Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants.

BACKGROUND: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). METHODS: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. RESULTS: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1. CONCLUSIONS: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.

Continuous transversus abdominis plane blocks in patients undergoing minimally invasive colorectal surgery: a randomized pilot study.

PURPOSE: Transversus abdominis plane (TAP) blocks are used in an attempt to decrease narcotic use and its subsequent consequences. The primary goal of this study was to see if TAP blocks decreased narcotic use in patients undergoing minimally invasive colorectal surgery. METHODS: A randomized pilot study was conducted. The amount of narcotic used examined in morphine milligram equivalents (MME) was collected for the first 4 post-operative days (PODs). Demographic data, length of stay (LOS), readmission rate, and 90-day mortality was also examined. Statistical analysis of the data was performed with a p < 0.05 determined to be significant. RESULTS: Eighty-eight patients were included. Forty-seven were randomized to the TAP group and 41 to the no TAP group. There was no difference in age, race, gender, indication for operation, or Charlson Comorbidity Index (p > 0.05). The median MME for each POD was similar for POD 1 (22.5 vs 37.5; p = 0.054), POD 3 (15 vs 22.5; p = 0.48), and POD 4 (22.5 vs 10.5; p = 0.42) on bivariate analysis. On POD 2, the TAP group had significantly less narcotic intake than the no TAP group (17.5 vs 30; p = 0.047). However, on multivariate analysis when controlling for other variables, there was no statistical difference between the groups. Median LOS was 3 days for both groups. Readmissions, post-operative complications, and mortality were also similar between the two groups (p > 0.05). CONCLUSION: Our findings indicate that continuous TAP blocks do not decrease the amount of MME used during the first 4 post-operative days compared to patient receiving traditional pain control measures.

Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants.

BACKGROUND: Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission. METHODS: A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis. RESULTS: Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1-6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding. CONCLUSIONS: Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.

Willingness to Take Multidrug-resistant Tuberculosis (MDR-TB) Preventive Therapy Among Adult and Adolescent Household Contacts of MDR-TB Index Cases: An International Multisite Cross-sectional Study.

BACKGROUND: Household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB) are at high risk of infection and subsequent disease. There is limited evidence on the willingness of MDR-TB HHCs to take MDR-TB preventive therapy (MDR TPT) to decrease their risk of TB disease. METHODS: In this cross-sectional study of HHCs of MDR-TB and rifampicin-resistant tuberculosis (RR-TB) index cases from 16 clinical research sites in 8 countries, enrollees were interviewed to assess willingness to take a hypothetical, newly developed MDR TPT if offered. To identify factors associated with willingness to take MDR TPT, a marginal logistic model was fitted using generalized estimating equations to account for household-level clustering. RESULTS: From 278 MDR-TB/RR-TB index case households, 743 HHCs were enrolled; the median age of HHCs was 33 (interquartile range, 22-49) years, and 62% were women. HHC willingness to take hypothetical MDR TPT was high (79%) and remained high even with the potential for mild side effects (70%). Increased willingness was significantly associated with current employment or schooling (adjusted odds ratio [aOR], 1.83 [95% confidence interval {CI}, 1.07-3.13]), appropriate TB-related knowledge (aOR, 2.22 [95% CI, 1.23-3.99]), confidence in taking MDR TPT (aOR, 7.16 [95% CI, 3.33-15.42]), and being comfortable telling others about taking MDR TPT (aOR, 2.29 [95% CI, 1.29-4.06]). CONCLUSIONS: The high percentage of HHCs of MDR-TB/RR-TB index cases willing to take hypothetical MDR TPT provides important evidence for the potential uptake of effective MDR TPT when implemented. Identified HHC-level variables associated with willingness may inform education and counseling efforts to increase HHC confidence in and uptake of MDR TPT.

Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.

BACKGROUND: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. METHODS: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. RESULTS: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. CONCLUSIONS: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

Rate of conversion to an open procedure is reduced in patients undergoing robotic colorectal surgery: A single-institution experience.

BACKGROUND: Robotic-assisted surgery is becoming increasingly used in colorectal operations. It has many advantages over laparoscopic surgery including three-dimensional viewing, motion scaling, improved dexterity and ergonomics as well as increased precision. However, there are also disadvantages to robotic surgery such as lack of tactile feedback, cost as well as limitations on multi-quadrant surgeries. The purpose of this study was to compare the rate of conversion to an open surgery in patients undergoing robotic-assisted colorectal surgery and traditional laparoscopic surgery. METHODS: Patients undergoing minimally invasive colorectal surgery for neoplastic and dysplastic disease from 2009 to 2016 were identified and examined retrospectively. The statistical software SAS, manufactured by SAS Institute, Cary, North Carolina. Continuous variables were analysed using analysis of variance test. Chi-square test was used to analyse categorical variables. P <0.05 was considered statistically significant. RESULTS: Two hundred and thirty-five patients were identified that underwent minimally invasive colorectal surgery. One hundred and sixty-four underwent laparoscopic resection and 71 underwent robotic-assisted resection. There was no statistical difference in gender or race between the two groups (both P > 0.05). Patients that underwent robotic-assisted resection were slightly younger than patients that underwent laparoscopic resection (61.6 years vs. 65.6 years; P= 0.02). When examining conversion to an open procedure, patients that underwent robotic-assisted resection had a significantly lower chance of conversion than did the patients undergoing a laparoscopic approach (11.27% vs. 29.78%; P= 0.0018). CONCLUSION: Conversion rates from a minimally invasive procedure to an open procedure appear to be lower with robotic-assisted surgery compared to laparoscopic surgery.

Evaluating the frequency of upgrade to malignancy following surgical excision of high-risk breast lesions and ductal carcinoma in situ identified by core needle biopsy.

Excision of high-risk breast lesions (HRL) continues to be standard of care. Previous studies have shown that HRLs can be upgraded to carcinoma in situ (CIS) or invasive carcinoma (IC) upon excision. A single institution retrospective review was conducted to determine the rate of upgrade of HRLs and ductal carcinoma in situ (DCIS) identified on image-guided biopsy upon excision. Eight hundred and fifty-seven patients who underwent core needle biopsy (CNB) following the detection of suspicious lesions (BI-RADS IV) on mammograms were identified. HRLs and DCIS warranting subsequent surgical excision were found in 129 of 857 patients (15.1%). Overall, 19.6% (10/51) of DCIS, 52.4% (11/21) of ADH, and 17.6% (3/17) of papillomas were upgraded on surgical excision. A statistically significant difference was found between the concordant and discordant groups regarding the number of cores obtained (P = 0.01) and the needle size used to retrieve specimens on CNB (P = 0.01). This study reveals an upgrade rate of 26.7% of HRLs and DCIS diagnosed by CNB on surgical excision and emphasizes the continued use of large bore needles with an adequate number of core specimens when investigating a suspicious breast lesion.

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

AIMS: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability. RESULTS: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell. CONCLUSIONS: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

Exposure to mixtures of mercury, cadmium, lead, and arsenic alters the disposition of single metals in tissues of Wistar rats.

Humans throughout the world are exposed regularly to mixtures of environmental toxicants. Four of the most common heavy metal toxicants in the environment are mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As). Numerous studies have assessed the effects and disposition of individual metals in organ systems; however, humans are usually exposed to mixtures of toxicants or metals rather than to a single toxicant. Therefore, the purpose of the current study was to test the hypothesis that exposure to a mixture of toxic heavy metals alters the disposition of single metals in target organs. Wistar rats (Rattus norvegicus) were exposed to Hg, Cd, Pb, or As as a single metal or as a mixture of metals. Rats were injected intravenously for three days, following which kidneys, liver, brain, and blood were harvested. Samples were analyzed for content of Hg, Cd, Pb, and As via inductively coupled plasma mass spectrometry. In general, exposure to a mixture of metals reduced accumulation of single metals in target organs. Interestingly, exposure to mixtures of metals with Pb and/or As increased the concentration of these metals specifically in the liver. The findings from this study indicate that exposure to mixtures of toxic heavy metals may alter significantly the distribution and accumulation of these metals in target organs and tissues.

Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel.

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.

Evaluation of tuberculosis diagnostics in children: 2. Methodological issues for conducting and reporting research evaluations of tuberculosis diagnostics for intrathoracic tuberculosis in children. Consensus from an expert panel.

Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.

Sociodemographic disparities in preterm birth and low birthweight in the State of Georgia: Results from the 2017-2018 Pregnancy Risk Assessment Monitoring System.

PURPOSE: To update the overall prevalence of preterm birth (PTB) (<37 weeks gestation) and low birthweight (LBW) (<2,500 g) in the State of Georgia, including rural and urban counties. METHODS: A sample was drawn from the 2017-2018 Georgia Pregnancy Risk Assessment Monitoring System (PRAMS). In the complete-case data of singleton births (n=1,258), we estimated the weighted percentage prevalence of PTB, LBW, early/late PTB, and moderately/very LBW subcategories in association with maternal sociodemographic characteristics, and the prevalence stratified by rural/urban county of residence. Univariate and multivariate logistic regression models were fitted to estimate the odds ratios (ORs) of PTB and LBW adjusting for selected covariates. Logistic regression results from multiple imputation by chained equations (MICE) were used for comparison. FINDINGS: The overall rate for PTB was 9.3% and 6.8% for LBW and among them, 2.3% were early PTB, 7.0% were late PTB, 5.4% were moderately LBW (MLBW), and 1.3% were very LBW (VLBW). Non-Hispanic Black women had the highest prevalence of PTB, LBW, early PTB, MLBW, and VLBW, as well as PTB and LBW in urban counties and LBW in rural counties. The odds of PTB (aOR 1.38; 95% CI: 0.81, 2.35) and LBW (aOR 2.68; 95% CI: 1.32, 5.43) were also higher among non-Hispanic Black relative to non-Hispanic White women and among women who received adequate-plus prenatal care compared to inadequate prenatal care. CONCLUSIONS: Socioeconomic and health disparities created by disadvantage should be a focus of state policy to improve neonatal outcomes in the State of Georgia.

Factors Associated with Postpartum Maternal Functioning in Black Women: A Secondary Analysis.

In the United States, 29−44% of Black women experience postpartum depressive symptoms (PDS), yet few are properly identified and/or connected to mental care services. The purpose of this secondary analysis was to examine the relationship between maternal functioning and clinical variables (PDS, maternal−infant attachment), racial variable (Black racial identity types­low race salience, assimilated and miseducated, self-hating, anti-White, multiculturalist, and conflicted), and sociodemographic characteristics (relationship status, education, insurance, childbirth type). A total of 116 women living in the southern United States were included in the analysis. Multivariate analyses revealed that Black racial identity (p = 0.02), PDS (p < 0.0001), maternal−infant attachment (p < 0.0001), and educational level (p = 0.03) were independently associated with maternal functioning. This work provides new evidence regarding the role of various clinical and racial factors on Black postpartum women's adjustment to motherhood. This analysis also adds to the growing body of evidence of reliability for the BIMF in Black postpartum women.

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients.

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1, or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations, which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild-type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting because its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.

Safety and immunogenicity of early measles vaccination in children born to HIV-infected mothers in the United States: results of Pediatric AIDS Clinical Trials Group (PACTG) protocol 225.

UNLABELLED: BACKGROUND.: ACTG (Pediatric AIDS Clinical Trials Group) 225, a multicenter, randomized, open-label trial in the United States evaluated reactogenicity and immunogenicity of 2 vaccination regimens: monovalent measles vaccine (Attenuvax) at 6 months of age and measles, mumps, and rubella, live attenuated (MMRII) vaccine at 12 months of age (2D), or only MMRII at 12 months of age (1D) in human immunodeficiency virus-infected (HIV-infected) (POS) and uninfected (NEG) children in the pre-highly active antiretroviral therapy (pre-HAART) period. METHODS: Plaque-reduction neutralization (PRN) of measles-neutralizing antibody titers were evaluated at study weeks 0, 6, 26, 32, 52, and 130 (∼3 years of age). RESULTS: The 110 subjects included: 65 2DNEG; 30 1DNEG; 7 2DPOS and 8 1DPOS. Vaccinations (n=175) were associated with no adverse experiences >Grade 2 except for Grade 3 fever (n=2, 1 1DPOS and 1 1DNEG). Six weeks after Attenuvax, all 2DPOS subjects (7/7) seroresponded (PRN titers ≥120 mIU/mL) with median titers significantly exceeding 2DNEG titers (2115 vs 628 mIU/mL, respectively; P=.023). At ∼3 years of age, 67% 1DPOS (4/6) and 83% 2DPOS (4/5) subjects maintained titers ≥120 mIU/mL. Prevaccination titers ≥25 mIU/mL among 2DNEG subjects correlated inversely with the likelihood of achieving titers ≥120 mIU/mL (56% vs 90%; P=.004). CONCLUSIONS: Among HIV-infected children pre-HAART, Attenuvax at 6 months was well tolerated and immunogenic. These data support the current World Health Organization (WHO) recommendation to administer a first dose of measles vaccine at 6 months of age to HIV-infected children.

Improving management of ventilator associated tracheitis in a level IV NICU.

BACKGROUND: There are no published guidelines regarding the diagnosis and treatment of ventilator-associated tracheitis (VAT) in the neonatal intensive care unit (NICU). VAT is likely over-diagnosed and over-treated, increasing antibiotic burden and cost. LOCAL PROBLEM: Diagnosis and treatment of VAT were entirely NICU provider dependent. METHODS: Retrospective pre- and post-intervention chart reviews were performed. INTERVENTIONS: A VAT diagnosis and treatment algorithm was created for use in the care of intubated patients without tracheostomies. 3 plan-do-study-act (PDSA) cycles were used to implement change. RESULTS: Intubated patients treated for VAT with <25 PMNs on Gram stain decreased from 79% to 35% following the quality improvement (QI) initiative. Treatment of VAT with >7 days of antibiotic therapy decreased from 42% to 10%. CONCLUSION: Implementing a QI initiative to improve the diagnosis and treatment of VAT in the NICU decreased the percent of patients treated inappropriately for VAT.

Augmentation of the Esophageal Sphincter Using LINX.

Gastroesophageal reflux disease (GERD) is the retrograde flow of gastric contents into the distal esophagus and may be treated medically or surgically. Magnetic sphincter augmentation surgery using LINX has recently demonstrated comparable results to Nissen fundoplication. We aimed to evaluate preoperative patient risk factors that were associated with LINX removal rates or postoperative EGD with dilation rates (POEGDD). This is a single institution retrospective review of patients undergoing LINX between 2015 and 2021. One hundred and twelve patients were reviewed, 106 included within the study; those excluded had prior foregut surgery or device fracture. Variables including age, sex, BMI, size of device, DeMeester score, manometry, GERD Health-Related Quality of Life (GERD HRQL) questionnaires, POEGDD, and removal rates were recorded. Comparing removal and dilation status, the chi-square or Fisher's exact test and the Mann-Whitney U test were used to analyze categorical and continuous variables, respectively. A P < .05 was considered to be statistically significant. Eleven LINX devices were removed (10%); of these, 9 (81%) underwent POEGDD (P = .0023). There was no difference in DeMeester scores, size of device, or BMI in patients requiring LINX removal compared to those not removed or POEGDD rates. Patients who required LINX removal had higher GERD HRQL scores both preoperatively (median 34 vs 28) and postoperatively at all visits compared to those patients who did not undergo removal (P = .032). Manometry and DeMeester scores were not associated with LINX removal suggesting a less invasive GERD HRQL questionnaire may be a better predictor of patients who will succeed with LINX surgery.

Insurance Status in Rectal Cancer is Associated With Age at Diagnosis and May be Associated With Overall Survival.

BACKGROUND: There are approximately 44 180 new cases of rectal cancer diagnosed annually. While surgical resection remains the standard of care for definitive treatment, neoadjuvant chemoradiation therapy (NCRT) has significantly reduced recurrence rates postoperatively. NCRT is indicated for T3/T4 tumors, and relative indications include patients with T1/T2 lesions with clinically positive nodes. While this remains the standard of care, all patients may not receive equal treatment for their rectal cancer depending on various healthcare disparities. We aimed to discover how insurance status affected rectal cancer patients' time of diagnosis to treatment, age of diagnosis, and overall vitality. METHODS: A single-center retrospective chart and cancer registry review was performed for all patients diagnosed with rectal cancer of any stage between 2011 and 2018. A total of 94 rectal cancer patients were included in the analysis. Age, race, sex, insurance status, vitality, and grade were assessed. Time in days of diagnosis to the time of first treatment (neoadjuvant chemotherapy or radiation) was measured. Continuous variables were reported as means and SDs or medians and interquartile ranges and were analyzed with the unpaired t-test or Mann-Whitney U-test. Categorical variables were reported as frequencies and percentages and were analyzed with Fisher's exact test. Statistical significance was determined with a P < .05. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA). RESULTS: Total race breakdown was as follows: white (61%), African-American (30%), and other (3%). There was no statistically significant difference in diagnosis time to first treatment in the uninsured versus insured groups (P = .9). There was a statistically significant difference in the age of diagnosis with insured mean age of 60.9 years and uninsured mean age of 52.4 years (P = .0080). There was no statistically significant difference in survival between the 2 groups (P = .54). For those who went onto have surgery, there was no difference in the median number of lymph nodes harvested between the 2 groups (P = .73). CONCLUSION: Insurance status did not affect timing to treatment or survival. Uninsured patients had a younger age of diagnosis by approximately 8 years on average. Uninsured patients received the same quality surgeries as uninsured patients in regard to lymph node harvests.

The Impact of Stressful Life Events on the Incidence of Type 2 Diabetes in U.S. Adults From the Health and Retirement Study.

OBJECTIVES: We evaluated the association between cumulative stressful life events (SLE) and type of stress (lifetime vs recent) and incident diabetes (Type 2 diabetes mellitus [T2DM]) in middle-aged U.S. adults. METHODS: Data from the 2006-2014 waves of the Health and Retirement Study (HRS) were analyzed (n = 7,956). Stress-related differences in age at T2DM diagnosis were estimated using Cox proportional hazards models. RESULTS: The adjusted risk of T2DM significantly increased by 6% per unit increase in cumulative SLE (95% confidence interval [CI] = 1.03, 1.11), by 5% per unit increase in lifetime stress (95% CI = 1.00, 1.09), and by 23% per unit increase in recent stress (95% CI = 1.12, 1.36). Each level of cumulative SLE (1, 2, 3, and ≥4 events) and recent stress (1 and ≥2 events) compared to no stress was significantly associated with an increased risk of T2DM. Each level of lifetime stress compared to no stress was significantly associated with an elevated risk of T2DM except for 3 events. DISCUSSION: Cumulative SLE and type of stress were associated with incident T2DM in middle-aged adults. Reducing the direct effect of stress with management interventions may reduce the indirect effect of developing T2DM and warrants further investigation.

Raltegravir (RAL) in Neonates: Dosing, Pharmacokinetics (PK), and Safety in HIV-1-Exposed Neonates at Risk of Infection (IMPAACT P1110).

BACKGROUND: Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection. METHODS: IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of raltegravir in infants exposed to HIV-1 infection. A 2-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received 2 single doses of raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2. RESULTS: A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N = 16) and cohort 2 (N = 36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through day 7; 3 mg/kg twice daily from days 8-28 of life; and 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks. CONCLUSIONS: Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. This regimen is not recommended for use in premature infants in a new version of P1110.