Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

Initial feasibility and challenges of hyperpolarized 129 Xe MRI in neonates with bronchopulmonary dysplasia.

PURPOSE: The underlying functional and microstructural lung disease in neonates who are born preterm (bronchopulmonary dysplasia, BPD) remains poorly characterized. Moreover, there is a lack of suitable techniques to reliably assess lung function in this population. Here, we report our preliminary experience with hyperpolarized 129 Xe MRI in neonates with BPD. METHODS: Neonatal intensive care patients with established BPD were recruited (N = 9) and imaged at a corrected gestational age of median:40.7 (range:37.1, 44.4) wk using a 1.5T neonatal scanner. 2D 129 Xe ventilation and diffusion-weighted images and dissolved phase spectroscopy were acquired, alongside 1 H 3D radial UTE. 129 Xe images were acquired during a series of short apneic breath-holds (˜3 s). 1 H UTE images were acquired during tidal breathing. Ventilation defects were manually identified and qualitatively compared to lung structures on UTE. ADCs were calculated on a voxel-wise basis. The signal ratio of the 129 Xe red blood cell (RBC) and tissue membrane (M) resonances from spectroscopy was determined. RESULTS: Spiral-based 129 Xe ventilation imaging showed good image quality and sufficient sensitivity to detect mild ventilation abnormalities in patients with BPD. 129 Xe ADC values were elevated above that expected given healthy data in older children and adults (median:0.046 [range:0.041, 0.064] cm2 s-1 ); the highest value obtained from an extremely pre-term patient. 129 Xe spectroscopy revealed a low RBC/M ratio (0.14 [0.06, 0.21]). CONCLUSION: We have demonstrated initial feasibility of 129 Xe lung MRI in neonates. With further data, the technique may help guide management of infant lung diseases in the neonatal period and beyond.

Quality of life among people living with HIV aged 50 years and over in Australia: Identifying opportunities to support better ageing.

OBJECTIVES: Improved life expectancy has led to an ageing population of people living with HIV in most countries. Research on ageing among people living with HIV has predominantly focused on physical and health-related quality of life rather than multidimensional quality of life. We measured quality of life among older people living with HIV in Australia and identified opportunities to guide the development and implementation of appropriate interventions. METHODS: In a national health and wellbeing survey of Australian people living with HIV, participants aged ≥50 years completed additional questions relevant to ageing. Quality of life was measured using PozQoL, a validated multidimensional instrument assessing quality of life among people living with HIV (range 1-5). Exploratory bivariate analyses aimed to identify sociodemographic characteristics associated with quality of life. Adjusted linear regressions aimed to assess changes in PozQoL score associated with recent experiences (last 12 months) of four exposures: food insecurity, HIV-related stigma, isolation from the HIV community, and difficulties accessing non-HIV health services. RESULTS: Among 319 older people living with HIV, the mean PozQol score was 3.30 (95% confidence interval [CI] 3.20-3.39). In bivariate analyses, PozQol scores were significantly higher among participants who were older (p = 0.006), had higher educational attainment (p = 0.009), were in a relationship (p = 0.005), were employed (p = 0.005), and had a higher income (p = 0.001). In adjusted regression models, PozQoL scores were lower among participants who reported recent experiences of food insecurity (ß -0.49; 95% CI -0.74 to -0.24), stigma (ß -0.53; 95% CI -0.73 to -0.33), isolation from the HIV community (ß -0.49; 95% CI -0.70 to -0.29), and difficulties accessing non-HIV health services (ß -0.50; 95% CI -0.71 to -0.30). CONCLUSIONS: Overall, older people living with HIV in this study had a moderate quality of life. Our findings suggest that HIV services should integrate programmes to support economic security and foster connections within the HIV community and across health services.

Selective Carbon-Carbon Bond Cleavage of Cyclopropanols.

The carbon-carbon (C-C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, ß-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C-C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C-C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor-acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

Metal(loid) accumulation in the leaves of the grey mangrove (Avicennia marina): Assessment of robust sampling requirements and potential use as a bioindicator.

This study assessed the appropriate sampling design required for quantifying variability in metal accumulation in the leaf tissues of A. marina, a dominant mangrove inhabiting Australian estuaries, by applying a hierarchical nested sampling design to sample mangroves at various levels of biological and spatial hierarchies (leaf, branch, tree, site). It was revealed that most variation in metal accumulation occurred among trees and branches, with insignificant variation between sites and among leaves. We also examined the accumulation of metal (loid)s in the leaf tissues collected from six locations across the Georges River estuary in southern Sydney, which differ in metal contamination history. Prospect Creek and Salt Pan Creek were the most contaminated locations, which exceeded sediment quality guideline values for Cu (66.71 ± 2.18 µg/g), Zn (317.14 ± 46.14 µg/g) and Pb (81.02 ± 2.79 µg/g). All metal(loid) concentrations in leaf tissues were much lower than their concentrations in sediment, but essential metals exhibited greater mobility. Out of 10 metal(loid)s, Mn, Co and Pb in leaves showed linear relationships (R2 = 0.28-0.47) with sediment, indicating that mangrove leaves may be used as a bioindicator of environmental loads for these metals.

The measurement of compassionate leadership: Adaptation and Spanish validation of the compassionate leadership self-reported scale.

BACKGROUND: A culture of shared leadership is widespread among palliative care teams based on a commitment to valuing and including all people equally. As compassion is a core value for end-of-life care work, compassionate leadership may be the best way to lead in palliative care. AIMS: The aims of this study were twofold: (1) to adapt and validate the Compassionate Leadership Self-reported Scale in a sample of palliative care professionals; and (2) to study the relation between compassionate leadership and associated concepts of self-compassion, awareness and self-care. METHODS: A cross-sectional survey of 296 Spanish end-of-life care professionals was conducted. Analyses included descriptive statistics, a confirmatory factor analysis (CFA) with four-correlated factors, reliability estimates and a structural model. RESULTS: Results suggested there were medium to high levels of compassionate leadership in the sample. The CFA showed an adequate overall fit: χ2 (98) = 277.595 (p < 0.001); CFI = 0.986; SRMR = 0.047; RMSEA = 0.088 [0.076, 0.100]. Reliability estimates for four subscales of compassionate leadership (attending, understanding, empathising and helping) were also adequate, ranging from 0.72 to 0.96. Finally, the structural model predicting compassionate leadership suggested that the dimensions of attending and understanding were most highly related to positive self-compassion and awareness; empathising, to self-care and awareness; and helping, to positive self-compassion and self-care. CONCLUSION: The Compassionate Leadership Scale has adequate psychometric properties when used to assess compassionate leadership in the context of end-of-life care. Our results indicate that self-compassion, awareness and self-care are important correlates of such compassionate leadership.

Gene therapy for Fabry disease: Progress, challenges, and outlooks on gene-editing.

Gene therapy is the delivery of a therapeutic gene for endogenous cellular expression with the goal of rescuing a disease phenotype. It has been used to treat an increasing number of human diseases with many strategies proving safe and efficacious in clinical trials. Gene delivery may be viral or non-viral, performed in vivo or ex vivo, and relies on gene integration or transient expression; all of these techniques have been applied to the treatment of Fabry disease. Fabry disease is a genetic disorder of the α-galactosidase A gene, GLA, that causes an accumulation of glycosphingolipids in cells leading to cardiac, renal and cerebrovascular damage and eventually death. Currently, there are no curative treatments available, and the therapies that are used have significant drawbacks. These treatment concerns have led to the advent of gene therapies for Fabry disease. The first Fabry patients to receive gene therapy were treated with recombinant lentivirus targeting their hematopoietic stem/progenitor cells. Adeno-associated virus treatments have also begun. Alternatively, the field of gene-editing is a new and rapidly growing field. Gene-editing has been used to repair disease-causing mutations or insert genes into cellular DNA. These techniques have the potential to be applied to the treatment of Fabry disease provided the concerns of gene-editing technology, such as safety and efficiency, were addressed. This review focuses on the current state of gene therapy as it is being developed for Fabry disease, including progresses and challenges as well as an overview of gene-editing and how it may be applied to correct Fabry disease-causing mutations in the future.

Value of 10-2 Visual Field Testing in Glaucoma Patients with Early 24-2 Visual Field Loss.

PURPOSE: To determine whether the 10-2 test of the Humphrey Field Analyzer detected a higher proportion of abnormal visual fields compared with the 24-2 test in the central 10° of patients with early glaucomatous visual field damage. DESIGN: Prospective observational study. PARTICIPANTS: Patients with open-angle glaucoma and healthy control participants. METHODS: All participants underwent a 24-2 and 10-2 test. Only the 12 central test locations of the 24-2 test were included to analyze equivalent visual field areas. The performance of the 2 tests was compared across 4 pointwise criteria: total deviation (TD) and pattern deviation (PD) analyses at the 5% and 2% levels. Analyses also were conducted for 2 pairs of follow-up tests, each performed 4 months apart. MAIN OUTCOME MEASURES: (1) Area under the receiver operating characteristic curve (AUC), (2) sensitivity at identically matched specificity for the 4 criteria, (3) overlap (entire field and by quadrant) of abnormal visual fields with both tests, and (4) repeatability of the findings in 2 subsequent follow-up tests. RESULTS: One eye each of 97 glaucoma patients (median mean deviation, -2.31 dB) and 65 control participants were included in the study. The AUCs for the 24-2 and 10-2 tests were not significantly different for any of the 4 criteria and ranged from 0.88 to 0.93 and from 0.91 to 0.94, respectively. At matched specificity, the sensitivity of the 24-2 test was significantly higher for all criteria except for PD analysis at 5%. In patients with an abnormal field with either test, the overlap varied from 60% to 86% depending on the criterion, whereas by quadrant, concordance ranged from 70% to 87%. Over the follow-up, the repeatability of test results (both 24-2 and 10-2 abnormal, either abnormal, or both normal) was achieved in 55% to 70% of patients. CONCLUSIONS: In this study of glaucoma patients with early damage with the 24-2 test, there was little evidence that adding the 10-2 test revealed additional undetected defects in the central visual field. It may be more prudent to reserve 10-2 testing for following up selected patients with higher risk of central visual field progression.

Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

OBJECTIVES: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs. METHODS: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs. RESULTS: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients. CONCLUSIONS: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.

Changes in neurocognitive assessment scores after initiating dolutegravir- versus elvitegravir-based antiretroviral therapy.

This prospective cohort study enrolled people living with HIV initiating antiretroviral therapy (ART) containing the integrase inhibitors, dolutegravir (DTG) or elvitegravir (EVG) and administered the Montreal Cognitive Assessment (MoCA) at baseline and again after approximately six months to compare changes in MoCA scores. The proportion of patients found to have cognitive impairment, as indicated by a MoCA score <26/30, on each agent were also compared and comparisons were made between changes in each domain assessed by the MoCA (visuospatial/executive, naming, attention, language, abstraction, delayed recall, and orientation). Thirty-five evaluable participants were enrolled, 18 on DTG and 17 on EVG. The median [interquartile range(IQR)] age was 44 (32 to 54) years, 63% were male, 57% were African American. The median (IQR) MoCA score at baseline was 25 (23 to 27) with no difference between groups (p=0.249). The median (IQR) change in MoCA score was 0 (-1 to 2) for DTG and 1 (0 to 3) for EVG (p = 0.183). Of those on DTG, 8 (44%) had MoCA scores <26 on follow-up compared to 11 (65%) on EVG (p = 0.229). There were no significant differences in changes in any of the individual MoCA domains.

Noise Exposure Alters Glutamatergic and GABAergic Synaptic Connectivity in the Hippocampus and Its Relevance to Tinnitus.

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience.

Evaluation of vitreous degeneration as a potential risk factor for retinal detachment after phacoemulsification in dogs.

PURPOSE: To evaluate vitreous degeneration as a potential risk factor for retinal detachment in dogs after phacoemulsification. METHODS: Medical records for dogs with preoperative ocular ultrasound and phacoemulsification between September 28, 2006, and August 2, 2016, were reviewed. Ultrasound images were reviewed by two observers independently, and vitreous echogenicity was graded using an established scale. The following factors were compared between eyes with and without retinal detachment: signalment, operated eye, cataract stage at the time of surgery, and presence or absence of the following: lens-induced uveitis (LIU), glaucoma, anterior vitreous presentation, lens subluxation, history of prophylactic retinopexy, diabetes mellitus, operating surgeon, concurrent prophylactic retinopexy, posterior capsular tear, phacoemulsification duration, use of automated anterior vitrectomy, placement of an artificial intraocular lens, and intraocular lens type (polymethyl methacrylate or acrylic foldable). Total follow-up time was recorded. Presence and time from surgery to onset of complications were recorded. Retinal detachment was diagnosed based on observation via indirect ophthalmoscopy or ocular ultrasound. RESULTS: Evaluation for association between vitreous degeneration and retinal detachment included 290 eyes of 180 dogs. There was no statistically significant correlation between vitreous degeneration and postoperative retinal detachment. Retinal detachment was observed in 17 of 290 eyes (5.9%). Vitreous degeneration was marked as present by at least one observer in 189 of 290 eyes (65%). CONCLUSIONS: Ultrasonically identifiable vitreous degeneration does not correlate with increased risk of retinal detachment following phacoemulsification.

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease.

Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids (mainly globotriaosylceramide, Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to Fabry cardiovascular diseases. We hypothesized that decreased tetrahydrobiopterin (BH4) plays a role in the pathogenesis of Fabry disease. We found that BH4 was decreased in the heart and kidney but not in the liver and aorta of Fabry mice. BH4 was also decreased in the plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels were inversely correlated with BH4 levels in animal tissues and cultured patient cells. To investigate the role of BH4 deficiency in disease phenotypes, 12-month-old Fabry mice were treated with gene transfer-mediated ERT or substrate reduction therapy (SRT) for 6 months. In the Fabry mice receiving SRT but not ERT, BH4 deficiency was restored, concomitant with ameliorated cardiac and renal hypertrophy. Additionally, glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels were closely correlated with glutathione levels and inversely correlated with cardiac and kidney weight. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to the pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease.

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

BACKGROUND: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (ß: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Oral delivery of the anti-tumor necrosis factor α domain antibody, V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys.

OBJECTIVE: V565 is a novel oral anti-tumor necrosis factor (TNF)-α domain antibody being developed for topical treatment of inflammatory bowel disease (IBD) patients. Protein engineering rendered the molecule resistant to intestinal proteases. Here we investigate the formulation of V565 required to provide gastro-protection and enable optimal delivery to the lower intestinal tract in monkeys. METHODS: Enteric-coated V565 mini-tablets were prepared and dissolution characteristics tested in vitro. Oral dosing of monkeys with enteric-coated mini-tablets containing V565 and methylene blue dye enabled in vivo localization of mini-tablet dissolution. V565 distribution in luminal contents and feces was measured by enzyme-linked immunosorbent assay (ELISA). To mimic transit across the damaged intestinal epithelium seen in IBD patients an intravenous (i.v.) bolus of V565 was given to monkeys and pharmacokinetic parameters of V565 measured in serum and urine by ELISA. RESULTS: Enteric-coated mini-tablets resisted dissolution in 0.1 M HCl, before dissolving in a sustained release fashion at neutral pH. In orally dosed monkeys methylene blue intestinal staining indicated the jejunum and ileum as sites for mini-tablet dissolution. Measurements of V565 in monkey feces confirmed V565 survival through the intestinal tract. Systemic exposure after oral dosing was very low consistent with limited V565 mucosal penetration in healthy monkeys. The rapid clearance of V565 after i.v. dosing was consistent with renal excretion as the primary route for elimination of any V565 reaching the circulation. CONCLUSIONS: These results suggest that mini-tablets with a 24% Eudragit enteric coating are suitable for targeted release of orally delivered V565 in the intestine for topical treatment of IBD.

Association of HIV Preexposure Prophylaxis With Incidence of Sexually Transmitted Infections Among Individuals at High Risk of HIV Infection.

Importance: Emerging evidence suggests that risk of bacterial sexually transmitted infections (STIs) increases among gay and bisexual men following initiation of HIV preexposure prophylaxis (PrEP). Objective: To describe STI incidence and behavioral risk factors among a cohort of predominantly gay and bisexual men who use PrEP, and to explore changes in STI incidence following PrEP commencement. Design, Setting, and Participants: The Pre-exposure Prophylaxis Expanded (PrEPX) Study, a multisite, open-label intervention study, was nested within the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) clinic network. A total of 4275 participants were enrolled (July 26, 2016-April 1, 2018) in Victoria, Australia. Of these, 2981 enrolled at 5 ACCESS clinics (3 primary care, 1 sexual health, and 1 community-based HIV rapid testing service), had at least 1 follow-up visit, and were monitored until April 30, 2018. Exposures: Upon enrollment, participants received daily oral tenofovir disoproxil fumurate and emtricitabine for HIV PrEP, quarterly HIV and STI testing, and clinical monitoring. Main Outcomes and Measures: The primary outcome was incidence of chlamydia, gonorrhea, or syphilis. Incidence rates and hazard ratios describing behavioral risk factors of STI diagnosis were calculated. Incidence rate ratios (IRRs), adjusted for change in testing frequency, described changes in STI incidence from 1-year preenrollment to study follow-up among participants with preenrollment testing data (n = 1378). Results: Among the 2981 individuals (median age, 34 years [interquartile range, 28-42]), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person-years), 2928 STIs were diagnosed among 1427 (48%) participants (1434 chlamydia, 1242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person-years, with 736 participants (25%) accounting for 2237 (76%) of all STIs. Among 2058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person-years prior to enrollment to 98.4 per 100 person-years during follow-up (IRR, 1.41 [95% CI, 1.29-1.56]). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 [95% CI, 1.02-1.23]) and for chlamydia (adjusted IRR, 1.17 [95% CI, 1.04-1.33]). Conclusions and Relevance: Among gay and bisexual men using PrEP, STIs were highly concentrated among a subset, and receipt of PrEP after study enrollment was associated with an increased incidence of STIs compared with preenrollment. These findings highlight the importance of frequent STI testing among gay and bisexual men using PrEP.

Synthesis of Nitrile-Bearing Quaternary Centers by an Equilibrium-Driven Transnitrilation and Anion-Relay Strategy.

The efficient preparation of nitrile-containing building blocks is of interest due to their utility as synthetic intermediates and their prevalence in pharmaceuticals. As a result, significant efforts have been made to develop methods to access these motifs which rely on safer and non-toxic sources of CN. Herein, we report that 2-methyl-2-phenylpropanenitrile is an efficient, non-toxic, electrophilic CN source for the synthesis of nitrile-bearing quaternary centers by a thermodynamic transnitrilation and anion-relay strategy. This one-pot process leads to nitrile products resulting from the gem-difunctionalization of alkyl lithium reagents.