Design of substituted tetrahydrofuran derivatives for HIV-1 protease inhibitors: synthesis, biological evaluation, and X-ray structural studies.

Substituted tetrahydrofuran derivatives were designed and synthesized to serve as the P2 ligand for a series of potent HIV-1 protease inhibitors. Both enantiomers of the tetrahydrofuran derivatives were synthesized stereoselectivity in optically active forms using lipase-PS catalyzed enzymatic resolution as the key step. These tetrahydrofuran derivatives are designed to promote hydrogen bonding and van der Waals interactions with the backbone atoms in the S2 subsite of the HIV-1 protease active site. Several inhibitors displayed very potent HIV-1 protease inhibitory activity. A high-resolution X-ray crystal structure of an inhibitor-bound HIV-1 protease provided important insight into the ligand binding site interactions in the active site.

Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.

We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

Missed Opportunities When We Focus only on Risk: Using the Concerns Based Conversation Starter to Identify Potential PrEP Candidates.

Collection and use of self-reported HIV sexual risk-behaviors to identify pre-exposure prophylaxis (PrEP) candidates is common practice in PrEP providing and referral services. Critiques of this strategy highlight overreliance on self-report and contribution to ongoing PrEP stigma. As an alternative (or complimentary) approach, we evaluated a 5-item Concerns Based Conversation Starter (CBCS) that could be used to identify individuals who could benefit from PrEP. The CBCS was included in the 2019 cycle of the American Men's Internet Survey. Item responses were characterized overall and in relation to CDC risk-based PrEP indication and reported willingness to use PrEP. In total, 1606 HIV-negative men who have sex with men not on PrEP were evaluated. Of these, 50% were below the age of 25, 11% Black, 16% Latino, and 64% White. Across the sample, 61% (986) met risk-based criteria for PrEP indication, 80% (1278) were identified by the CBCS, and 52% (835) were flagged by both. The CBCS uniquely identified 28% (443) for follow-up PrEP discussions that would have been missed by a risk-based only approach. Only 9% (151) of the sample had risk-based indication but did not report concerns. Over half of those flagged by the CBCS expressed willingness to use PrEP. The CBCS identified more people than a risk-based indication approach, with most also reporting an interest in using PrEP. A small percentage of risk-indicated participants were 'missed' by the CBCS. As PrEP options and access points expand, implementation tools like the CBCS can facilitate more wide-scale, values-focused PrEP implementation.

Dampened psychobiological responses to stress and substance use in adolescence.

Substance use increases throughout adolescence, and earlier substance use may increase risk for poorer health. However, limited research has examined whether stress responses relate to adolescent substance use, especially among adolescents from ethnic minority and high-adversity backgrounds. The present study assessed whether blunted emotional and cortisol responses to stress at age 14 related to substance use by ages 14 and 16, and whether associations varied by poverty status and sex. A sample of 277 Mexican-origin youth (53.19% female; 68.35% below the poverty line) completed a social-evaluative stress task, which was culturally adapted for this population, and provided saliva samples and rated their anger, sadness, and happiness throughout the task. They also reported whether they had ever used alcohol, marijuana, cigarettes, and vaping of nicotine at age 14 and again at age 16. Multilevel models suggested that blunted cortisol reactivity to stress was associated with alcohol use by age 14 and vaping nicotine by age 16 among youth above the poverty line. Also, blunted sadness and happiness reactivity to stress was associated with use of marijuana and alcohol among female adolescents. Blunted stress responses may be a risk factor for substance use among youth above the poverty line and female adolescents.

Outcomes of Open Reduction in Children With Developmental Hip Dislocation: A Multicenter Experience Over a Decade.

BACKGROUND: Open reduction of the hip is commonly performed in children with severe developmental dysplasia of the hip, or in cases that are refractory to nonoperative forms of treatment. The open reduction has been associated with numerous complications including avascular necrosis (AVN) of the femoral head, the need for reoperation, and residual radiographic dysplasia. This study seeks to determine the effects of preoperative severity of dysplasia, associated procedures (femoral and acetabular osteotomies), age on AVN, and the need for reoperation. METHODS: Children with developmental dysplasia of the hip and a minimum of 2 years of follow-up who underwent open reduction were identified. The following data points were recorded: sex, laterality of hip involvement, simultaneous procedures, surgical approach used, age, acetabular index, and International Hip Dysplasia Institute grade. We analyzed the effects of preoperative International Hip Dysplasia Institute, age, surgical approach (anterior/medial), bilateral reduction, and simultaneous femoral shortening or pelvic osteotomy on the outcomes of AVN and reoperation. RESULTS: One hundred eighty-five hips in 149 patients were included in this study with an average follow-up of 4 years (range: 2 to 5 y). The average age at index surgery was 23 months (range: 1 to 121 mo). Overall, 60 hips (32.4%) required secondary surgical procedures at an average age of 58.5 months. High-grade AVN was noted in 24 hips (13.0%) and was found to be associated with the severity of the hip dislocation ( P = 0.02). A higher rate of reoperation was found in children over 18 months at the time of open reduction who did not receive an acetabular osteotomy ( P = 0.012). CONCLUSION: Approximately 1/3 of patients require another operative intervention within the first 4 years after open reduction of the hip. We found the severity of hip dislocation to be associated with a higher risk of AVN development. These findings support performing an acetabular osteotomy in children over 18 months of age at the time of open reduction to decrease the likelihood of requiring future reoperation during the first 4 years after the index procedure. LEVEL OF EVIDENCE: Level III.

Descriptive Epidemiology of Upper Extremity Septic Arthritis in Children-Review of a Retrospective Multicenter Database.

BACKGROUND: There is limited information on the presentation and management of upper extremity septic arthritis (UESA) in children. Our purpose was to report on the characteristics and short-term treatment outcomes of pediatric UESA from a multicenter database. METHODS: Patients with UESA were identified from a multicenter retrospective musculoskeletal infection database. Demographics, laboratory tests, culture results, number of surgeries, and complications were collected. RESULTS: Of 684 patients with septic arthritis (SA), 68 (10%) patients had UESA. Septic arthritis was most common in the elbow (53%), followed by the shoulder (41%) and wrist (4%). The median age at admission was 1.7 years [interquartile range(IQR, 0.8-8.0 y)] and 66% of the cohort was male. Blood cultures were collected in 65 (96%) patients with 23 (34%) positive results. Joint aspirate and/or tissue cultures were obtained in 66 (97%) patients with 49 (72%) positive results. Methicillin-sensitive Staphylococcus aureus (MSSA) was the most common causative organism overall, but Streptococcus was the most common pathogen in the shoulder. Sixty-six (97%) patients underwent irrigation and debridement, with 5 (7%) patients requiring 2 surgeries and 1 patient (1%) requiring 3 surgeries. The median length of stay was 4.9 days (IQR, 4.0-6.3 d). Thirty-one (46%) children had adjacent musculoskeletal infections and/or persistent bacteremia. No patients experienced venous thromboembolism, and 4 patients with associated osteomyelitis experienced a musculoskeletal complication (3 avascular necrosis, 1 pathologic fracture). One child had re-admission and 3 children with associated osteomyelitis had a recurrence of UESA. Comparison between elbow and shoulder locations showed that children with septic arthritis of the shoulder were younger (4.6 vs. 1.0 y, P =0.001), and there was a difference in minimum platelet count (280 vs. 358 ×10 9 cells/L, P =0.02). CONCLUSIONS: UESA comprises 10% of cases of septic arthritis in children. The elbow is the most common location. Shoulder septic arthritis affects younger children. MSSA is the most common causative organism in UESA, but Streptococcus is common in shoulder septic arthritis. Irrigation and debridement result in excellent short-term outcomes with a low complication rate. Re-admissions and repeat surgical interventions are rare. LEVEL OF EVIDENCE: Level IV, prognostic.

An Analysis of Scoliosis in Autism Spectrum Disorder.

BACKGROUND: Children with autism/Asperger are grouped into the diagnosis of autism spectrum disorder (ASD). It remains uncertain whether children with ASD and scoliosis have radiographic and clinical outcomes similar to idiopathic scoliosis (IS) patients. METHODS: A single-center, retrospective review of a prospective scoliosis registry evaluated patients who had a posterior spinal fusion±Anterior Spinal Fusion and an underlying diagnosis of ASD between 1990 and 2021. A 2:1 match with AIS patients by age and sex was compared using demographic, radiographic, intraoperative, and SRS-22/30 variables. RESULTS: Thirty patients with ASD (63% male, mean age at surgery 14.6±2.5 y) met inclusion criteria, with a follow-up of 2.46±1.00 years. Despite no differences in curve magnitude preoperatively, patients with ASD had a higher percent correction at 2-year follow-up (66% vs. 57%, P =0.01) and improved mean curve magnitude (20±10 degrees) at 2-year follow-up compared with IS patients (27±11 degrees, P <0.01). ASD patients had less lumbar lordosis preoperatively (40±12 vs. 53±14, P <0.01), but there were no significant differences in sagittal parameters at 2-year follow-up. There were no significant differences in the rate of complications at 2-year follow-up between ASD and AIS cohorts. CONCLUSIONS: Although patients with ASD exhibited decreased lordosis compared with IS patients preoperatively, their radiographic outcomes at 2-year follow-up were the same. In addition, ASD patients maintained greater curve correction than IS patients at 2 years follow-up. LEVEL OF EVIDENCE: Prognostic retrospective study.

Do Children With Medicaid Insurance Have Increased Revision Rates 5 Years After Posterior Spinal Fusions?

BACKGROUND: Socioeconomic disparities in musculoskeletal care are increasingly recognized, however, no studies to date have investigated the role of the insurance carrier on outcomes after posterior spinal fusion (PSF) with segmental spinal instrumentation for adolescent idiopathic scoliosis (AIS). METHODS: A US insurance dataset was queried using the PearlDiver Mariner software for all patients aged 10 to 18 undergoing PSF for a primary diagnosis of AIS between 2010 and 2020. Age, sex, geographic region, number of levels fused, and baseline medical comorbidities were queried. Complications occurring within 90 days of the index surgery were queried using the International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, 10th Revision (ICD-10) codes. Revision surgery was also queried up to 5 years after the index PSF. Categorical variables were compared using the Fisher χ 2 tests and continuous variables were compared using independent t tests. All-cause revision within 5 years was compared using the Kaplan-Meier analysis and a log-rank test. Significance was set at P -value <0.05. RESULTS: A total of 10,794 patients were identified with 9006 (83.4%) patients with private insurance and 1788 (16.6%) patients insured by Medicaid. The mean follow-up in the database was 5.36±3 years for patients with private insurance and 4.78±2.9 years for patients with Medicaid insurance ( P <0.001). Children with AIS and Medicaid insurance had a significantly higher prevalence of asthma, hypertension, and obesity. A larger percentage of children with Medicaid insurance (41.3%) underwent a ≥13-level PSF compared with privately insured children (34.5%) ( P <0.001). Medicaid patients did not experience higher odds of postoperative complications; in addition, revision surgeries occurred in 1.1% and 1.8% of patients with private insurance and Medicaid insurance, respectively at 5 years postoperatively ( P =0.223). CONCLUSION: Despite worse baseline comorbidities and longer fusion constructs, AIS patients insured with Medicaid did not have higher rates of complications or revisions at 5-year follow-up versus privately insured patients. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Geospatial Prioritization to Reach Hispanic or Latino and Other Priority Populations Through HIV Home Testing Services.

CONTEXT: Hispanic or Latino men who have sex with men (HLMSM) are disproportionately affected by the HIV/AIDS epidemic in New York State (NYS) and nationally. In 2019, HLMSM comprised 13% of all new diagnoses and 21% of new diagnoses among men who have sex with men (MSM) in NYS excluding New York City. HIV home testing programs are effective methods for increasing HIV testing. OBJECTIVE: This pilot sought to determine whether the NYS HIV Home Test Giveaway (HHTG) can effectively reach priority populations, specifically HLMSM/transgender/gender nonconforming persons who have sex with men, to increase uptake of HIV home testing services and identify new HIV infections. DESIGN/SETTING: We recruited participants using media campaigns linked to a brief self-administered eligibility survey. Eligible participants provided their e-mail address to receive a code for a free HIV home test and were sent a self-administered follow-up survey 4 to 11 weeks after eligibility survey completion. PARTICIPANTS: The 2018 and 2019 NYS HHTG reached 1214 and 1340 participants, respectively. A total of 606 participants in 2018 and 736 participants in 2019 were eligible to receive the HHTG home test kit. MAIN OUTCOME MEASURES: HHTG utilization and test results. RESULTS: Hispanic or Latino persons participated at higher rates (34.8% and 25.4% in 2018 and 2019, respectively) than the percentage of Hispanic men in prioritized zip codes (15.7% and 15.6% in 2018 and 2019, respectively). The majority of participants who received HHTG test kits used them to test themselves (87.5% in 2018 and 90.6% in 2019). Across both rounds, 4 participants reported new HIV-positive results, for a seropositivity rate of approximately 1%. CONCLUSION: Geospatial prioritization was successful in reaching Hispanic or Latino priority populations for HIV testing. HIV self-testing programs such as the HHTG are beneficial methods to reach priority populations for state and national Ending the HIV Epidemic initiatives.

Angiotensin II differentially affects hippocampal glial inflammatory markers in young adult male and female mice.

Hypertension is a risk factor for neurodegenerative disorders involving inflammation and inflammatory cytokine-producing brain cells (microglia and astrocytes) in the hippocampus and medial prefrontal cortex (mPFC). Here we investigated the effect of slow-pressor angiotensin II (AngII) on gliosis in the hippocampus and mPFC of young adult (2-mo-old) male and female mice. In males, AngII induced hypertension, and this resulted in an increase in the density of the astrocyte marker glial fibrillary acidic protein (GFAP) in the subgranular hilus and a decrease in the density of the microglial marker ionized calcium binding adapter molecule (Iba-1) in the CA1 region. Females infused with AngII did not show hypertension but, significantly, showed alterations in hippocampal glial activation. Compared with vehicle, AngII-infused female mice had an increased density of Iba-1 in the dentate gyrus and CA2/3a region. Like males, females infused with AngII exhibited decreased Iba-1 in the CA1 region. Neither male nor female mice showed differences in GFAP or Iba-1 in the mPFC following AngII infusion. These results demonstrate that the hippocampus is particularly vulnerable to AngII in young adulthood. Differences in gonadal hormones or the sensitivity to AngII hypertension may account for divergences in GFAP and Iba-1 in males and females.

Estrogen Receptor ß Contributes to Both Hypertension and Hypothalamic Plasticity in a Mouse Model of Peri-Menopause.

Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor ß (ERß) reporter mice was induced by 4-vinylcyclohexene diepoxide in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERß agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not in age-matched male mice. It was also found that ERß agonist administration in peri-AOF females, but not males, suppressed the heightened NMDAR signaling and reactive oxygen production in ERß neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ERß in the PVN of gonadally intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ERß signaling in the PVN plays an important role in blood pressure regulation in female mice and contributes to hypertension susceptibility in females at an early stage of ovarian failure comparable to human perimenopause.

Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients.

BACKGROUND: Hearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection. METHODS: We conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir-velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation. RESULTS: A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders. CONCLUSIONS: In patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.).

Randomized Controlled Trial of a Remote Coaching mHealth Adherence Intervention in Youth Living with HIV.

Youth living with HIV (YLWH) in the US have low rates of viral suppression (VS). In a prospective randomized clinical trial (ATN152) that enrolled 89 YLWH on antiretroviral therapy (ART) with detectable viral load, we evaluated a 12 week triggered escalating real-time adherence (TERA) intervention with remote coaching, electronic dose monitoring (EDM), and outreach for missed/delayed doses compared to standard of care (SOC). Median [Q1, Q3] percent days with EDM opening was higher in TERA (72% (47%, 89%)) versus SOC (41% (21%, 59%); p < 0.001) and incidence of numbers of 7 day gaps between openings were lower (TERA to SOC ratio: 0.40; 95% CI 0.30, 0.53; p < 0.001). There were no differences in VS at week 12 (TERA 35%; 95% CI 21%, 51% versus SOC 36%; 95% CI 22%, 51%; p > 0.99) or later time-points. The intervention improved adherence but not VS in heavily ART-experienced YLWH. Remote coaching more closely tailored to the unique dosing patterns and duration of need for youth struggling to reach VS warrants further investigation.

Chest Compression Fraction Alone Does Not Adequately Measure Cardiopulmonary Resuscitation Quality in Out-of-Hospital Cardiac Arrest.

BACKGROUND: High-quality cardiopulmonary resuscitation in out-of-hospital cardiac arrest is important for increased survival and improved neurological outcome. Chest compression fraction measures the proportion of time chest compressions are given during a cardiac arrest resuscitation. Chest compression fraction has not been compared with the quality of chest compressions delivered at the recommended rate and depth of 100-120/min and 2.0-2.4 inches, respectively. OBJECTIVES: We evaluate whether chest compression fraction correlates with compressions at a target rate of 100-120/min and depth of 2.0-2.4 inches in chest diameter. METHODS: A prospective, observational study design was used to compare chest compression fraction to compressions in target in out-of-hospital cardiac arrest patients in a prehospital urban setting. We include all adult, non-traumatic out-of-hospital cardiac arrest patients with a resuscitation attempt during January 1, 2019 through September 30, 2019, for a total of 9 months. Spearman's rank correlation was used to determine correlation between compression fraction and compressions in target. RESULTS: A total of 120 out-of-hospital cardiac arrest cases were included in the study. We found a high chest compression fraction median of 83% (interquartile range 72-90%), but a low compression in target median of 13% (interquartile range 5-29%). There was no significant correlation between chest compression fraction and compressions in target when analyzed linearly (Spearman's Rho = 0.165, p = 0.072). No difference was found when dichotomizing chest compression fraction into high and low variables in comparison with compressions in target (14% vs. 10%, p = 0.119). CONCLUSION: Chest compression fraction is not associated with compressions in target for rate and depth for out-of-hospital cardiac arrest cardiopulmonary resuscitation.

Prioritizing Elective Surgical Cases During a Pandemic or Global Crisis: The Elective-Pediatric Orthopedic Surgical Timing (E-POST) Score.

BACKGROUND: As the first wave of the COVID-19 pandemic stabilized and resources became more readily available, elective surgery was reinitiated and hospitals realized that there was little guidance on how to prioritize elective cases. METHODS: A prioritization tool was formulated based on clinically relevant elements and previous literature. Nine pediatric orthopaedic surgeons from North American institutions evaluated 25 clinical scenarios on 2 occasions separated in time. Intra-rater and inter-rater reliability were calculated [intraclass correlation coefficient (ICC)]. Surgeons also ranked the importance of each element and how confident they were with scoring each factor. RESULTS: Intra-rater ICC for total score showed good to excellent consistency; highest at 0.961 for length of stay (LOS) and lowest at 0.705 for acuity. Inter-rater ICC showed good to excellent agreement for American Society of Anesthesiologists score, LOS, duration of surgery, and transfusion risk and moderate agreement for surgical acuity and personal protective equipment (PPE) use. Transfusion risk and duration of surgery were deemed least important, and surgeons were least confident in scoring PPE and transfusion risk. Based on findings, the novel Elective-Pediatric Orthopedic Surgical Timing (E-POST) score for prioritizing elective cases was developed, consisting of 5 factors: surgical acuity, global health status, LOS, duration of surgery, and PPE requirement. CONCLUSIONS: The E-POST numeric total score or subscore may help objectively prioritize elective cases during a global crisis. LEVEL OF EVIDENCE: Level V.

Combating Stigma Through HIV Self-Testing: New York State's HIV Home Test Giveaway Program for Sexual Minorities.

CONTEXT: Gay, bisexual, and men who have sex with men (MSM) are disproportionately affected by the HIV/AIDS epidemic more than any other group. In New York State (NYS) outside of New York City (NYC), MSM accounted for 57% of new HIV/AIDS diagnoses in 2017. HIV/AIDS home testing initiatives have been effective at getting priority populations tested for HIV. OBJECTIVES: The NYS Department of Health (NYSDOH) administered the HIV Home Test Giveaway (HHTG) program through social media and mobile applications popular among the priority populations to (1) promote HIV screening among gay and bisexual men, MSM, transgender (TG), and gender queer/gender nonconforming (GNC) individuals who have sex with men, and (2) identify individuals with undiagnosed HIV infection. DESIGN/SETTING: The NYSDOH recruited participants from NYS (excluding NYC) through social media campaigns between November 2016 and January 2018. Interested individuals were directed to an online eligibility survey. Eligible participants received a coupon via e-mail for a free HIV self-test (HIVST) kit through the manufacturer's Web site. Eligible participants received a $20 to $25 Amazon online gift card if they completed a voluntary online follow-up survey regarding their test results, experiences with the HHTG, and HIV/AIDS risk behaviors. Participants were also able to request assistance from the NYSDOH with further testing and various prevention and supportive services. PARTICIPANTS: In total, 6190 individuals participated and 3197 (52%) were eligible and received a coupon. Of the eligible, 2022 (63%) redeemed coupons for HIVST. RESULTS: Among eligible participants, 976 (31%) reported having never been tested for HIV. On the follow-up survey, 922 (29%) participants reported having used the HIVST kit for themselves; 203 (22%) were first-time testers; and 7 (0.8%) tested HIV reactive. Of the follow-up survey participants, 761 (59%) requested assistance with various services. CONCLUSIONS: Media campaigns were effective in promoting HIV testing among priority populations and reaching individuals who have never been tested for HIV.

DPP4 inhibition mitigates ANG II-mediated kidney immune activation and injury in male mice.

Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ∼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8+ T cells, resident macrophages (CD11bhiF4/80loLy6C-), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation.NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8+ T cells, Ly6C- macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.

Acute Delta 9-tetrahydrocannabinol administration differentially alters the hippocampal opioid system in adult female and male rats.

Our prior studies demonstrated that the rat hippocampal opioid system can undergo sex-specific adaptations to external stimuli that can influence opioid-associated learning processes. This opioid system extensively overlaps with the cannabinoid system. Moreover, acute administration of Δ9 Tetrahydrocannabinoid (THC), the primary psychoactive constituent of cannabis, can alter cognitive behaviors that involve the hippocampus. Here, we use light and electron microscopic immunocytochemical methods to examine the effects of acute THC (5 mg/kg, i.p., 1 h) on mossy fiber Leu-Enkephalin (LEnk) levels and the distribution and phosphorylation levels of delta and mu opioid receptors (DORs and MORs, respectively) in CA3 pyramidal cells and parvalbumin dentate hilar interneurons of adult female and male Sprague-Dawley rats. In females with elevated estrogen states (proestrus/estrus stage), acute THC altered the opioid system so that it resembled that seen in vehicle-injected females with low estrogen states (diestrus) and males: (1) mossy fiber LEnk levels in CA2/3a decreased; (2) phosphorylated-DOR levels in CA2/3a pyramidal cells increased; and (3) phosphorylated-MOR levels increased in most CA3b laminae. In males, acute THC resulted in the internalization of MORs in parvalbumin-containing interneuron dendrites which would decrease disinhibition of granule cells. In both sexes, acute THC redistributed DORs to the near plasma membrane of CA3 pyramidal cell dendrites, however, the dendritic region varied with sex. Additionally, acute THC also resulted in a sex-specific redistribution of DORs within CA3 pyramidal cell dendrites which could differentially promote synaptic plasticity and/or opioid-associated learning processes in both females and males.

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats.

Oxycodone (Oxy) conditioned place preference (CPP) in Sprague Dawley rats results in sex-specific alterations in hippocampal opioid circuits in a manner that facilitates opioid-associative learning processes, particularly in females. Here, we examined if Oxy (3 mg/kg, I.P.) or saline (Sal) injections not paired with behavioral testing similarly affect the hippocampal opioid system. Sal-injected females compared to Sal-injected males had: (1) higher densities of cytoplasmic delta opioid receptors (DOR) in GABAergic hilar dendrites suggesting higher baseline reserve DOR pools and (2) elevated phosphorylated DOR levels, but lower phosphorylated mu opioid receptor (MOR) levels in CA3a suggesting that the baseline pools of activated opioid receptors vary in females and males. In contrast to CPP studies, Oxy-injections in the absence of behavioral tests resulted in few changes in the hippocampal opioid system in either females or males. Specifically, Oxy-injected males compared to Sal-injected males had fewer DORs near the plasma membrane of CA3 pyramidal cell dendrites and in CA3 dendritic spines contacted by mossy fibers, and lower pMOR levels in CA3a. Oxy-injected females compared to Sal-injected females had higher total DORs in GABAergic dendrites and lower total MORs in parvalbumin-containing dendrites. Thus, unlike Oxy CPP, Oxy-injections redistributed opioid receptors in hippocampal neurons in a manner that would either decrease (males) or not alter (females) excitability and plasticity processes. These results indicate that the majority of changes within hippocampal opioid circuits that would promote opioid-associative learning processes in both females and males do not occur with Oxy administration alone, and instead must be paired with CPP.

Organophosphate pesticide exposure during pregnancy and childhood and onset of juvenile delinquency by age 16 years: The CHAMACOS cohort.

BACKGROUND: Though prenatal organophosphate pesticide (OP) exposure has been associated with lower intellectual quotient and behavioral disorders in childhood, factors related to later delinquency, no research has directly evaluated the impact of OPs on delinquency. OBJECTIVE: To evaluate the association between prenatal and childhood OP exposure and juvenile delinquency in Mexican-American youth in the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS). METHODS: We measured dialkyl phosphate (DAPs) urinary metabolites of OPs in two prenatal maternal samples and in five child samples collected between six months and five years of age. Youth completed delinquency questionnaires at 16 years. We examined associations of prenatal and childhood DAPs with several delinquency outcomes (n = 313) using survival and generalized linear models. RESULTS: Almost 60% of youth reported delinquent acts (mostly minor), and 8% reported a police arrest. We observed largely null results of prenatal or childhood DAP concentrations and delinquency outcomes, with some isolated associations. A ten-fold increase in maternal dimethylphosphate (DM) concentrations measured after 20 weeks gestation was associated with an earlier age of first delinquent act (Hazard Ratio = 1.38, 95% CI: 1.01, 1.88) and an increased Odds Ratio (OR) of having committed 1-3 or ≥4 delinquent acts, compared to the no delinquency reference group (OR = 1.77, 95% CI: 1.01-3.08 and 2.17, 95% CI: 1.13-4.17, respectively). Higher childhood diethylphosphate (DE) concentrations were associated with a later age of first delinquent act (HR: 0.67; 95% CI: 0.46-0.97). DISCUSSION: We did not find strong evidence of association between prenatal or childhood OP exposure and juvenile delinquency in the present cohort. There is an increasing literature that relates OP exposure to neurobehavioral impairments in childhood, and there is a need to understand long-term potential neurodevelopmental effects of early-life OP exposure.