers thought the proposed group-based transition skills-building intervention was a good idea. TAY expressed wanting someone with lived experience to lead it and a desire to meet other youth with chronic conditions. All caregivers would want their TAY to participate if given the opportunity. Both TAY and caregivers voiced the importance of mental health topics as many TAY experienced anxiety or depression over managing their illness. Nearly 50% of TAY and caregivers thought parents should attend some or all group sessions, though TAY and caregivers within the same family did not always agree. Conclusions Findings establish the relevancy and fit of a peer-mentored intervention focused on skill development to successfully transition to adult healthcare. Practice implications The group intervention designed using a SDT framework may be particularly relevant as autonomy, competence, and relatedness undergo major developmental changes during adolescence.

Purpose Preterm birth (PTB) is a major cause of neonatal mortality. The vaginal microbiome is associated with PTB, but results vary across racial/ethnic populations. Some evidence suggests gestational age affects this association. We investigated these associations in a novel population, conducting a post hoc analysis assessing if associations differed between women swabbed at different gestational ages. Methods We compared vaginal microbiomes from women with PTB (n = 25) to a random sample of women with term births (n = 100) among participants in the Pregnancy Outcomes, Maternal and Infant Study, conducted in Lima, Peru. Using DADA2, we identified taxa from 16S DNA sequencing and used Dirichlet multinomial mixture models to group into community state types (CSTs). Results If gestational age at sampling was not considered, no CST (diverse, Lactobacillus-dominated or Lactobacillus iners–dominated), was associated with PTB. Among women sampled before 12 weeks' gestation, women with Lactobacillus-dominated CSTs were less likely to have a PTB than those with a diverse CST. Among those swabbed between 12 and 16 weeks' gestation, the reverse was true. Conclusions Our study supports previous literature suggesting that what constitutes a healthy vaginal microbiome varies by race/ethnicity. Longitudinal studies are necessary to disentangle effects of vaginal microbiome differences over gestation. Instituto Eunice Kennedy Shriver de Salud Infantil y Desarrollo Humano, Estados Unidos (R01-HD-059835).

The approximately 1011 viruses and microbial cells per gram of fecal matter (dry weight) in the large intestine are important to human health. The responses of three common gut bacteria species, and one opportunistic pathogen, to 117 commonly consumed foods, chemical additives, and plant extracts were tested. Many compounds, including Stevia rebaudiana and bee propolis extracts, exhibited species-specific growth inhibition by prophage induction. Overall, these results show that various foods may change the abundances of gut bacteria by modulating temperate phage and suggests a novel path for landscaping the human gut microbiome.

ICD codes are used to identify patients with appendicitis and to classify disease severity for reimbursement and research purposes. We sought to compare the accuracy of ICD-9 vs ICD-10 codes in classifying appendicitis as uncomplicated vs complicated (defined as perforated, necrotic, or abscess) compared with the clinical gold standard: surgeon characterization of the appendix in the operative report.This is a retrospective review of operative reports and discharge ICD-9/10 codes for patients 18 years or older who underwent noninterval, nonincidental appendectomy from January 2012 to December 2019 at a tertiary referral center. Sensitivity, specificity, and positive predictive value were calculated for ICD-9/10 codes to classify appendicitis as complicated when compared with surgeon description. Chi-square testing was used to compare agreement between ICD-9/10 codes and surgeon description.A total of 1,585 patients underwent appendectomy. ICD-9 codes had higher sensitivity than ICD-10 codes for complicated appendicitis (sensitivity 0.84 and 0.54, respectively) and a similar positive predictive value (0.77 and 0.76, respectively). Overall, 91% of ICD-9 codes agreed with surgical description of disease, but 84.4% of ICD-10 codes agreed with surgical description (p0.01). Among cases classified as complicated by the surgeon, 84% (79/94) had an accurate ICD-9 code for complicated disease, but only 53.8% (57/106) of cases had an accurate ICD-10 code (p0.01).Compared with ICD-9 codes, ICD-10 codes were less accurate in characterizing severity of appendicitis. The ICD-10 coding schema does not provide an accurate representation of disease severity. Until this system is improved, significant caution is needed for people who rely on these data for billing, quality improvement, and research purposes.

The COVID-19 pandemic has accelerated neurological, mental health disorders, and neurocognitive issues. However, there is a lack of inexpensive and efficient brain evaluation and screening systems. As a result, a considerable fraction of patients with neurocognitive or psychobehavioral predicaments either do not get timely diagnosed or fail to receive personalized treatment plans. This is especially true in the elderly populations, wherein only 16% of seniors say they receive regular cognitive evaluations. Therefore, there is a great need for development of an optimized clinical brain screening workflow methodology like what is already in existence for prostate and breast exams. Such a methodology should be designed to facilitate objective early detection and cost-effective treatment of such disorders. In this paper we have reviewed the existing clinical protocols, recent technological advances and suggested reliable clinical workflows for brain screening. Such protocols range from questionnaires and smartphone apps to multi-modality brain mapping and advanced imaging where applicable. To that end, the Society for Brain Mapping and Therapeutics (SBMT) proposes the Brain, Spine and Mental Health Screening (NEUROSCREEN) as a multi-faceted approach. Beside other assessment tools, NEUROSCREEN employs smartphone guided cognitive assessments and quantitative electroencephalography (qEEG) as well as potential genetic testing for cognitive decline risk as inexpensive and effective screening tools to facilitate objective diagnosis, monitor disease progression, and guide personalized treatment interventions. Operationalizing NEUROSCREEN is expected to result in reduced healthcare costs and improving quality of life at national and later, global scales.

The COVID-19 pandemic has led to decreased access to care and social isolation, which have the potential for negative psychophysical effects. We examine the impact of the pandemic on physical and mental health outcomes after trauma.Patients in a prospective study were included. The cohort injured during the pandemic was compared to a cohort injured before the pandemic. We performed regression analyses to evaluate the association between the COVID-19 pandemic and physical and mental health outcomes.1,398 patients were included. In adjusted analysis, patients injured during the pandemic scored significantly worse on the SF-12 physical composite score (OR 2.21; [95% CI 0.69-3.72]; P = 0.004) and were more likely to screen positive for depression (OR 1.46; [1.02-2.09]; P = 0.03) and anxiety (OR 1.56; [1.08-2.26]; P = 0.02). There was no significant difference in functional outcomes.Patients injured during the COVID-19 pandemic had worse mental health outcomes but not physical health outcomes.

SNAKE ENVENOMATION REPRESENTS AN IMPORTANT HEALTH PROBLEM IN much of the world. In 2009, it was recognized by the World Health Organization (WHO) as a neglected tropical disease, and in 2017, it was elevated into Category A of the Neglected Tropical Diseases list, further expanding access to funding for research and antivenoms.(1) However, snake envenomation occurs in both tropical and temperate climates and on all continents except Antarctica. Worldwide, the estimated number of annual deaths due to snake envenomation (80,000 to 130,000) is similar to the estimate for drug-resistant tuberculosis and for multiple myeloma.(2,3) In countries with adequate resources, deaths are infrequent (e.g.

Background Emergency general surgery (EGS) represents a diverse set of operations performed on acutely ill patients. Those undergoing EGS are at higher likelihood of complications, readmission, and death, but the effect of primary language on EGS outcomes has not been evaluated. We aimed to evaluate the association of non-English primary language on outcomes after EGS operations. Methods The New Jersey Statewide Inpatient Database from 2009 to 2014 was used to evaluate cases representing 80% of the national burden of EGS. Cases were restricted to ages ≥18 y, emergency department admissions, noted to be emergent or urgent, and performed between 0 and 2 d after admission. We evaluated Spanish speakers and non-English, non-Spanish (NENS) speakers compared with English. Outcomes included in-hospital mortality, 7-d readmission, and hospital length of stay (LOS). Logistic and negative binomial regression was used, and generalized linear mixed models were used to account for hierarchy in the data. Results There were 105,171 patients included. English speakers were majority white and with private insurance; Spanish speakers were younger and with fewer comorbidities. Where differences between Spanish and NENS speakers existed, NENS were more like the English-speaking group. Adjusted results indicate that Spanish speakers had reduced LOS after appendectomy (IRR: 0.92 [0.89-0.95]) and lysis of adhesion [0.93 (0.88-0.97)]. Spanish speakers had an increased LOS after higher risk operations (IRR: 1.14 [1.10-1.20]). NENS speakers had a reduced LOS after adhesiolysis (IRR: 0.94 [0.89-0.99]). There was no difference in mortality or short-term readmission Conclusions These data from a large database suggest that the effect of primary language on LOS after EGS depends on the type of operation. Future studies should focus on long-term outcomes and determining if the lack of association we observed is generalizable to other regions of the United States.

International Classification of Disease, ninth/tenth revision codes are used to identify patients with appendicitis and classify severity of disease for research and hospital reimbursement. We sought to determine accuracy of International Classification of Disease, ninth/tenth revision codes in classifying appendicitis as uncomplicated versus complicated (defined as perforated, necrotic, or abscess) compared with the clinical gold standard: surgeon characterization of the appendix in the operative report.Retrospective review of operative reports and discharge International Classification of Disease, ninth/tenth revision codes for patients ≥18 years old who underwent noninterval, nonincidental appendectomy between January 2012 and December 2019 at a tertiary referral center. Sensitivity, specificity, and positive predictive value were calculated for International Classification of Disease, ninth/tenth revision codes to classify appendicitis accurately as complicated compared with surgeon description. ICD-9/10 codes and surgeon description were categorized into complicated/uncomplicated based on the American Association for the Surgery of Trauma grading system.In the study, 1,495 patients with acute appendicitis underwent appendectomy. Per surgeon description, 200 (13%) were complicated and 1,295 (87%) uncomplicated. Compared with surgeon description, discharge International Classification of Disease, ninth/tenth revision codes did not accurately identify complicated appendicitis: sensitivity = 0.68, positive predictive value = 0.77. As a sensitivity analysis, the cohort was stratified by public versus private payers, and the results did not change.International Classification of Disease, ninth/tenth revision codes do not accurately identify surgeon-described complicated appendicitis. Nearly one-third of the cases of complicated appendicitis were coded as uncomplicated. Such misclassification negatively impacts reimbursement for complicated appendicitis care and could lead to misleading results in research and quality improvement activities that rely on these codes.

Here, salivary microbiota and major histocompatibility complex (MHC) human leukocyte antigen (HLA) alleles were compared between 47 (12.6%) young adults with recent suicidal ideation (SI) and 325 (87.4%) controls without recent SI. Several bacterial taxa were correlated with SI after controlling for sleep issues, diet, and genetics. Four MHC class II alleles were protective for SI including DRB1*04, which was absent in every subject with SI while present in 21.7% of controls. Increased incidence of SI was observed with four other MHC class II alleles and two MHC class I alleles. Associations between these HLA alleles and salivary bacteria were also identified. Furthermore, rs10437629, previously associated with attempted suicide, was correlated here with SI and the absence of Alloprevotella rava, a producer of an organic acid known to promote brain energy homeostasis. Hence, microbial-genetic associations may be important players in the diathesis-stress model for suicidal behaviors.

T cell-based therapies like genetically modified immune cells expressing chimeric antigen receptors have shown robust anti-cancer activity in vivo, especially in patients with blood cancers. However, extending this approach to an "off-the-shelf" setting can be challenging, as allogeneic T cells carry a significant risk of graft-versus-host disease (GVHD). By contrast, allogeneic natural killer (NK) cells recognize malignant cells without the need for prior antigen exposure and have been used safely in multiple cancer settings without the risk of GVHD. However, similar to T cells, NK cell function is negatively impacted by tumor-induced transforming growth factor beta (TGF-β) secretion, which is a ubiquitous and potent immunosuppressive mechanism employed by most malignancies. Allogeneic NK cells for adoptive immunotherapy can be sourced from peripheral blood (PB) or cord blood (CB), and the authors' group and others have previously shown that ex vivo expansion and gene engineering can overcome CB-derived NK cells' functional immaturity and poor cytolytic activity, including in the presence of exogenous TGF-β. However, a direct comparison of the effects of TGF-β-mediated immune suppression on ex vivo-expanded CB- versus PB-derived NK cell therapy products has not previously been performed. Here the authors show that PB- and CB-derived NK cells have distinctive gene signatures that can be overcome by ex vivo expansion. Additionally, exposure to exogenous TGF-β results in an upregulation of inhibitory receptors on NK cells, a novel immunosuppressive mechanism not previously described. Finally, the authors provide functional and genetic evidence that both PB- and CB-derived NK cells are equivalently susceptible to TGF-β-mediated immune suppression. The authors believe these results provide important mechanistic insights to consider when using ex vivo-expanded, TGF-β-resistant PB- or CB-derived NK cells as novel immunotherapy agents for cancer.

Despite the ubiquity of rib fractures in patients with blunt chest trauma, long-term outcomes for patients with this injury pattern are not well described.The Functional Outcomes and Recovery after Trauma Emergencies (FORTE) project has established a multicenter prospective registry with 6- to 12-month follow-up for trauma patients treated at participating centers. We combined the FORTE registry with a detailed retrospective chart review investigating admission variables and injury characteristics. All trauma survivors with complete FORTE data and isolated chest trauma (Abbreviated Injury Scale score of ≤1 in all other regions) with rib fractures were included. Outcomes included chronic pain, limitation in activities of daily living, physical limitations, exercise limitations, return to work, and both inpatient and discharge pain control modalities. Multivariable logistic regression models were built for each outcome using clinically relevant demographic and injury characteristic univariate predictors.We identified 279 patients with isolated rib fractures. The median age of the cohort was 68 years (interquartile range, 56-78 years), 59% were male, and 84% were White. Functional and quality of life limitations were common among survivors of isolated rib fractures even 6 to 12 months after injury. Forty-three percent of patients without a preexisting pain disorder reported new daily pain, and new chronic pain was associated with low resilience. Limitations in physical functioning and exercise capacity were reported in 56% and 51% of patients, respectively. Of those working preinjury, 28% had not returned to work. New limitations in activities of daily living were reported in 29% of patients older than 65 years. Older age, higher number of rib fractures, and intensive care unit admission were independently associated with higher odds of receiving regional anesthesia. Receiving a regional nerve block did not have a statistically significant association with any patient-reported outcome measures.Isolated rib fractures are a nontrivial trauma burden associated with functional impairment and chronic pain even 6 to 12 months after injury.Prognostic/epidemiologic, level III.

Objective To evaluate the long-term ipsi- and contralateral hearing of patients with a unilateral enlarged vestibular aqueduct (EVA). Study design Multicenter retrospective cohort study. Setting Three tertiary otology and audiology referral centers. Patients and diagnostic interventions A total of 34 children with a unilateral enlarged vestibular aqueduct as identified on CT and/or MR imaging were evaluated with pure tone and speech perception audiometry. Mean outcome measures Radiologic measurements of the vestibular aqueduct, ipsi- and contralateral hearing loss, ipsi- and contralateral hearing loss progression over time and DNA test results. Results All patients in this cohort with unilateral EVA presented with hearing loss. Hearing loss was progressive in 38% of the ipsilateral ears. In 29% of the children, hearing loss was also found in the contralateral ear without EVA. In 90%, the contralateral hearing was stable, with a mean follow up of 4.2 years. We found a significant correlation between the severity of the hearing loss and the size of the EVA. A genetic diagnosis associated with EVA and/or SNHL was found in only 7%. Conclusion About a third of the children with unilateral EVA are at risk of developing hearing loss in the contralateral ear. This indicates that at least in some patients with a unilateral EVA, a bilateral pathogenic process underlies the hearing loss, in contrary to what the imaging results suggest. These findings are important for counseling of EVA patients and their parents and have implications for follow up.

Numerous tools for addressing gender inequality in governmental policies, programs, and research have emerged across the globe. Unfortunately, such tools have largely failed to account for the impacts of colonialism on Indigenous Peoples’ lives and lands. In Canada, Indigenous organizations have advanced gender-based analysis frameworks that are culturally-grounded and situate the understanding of gender identities, roles, and responsibilities within and across diverse Indigenous contexts. However, there is limited guidance on how to integrate Indigenous gender-based frameworks in the context of research. The authors of this paper are participants of a multi-site research program investigating intersectoral spaces of Indigenous-led renewable energy development within Canada. Through introspective methods, we reflected on the implementation of gender considerations into our research team’s governance and research activities. We found three critical lessons: (1) embracing Two-Eyed Seeing or Etuaptmumk while making space for Indigenous leadership, (2) trusting the expertise that stems from the lived experiences and relationships of researchers and team members, and (3) shifting the emphasis from ‘gender-based analysis’ to ‘gender-based relationality’ in the implementation of gender-related research considerations. Our research findings provide a novel empirical example of the day-to-day principles and practices that may arise when implementing Indigenous gender-based analysis frameworks in the context of research.

The present analysis uses the data of confirmed incidence of dengue cases in the metropolitan region of Panama from 1999 to 2017 and climatic variables (air temperature, precipitation, and relative humidity) during the same period to determine if there exists a correlation between these variables. In addition, we compare the predictive performance of two regression models (SARIMA, SARIMAX) and a recurrent neural network model (RNN-LSTM) on the dengue incidence series. For this data from 1999–2014 was used for training and the three subsequent years of incidence 2015–2017 were used for prediction. The results show a correlation coefficient between the climatic variables and the incidence of dengue were low but statistical significant. The RMSE and MAPE obtained for the SARIMAX and RNN-LSTM models were 25.76, 108.44 and 26.16, 59.68, which suggest that any of these models can be used to predict new outbreaks. Although, it can be said that there is a limited role of climatic variables in the outputs the models. The value of this work is that it helps understand the behaviour of cases in a tropical setting as is the Metropolitan Region of Panama City, and provides the basis needed for a much needed early alert system for the region.

BACKGROUND Firearm injury remains a major cause of morbidity and mortality in the United States. Due to prior lack of comprehensive data sources, there is a paucity of literature on nonfatal firearm injury. Associations have previously been shown between state-level firearm laws and firearm fatalities, but few studies have examined the effects of these laws on nonfatal firearm hospitalization rates. Our objective was to examine the relationship between state firearm laws and firearm injury-related hospitalization rates across all 50 states over a 17-year period. METHODS In this panel study design, we used fixed effects multivariate regression models to analyze the relationship between twelve laws and firearm state-level injury-related hospitalization rates from 2000-2016 utilizing the RAND Corporation Inpatient Hospitalizations for Firearm Injury Database. We utilized difference-in-differences to determine the impact of law passage in a given state compared to those states without the law, controlling for state-level covariates. The main outcome measure was the change in annual firearm injury-related inpatient hospitalization rates after passage or repeal of a state-level firearm law. RESULTS Examining each law individually, passage of violent misdemeanor, permitting, firearm removal from domestic violence offenders, and ten-round limit laws were associated with significant firearm injury-related hospitalization rate reductions. Examining multiple laws in the same model, passage of violent misdemeanor laws was associated with a 19.9% (CI 11.6, 27.4) reduction and removal of firearms from domestic violence offenders was associated with a 17.0% (CI 9.9, 23.6) reduction in hospitalization rates. CONCLUSIONS State laws related to preventing violent offenders from possessing firearms are associated with firearm injury-related hospitalization rate reductions. Given significant physical, mental, and social burdens of nonfatal firearm injury, determining the efficacy of firearm-related policy is critical to violence and injury prevention efforts.Study Type: EpidemiologicLevel of Evidence: III.

Health care practices are influenced by variety of factors. These factors that include social determinants, race and ethnicity, and gender not only affect access to health care but can also affect quality of care and patient outcomes. These are a source of health care disparities. This article acknowledges that these disparities exist in getting optimal care in structural heart disease, reviews the literature and proposes steps that can help reduce these disparities on personal and committee levels.

Background To assess if simulation-based training (SBT) of B-Lynch suture and uterine balloon tamponade (UBT) for the management of postpartum hemorrhage (PPH) impacted provider attitudes, practice patterns, and patient management in Guatemala, using a mixed-methods approach. Methods We conducted an in-country SBT course on the management of PPH in a governmental teaching hospital in Guatemala City, Guatemala. Participants were OB/GYN providers (n = 39) who had or had not received SBT before. Surveys and qualitative interviews evaluated provider knowledge and experiences with B-Lynch and UBT to treat PPH. Results Multiple-choice surveys indicated that providers who received SBT were more comfortable performing and teaching B-Lynch compared to those who did not (p = 0.003 and 0.005). Qualitative interviews revealed increased provider comfort with B-Lynch compared to UBT and identified multiple barriers to uterine balloon tamponade implementation. Conclusions Simulation-based training had a stronger impact on provider comfort with B-Lynch compared to uterine balloon tamponade. Qualitative interviews provided insight into the challenges that hinder uptake of uterine balloon tamponade, namely resource limitations and decision-making hierarchies. Capturing data through a mixed-methods approach allowed for more comprehensive program evaluation.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn(−/−) mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn(−/−) brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN – a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn(−/−) phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine and disease pathology in Grn(−/−) CNS, including microgliosis, lipofuscinosis and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Determine the proportion and characteristics of traumatic injury survivors who perceive a negative impact of the COVID-19 pandemic on their recovery and to define post-injury outcomes for this cohort.The COVID-19 pandemic has precipitated physical, psychological, and social stressors that may create a uniquely difficult recovery and reintegration environment for injured patients.Adult (≥18 years) survivors of moderate-to-severe injury completed a survey 6 to 14 months post-injury during the COVID-19 pandemic. This survey queried individuals about the perceived impact of the COVID-19 pandemic on injury recovery and assessed post-injury functional and mental health outcomes. Regression models were built to identify factors associated with a perceived negative impact of the pandemic on injury recovery, and to define the relationship between these perceptions and long-term outcomes.Of 597 eligible trauma survivors who were contacted, 403 (67.5%) completed the survey. Twenty-nine percent reported that the COVID-19 pandemic negatively impacted their recovery and 24% reported difficulty accessing needed healthcare. Younger age, lower perceived-socioeconomic status, extremity injury, and prior psychiatric illness were independently associated with negative perceived impact of the COVID-19 pandemic on injury recovery. In adjusted analyses, patients who reported a negative impact of the pandemic on their recovery were more likely to have new functional limitations, daily pain, lower physical and mental component scores of the Short-Form-12 and to screen positive for PTSD and depression.The COVID-19 pandemic is negatively impacting the recovery of trauma survivors. It is essential that we recognize the impact of the pandemic on injured patients while focusing on directed efforts to improve the long-term outcomes of this already at-risk population.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. Objective: The objective of this study was to evaluate the association between (1) different types of ACEs and migraine, and (2) the number of ACEs and migraine among adolescent mothers in Lima, Peru. Methods: Our cross-sectional study included 787 adolescent mothers (14- to 18-years of age) in Peru. In-person interviews were conducted postpartum, in hospital, within 2-days of delivery. Nine types of ACEs were assessed, including exposure to three categories of abuse, two categories of neglect, and four categories of household dysfunction. Multivariable logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between ACEs and migraine while adjusting for putative confounders. Results: Approximately 75% of adolescent mothers reported having experienced at least one type of ACE. Adolescent mothers who reported any childhood abuse had 1.49-fold increased odds of migraine (aOR = 1.49; 95% CI 1.03–2.18) compared to those with no history of childhood abuse. Adolescent mothers who reported experiencing household dysfunction had 1.56-fold increase odds of migraine (aOR = 1.56; 95% CI 1.09–2.24). Compared to participants who reported no ACE, those who experienced four or more ACEs had 3.09-fold (aOR = 3.09; 95% CI 1.80–5.40) increased odds of migraine (ptrend < 0.001). Conclusion: Exposure to ACEs is highly prevalent in adolescent-aged mothers postpartum and is associated with increased odds of migraine. These findings support the importance of screening for ACEs and migraine among adolescent mothers; and the need for providing culturally appropriate, trauma-informed headache care. National Institutes of Health Revisión por pares

The purpose of this study was to assess the practice and perceptions of shared decision-making (SDM) by both faculty and residents at Boston Medical Center and explore barriers and facilitators to implementing SDM at our institution.We created and distributed an online survey assessing provider demographic and training characteristics, experiences with the informed consent process, practices in SDM, and perceptions about SDM. We used descriptive statistics to summarize provider characteristics and survey responses and univariate analysis to determine associations between them.Fifteen surgeons and 19 surgical residents completed the survey (49% response rate). Most respondents were aware of and had a positive attitude toward SDM (91% and 76%, respectively); 35% reported having SDM training. Providers had varying levels of engagement with different SDM practices, and there were inconsistent associations between provider characteristics and the use of SDM. Often providers thought the patient's health literacy, foreign primary language, clinical condition, and socioeconomic factors were barriers to the SDM process.Although most general surgery faculty and residents at our institution had a positive view of SDM, they engaged in SDM behaviors inconsistently, with no clear association between clinician characteristics and specific behaviors. We identified several barriers to SDM consistent with those identified by providers in other specialties. This highlights the need for further research to study live general surgery provider-patient interactions, as well as structured SDM education to train general surgery providers to reliably engage their patients in effective SDM.

BACKGROUND The strength of one's social support network is a potentially modifiable factor that may have a significant impact on recovery after injury. We sought to assess the association between one's perceived social support (PSS) and physical and mental health outcomes 6 months to 12 months postinjury. METHODS Moderate to severely injured patients admitted to one of three Level I trauma centers were asked to complete a phone-based survey assessing physical and mental health outcomes in addition to return to work and chronic pain 6 months to 12 months postinjury. Patients were also asked to rate the strength of their PSS on a 5-point Likert scale. Multivariate linear and logistic regression models were built to determine the association between PSS and postdischarge outcome metrics. RESULTS Of 907 patients included in this study, 653 (72.0%) identified themselves as having very strong/strong, 182 (20.1%) as average, and 72 (7.9%) as weak/nonexistent PSS. Patients who reported a weak/nonexistent PSS were younger and were more likely to be male, Black, and to have a lower level of education than those who reported a very strong/strong PSS. After adjusting for potential confounders, patients with a weak/nonexistent PSS were more likely to have new functional limitations and chronic pain in addition to being less likely to be back at work/school and being more likely to screen positive for symptoms of posttraumatic stress disorder, depression and anxiety at 6 months to 12 months postinjury than those with a strong/very strong PSS. CONCLUSION Lower PSS is strongly correlated with worse functional and mental health outcome metrics postdischarge. The strength of one's social support network should be considered when trying to identify patients who are at greatest risk for poor postdischarge outcomes after injury. Our data also lend support to creating a system wherein we strive to build a stronger support network for these high-risk individuals. LEVEL OF EVIDENCE Prognostic/epidemiologic, level III.