Perspectives on long-acting formulations of pre-exposure prophylaxis (PrEP) among men who have sex with men who are non-adherent to daily oral PrEP in the United States.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) persistence among men who have sex with men (MSM) in real world clinical settings for HIV prevention is suboptimal. New longer-acting formulations of PrEP are becoming available, including injectables, subdermal implants, and other oral medications. These longer-acting formulations have the potential to improve retention among those who have challenges remaining adherent to daily oral PrEP. METHODS: We interviewed 49 MSM who had initiated but discontinued oral PrEP at three diverse clinics across the United States. We examined participants' perspectives about long-acting PrEP formulations and how long-acting options could affect PrEP use using thematic analysis. RESULTS: Participants were not very knowledgeable about long-acting formulations of PrEP but were open to learning about them and considering use. Participants were concerned about safety and efficacy of products given that they were still newer and/or in development. Finally, participants had clear preferences for oral pills, injectables, and then subdermal implants and were most interested in options that reduced the number of visits to the clinic. CONCLUSION: Long-acting formulations of PrEP are acceptable to MSM with suboptimal PrEP persistence and have the potential to improve PrEP persistence. However, many felt they needed more information on safety, efficacy, and use to consider these options. As these long-acting formulations are implemented, public health campaigns and clinical interventions to encourage may maximize uptake particularly among those who are not currently adherent to daily oral PrEP.

Facilitators for retaining men who have sex with men in pre-exposure prophylaxis care in real world clinic settings within the United States.

BACKGROUND: Pre-exposure prophylaxis (PrEP) can significantly reduce HIV acquisition especially among communities with high HIV prevalence, including men who have sex with men (MSM). Much research has been finding suboptimal PrEP persistence; however, few studies examine factors that enhance PrEP persistence in real-world settings. METHODS: We interviewed 33 patients who identified as MSM at three different PrEP clinics in three regions of the U.S. (Northeast, South, Midwest). Participants were eligible if they took PrEP and had been retained in care for a minimum of 6 months. Interviews explored social, structural, clinic-level and behavioral factors that influencing PrEP persistence. RESULTS: Through thematic analysis we identified the following factors as promoting PrEP persistence: (1) navigation to reduce out-of-pocket costs of PrEP (structural), (2) social norms that support PrEP use (social), (3) access to LGBTQ + affirming medical providers (clinical), (4) medication as part of a daily routine (behavioral), and (5) facilitation of sexual health agency (belief). DISCUSSION: In this sample, persistence in PrEP care was associated with structural and social supports as well as a high level of perceived internal control over protecting their health by taking PrEP. Patients might benefit from increased access, LGBTQ + affirming medical providers, and communications that emphasize PrEP can promote sexual health.

Age bias in survey sampling and implications for estimating HIV prevalence in men who have sex with men: insights from mathematical modelling.

Respondent-driven sampling (RDS) is widely used to estimate HIV prevalence in men who have sex with men (MSM). Mathematical models that are calibrated to these data may be compromised if they fail to account for selection biases in RDS surveys. To quantify the potential extent of this bias, an agent-based model of HIV in South Africa was calibrated to HIV prevalence and sexual behaviour data from South African studies of MSM, first reweighting the modelled MSM population to match the younger age profile of the RDS surveys (age-adjusted analysis) and then without reweighting (unadjusted analysis). The model estimated a median HIV prevalence in South African MSM in 2015 of 34.6% (inter-quartile range (IQR): 31.4-37.2%) in the age-adjusted analysis, compared with 26.1% (IQR: 24.1-28.4%) in the unadjusted analysis. The median lifetime risk of acquiring HIV in exclusively homosexual men was 88% (IQR: 82-92%) in the age-adjusted analysis, compared with 76% (IQR: 64-85%) in the unadjusted analysis. These results suggest that RDS studies may under-estimate the exceptionally high HIV prevalence rates in South African MSM because of over-sampling of younger MSM. Mathematical models that are calibrated to these data need to control for likely over-sampling of younger MSM.

Differential Expression of Glucocorticoid Receptor Noncoding RNA Repressor Gas5 in Autoimmune and Inflammatory Diseases.

Glucocorticoids have strong regulatory actions on the immune system and act as potent therapeutic compounds for autoimmune and inflammatory diseases. We previously reported that the long noncoding RNA growth arrest-specific 5 (Gas5), which accumulates inside the cells in response to cellular starvation/growth arrest, functions as a potent repressor of the glucocorticoid receptor (GR) through its RNA "glucocorticoid response element (GRE)". To evaluate potential roles of Gas5 in immune-related disorders, we examined Gas5 RNA levels in various autoimmune, inflammatory, and infectious diseases using the microarray data available in the Gene Expression Omnibus. We found that Gas5 levels were altered in whole blood or leukocytes of the patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and sarcoidosis. Gas5 levels were also altered in infectious diseases, such as by the human immunodeficiency virus type-1 and influenza virus, and bacterial sepsis. In our experimental analysis using mice, Gas5 levels were kept at high basal levels and did not respond to fasting in immune organs, such as spleen and thymus, while its levels in metabolic organs, including liver, fat, and skeletal muscles, were low at baseline and were highly elevated upon this treatment, possibly through suppression of the mTOR pathway. These results suggest that Gas5 plays a role in the regulation of immune functions and pathogenesis/pathophysiology of autoimmune, inflammatory, and infectious diseases in part through modulation of the GR transcriptional activity via its decoy RNA "GRE". Changes in the Gas5 levels may also influence disease response to immunosuppressive glucocorticoid therapy.

Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity.

Leishmaniaparasites are a major public health problem worldwide. Effective treatment of leishmaniasis is hampered by the high incidence of adverse effects to traditional drug therapy and the emergence of resistance to current therapeutics. A vaccine is currently not available. Host defense peptides have been investigated as novel therapeutic agents against a wide range of pathogens. Here we demonstrate that the antimicrobial peptide LL-37 and the three synthetic peptides E6, L-1018, and RI-1018 exhibit leishmanicidal activity against promastigotes and intramacrophage amastigotes ofLeishmania donovaniandLeishmania major We also report that theLeishmaniaprotease/virulence factor GP63 confers protection toLeishmaniafrom the cytolytic properties of alll-form peptides (E6, L-1018, and LL-37) but not thed-form peptide RI-1018. The results suggest that RI-1018, E6, and LL-37 are promising peptides to develop further into components for antileishmanial therapy.

Entrapping homogeneous catalysts by sol-gel methods: the bottom-up synthesis of catalysts that recycle and cascade.

Homogeneous catalysts entrapped in silica matrices, including ionic liquid containing 'ionogels', exhibit high selectivity, unexpected activity and excellent recyclability.

Bovine lactoferrin and lactoferricin interfere with intracellular trafficking of Herpes simplex virus-1.

Although both lactoferrin (Lf), a component of the innate immune system of living organisms, and its N-terminal pepsin cleavage product lactoferricin (Lfcin) have anti-herpes activity, the precise mechanisms by which Lf and Lfcin bring about inhibition of herpes infections are not fully understood. In the present study, experiments were carried out to characterize the activity of bovine Lf and Lfcin (BLf and BLfcin) against the Herpes simplex virus-1 (HSV-1). HSV-1 cellular uptake and intracellular trafficking were studied by immunofluorescence microscopy. In comparison to the untreated infected control cells, both the BLf- and BLfcin-treated cells showed a significant reduction in HSV-1 cellular uptake. The few virus particles that were internalized appeared to have a delayed intracellular trafficking. Thus, in addition to their interference with the uptake of the virus into host cells, Lf and Lfcin also exert their antiviral effect intracellularly.

Interactive effects of environmental stress and inbreeding on reproductive traits in a wild bird population.

1. Conservation biologists are concerned about the interactive effects of environmental stress and inbreeding because such interactions could affect the dynamics and extinction risk of small and isolated populations, but few studies have tested for these interactions in nature. 2. We used data from the long-term population study of song sparrows Melospiza melodia on Mandarte Island to examine the joint effects of inbreeding and environmental stress on four fitness traits that are known to be affected by the inbreeding level of adult birds: hatching success, laying date, male mating success and fledgling survival. 3. We found that inbreeding depression interacted with environmental stress to reduce hatching success in the nests of inbred females during periods of rain. 4. For laying date, we found equivocal support for an interaction between parental inbreeding and environmental stress. In this case, however, inbred females experienced less inbreeding depression in more stressful, cooler years. 5. For two other traits, we found no evidence that the strength of inbreeding depression varied with environmental stress. First, mated males fathered fewer nests per season if inbred or if the ratio of males to females in the population was high, but inbreeding depression did not depend on sex ratio. Second, fledglings survived poorly during rainy periods and if their father was inbred, but the effects of paternal inbreeding and rain did not interact. 6. Thus, even for a single species, interactions between the inbreeding level and environmental stress may not occur in all traits affected by inbreeding depression, and interactions that do occur will not always act synergistically to further decrease fitness.

Overexpression of PrfA leads to growth inhibition of Listeria monocytogenes in glucose-containing culture media by interfering with glucose uptake.

Listeria monocytogenes strains expressing high levels of the virulence regulator PrfA (mutant PrfA* or wild-type PrfA) show strong growth inhibition in minimal media when they are supplemented with glucose but not when they are supplemented with glucose-6-phosphate compared to the growth of isogenic strains expressing low levels of PrfA. A significantly reduced rate of glucose uptake was observed in a PrfA*-overexpressing strain growing in LB supplemented with glucose. Comparative transcriptome analyses were performed with RNA isolated from a prfA mutant and an isogenic strain carrying multiple copies of prfA or prfA* on a plasmid. These analyses revealed that in addition to high transcriptional up-regulation of the known PrfA-regulated virulence genes (group I), there was less pronounced up-regulation of the expression of several phage and metabolic genes (group II) and there was strong down-regulation of several genes involved mainly in carbon and nitrogen metabolism in the PrfA*-overexpressing strain (group III). Among the latter genes are the nrgAB, gltAB, and glnRA operons (involved in nitrogen metabolism), the ilvB operon (involved in biosynthesis of the branched-chain amino acids), and genes for some ABC transporters. Most of the down-regulated genes have been shown previously to belong to a class of genes in Bacillus subtilis whose expression is negatively affected by impaired glucose uptake. Our results lead to the conclusion that excess PrfA (or PrfA*) interferes with a component(s) essential for phosphotransferase system-mediated glucose transport.

Effects of halothane sensitivity on mobility status and blood metabolites of HAL-1843-normal pigs after rigorous handling.

The objective of this study was to determine if HAL-1843-normal pigs that respond abnormally to halothane anesthesia were more likely to become nonambulatory (NA) when subjected to rigorous handling than pigs that exhibit a normal response to halothane. After a 1,100-km transport, pigs exhibiting low (HS-L; n = 33), intermediate (HS-I; n = 10), and high (HS-H; n = 47) sensitivity to halothane were moved through a 36.6-m long aisle that was 2.1 m wide at each end and 0.6 m wide in the middle 18.3 m. Ten groups of 8 pigs were briskly moved down the aisle and back 4 times, receiving a minimum of 1 electrical prod per pass (8 prods/pig). Before testing, rectal temperature was measured, open-mouth breathing and skin discoloration were visually evaluated, and a blood sample was collected from each pig. After the test, the pigs were returned to their pens, and the same measurements were taken immediately posttest and 1 h posttest (no blood at 1 h posttest). Pigs that were HS-H were more prone to becoming NA compared with HS-L pigs (P < 0.02). Regardless of halothane status, a greater number of pigs exhibited open-mouth breathing and skin discolorations immediately posttest than at the pretest or 1 h posttest times (P < 0.05). No differences were observed in blood metabolites between the different halothane sensitivity categories. However, pigs that became NA had elevated blood levels of creatine phosphokinase, lactate, glycerol, nonesterified fatty acids, ammonia, and urea nitrogen before testing (P < 0.05). Collectively, these data suggest HS-H pigs are more susceptible to becoming NA than HS-L. The elevated pretest blood metabolites of NA pigs suggest that they were in a hypermetabolic state that predisposed them to becoming NA.

CT-angiography for the detection of a lower gastrointestinal bleeding source.

The evaluation of lower gastrointestinal bleeding (LGIB) often involves the collaborative efforts of the gastroenterologist, radiologist, and surgeon. Efforts to localize the acute LGIB have traditionally involved colonoscopy, technetium-labeled red blood cell (RBC) scintigraphy, angiography, or a combination of these modalities. The sensitivity of each method of diagnosis is limited, with the most common cause of a negative study the spontaneous cessation of hemorrhage. Other technical factors include vasospasm, lack of adequate contrast volume or exposure time, a venous bleeding source, and a large surface bleeding area. We report the use of multidetector computed tomography (MDCT), or CT-angiography (CT-A), in the initial evaluation of LGIB, and speculate on the incorporation of this technique into a diagnostic algorithm to treat LGIB. MDCT may offer a very sensitive means to evaluate the source of acute LGIB, while avoiding some of the morbidity and intense resource use of contrast angiography, and may provide unique morphologic information regarding the type of pathology. Screening with the more rapid and available MDCT, followed by either directed therapeutic angiography or surgical management, may represent a reasonable algorithm for the early evaluation and management of acute LGIB in which an active bleeding source is strongly suspected.

Feeding 2-hydroxy-4-(methylthio)-butanoic acid to periparturient dairy cows improves milk production but not hepatic metabolism.

Forty-eight Holstein cows, entering second or later lactation, were utilized to determine the effects of 2-hydroxy-4-(methylthio)-butanoic acid (HMB) on milk production, hepatic lipid metabolism, and gluconeogenesis during the periparturient period. Cows were fed one of 3 diets as TMR starting 21 d before expected calving. These diets contained 0 (the basal diet), 0.09 (+HMB), or 0.18 (++HMB)% HMB. From parturition to 84 DIM, cows were fed diets that contained 0, 0.13, or 0.20% HMB. Prepartum and postpartum dry matter intakes were similar among cows fed the basal diet, +HMB and ++HMB. There was a quadratic effect on milk yield such that cows fed +HMB had the greatest milk yield; yields of milk by cows fed the basal diet and ++HMB were similar. This led to trends for increased yields of 3.5% fat-corrected milk and total solids when cows were fed +HMB. Percentages of fat, protein, and total solids in milk were not affected by treatment. Despite differences in milk yield, calculated energy balance was not affected by treatment. Plasma concentrations of NEFA, beta-hydroxybutyrate, and glucose were not different among treatments. Liver triglyceride content was similar among treatments on d 1 postpartum and was increased for cows consuming +HMB on d 21 postpartum compared with the other dietary treatments. Capacities for metabolism of [1-14C]palmitate by liver slices in vitro were not affected by treatment; however, conversion of [1-14C]propionate to CO2 and glucose decreased as the amount of HMB consumed by cows increased on d 21 postpartum. Cows consuming +HMB had greater days to first ovulation compared with cows consuming the basal diet and ++HMB as measured by plasma progesterone concentrations. These data suggest that adding HMB to low Met diets to achieve a predicted Met supply of approximately 2.3% of metabolizable protein supply is beneficial for increasing milk production but does not appear to benefit hepatic energy metabolism during early lactation.

Peripheral blood and BM CD34+ CD38- cells show better resistance to cryopreservation than CD34+ CD38+ cells in autologous stem cell transplantation.

BACKGROUND: We and others have shown a critical role for CD34+ CD38- cells in hematopoietic recovery after autologous stem cell transplantation (ASCT), in particular for platelet reconstitution. Thus a routine assessment of CD34+ CD38- cells in freezing-thawing procedures for autografting could represent an important tool for predicting poor engraftment. METHODS: To compare the impact of cryopreservation on CD34+ CD38+ and CD34+ CD38- hematopoietic stem cell subsets, 193 autograft products collected in 84 patients with malignancies were assessed before controlled-rate cryopreservation in 10% DMSO and after thawing for autografting. RESULTS: Cell counts after thawing were significantly different from the pre-freezing counts for total CD34+ (P<0.0001) and CD34+ CD38+ (P<0.0001) cells, but not for CD34+ CD38- cells (P=0.252). Median losses for CD34+, CD34+ CD38+ and CD34+ CD38- cells were, respectively, 11.8%, 11.4% and 0.0%. The magnitude of fresh/post-thawing percentage cell variation was significantly different when comparing between the CD34+ CD38+ and CD34+ CD38- cell subsets (P<0.001). Moreover, CD34+ CD38- cells exhibited recovery values > or =100% in 85/160 graft products, compared with 51/193 in CD34+ CD38+ cells (P<0.0001). Also, recovery values > or =90% were significantly better in the CD34+ CD38- (98/160 grafts) than in the CD34+ CD38+ subsets (89/193 grafts) (P<0.01). DISCUSSION: In this work we have demonstrated that CD34+ cells that do not express the CD38 Ag show a significantly better resistance to cryopreservation. This could represent another example of the particular ability of less committed progenitor cells to overcome environmental injuries. Moreover, we consider routine assessment of CD34+ CD38- cells before freezing as clinically relevant, but post-thawing controls may be avoided because of their good resistance to freezing.

[Complications after harvesting of autologous bone from the ventral and dorsal iliac crest - a prospective, controlled study]. / Komplikationen nach Entnahme autologen Knochens aus dem ventralen und dorsalen Beckenkamm - eine prospektive, kontrollierte Studie.

INTRODUCTION: In a prospective, controlled study, donor site morbidity after bone graft harvesting from the anterior and posterior iliac crest was documented. METHODS: In 113 patients, monocortical to tricortical bone grafts were taken from the anterior (n = 73) or dorsal (n = 40) iliac crest. Bone graft size (0.4 - 43 cm 3, median 9.7 cm 3), Operation time (12 - 65 minutes, median 28 minutes), and postoperative donor site were documented. RESULTS: Donor site morbidity was higher after harvesting from the ventral than from the dorsal iliac crest: total morbidity 48 vs. 32.5 %, large haematomas 9.6 vs. 7.5 %, moderate haematomas 34.3 vs. 15 %, wound dehiscence 2.7 vs. 0 %. One revision operation was necessary because of a large haematoma at the ventral crest. After harvesting from the ventral iliac crest, there was one fracture ofthe iliac wing and one avulsion fracture of the iliac crest. There were no infections, no injuries of arteries or of the lateral femoral cutaneous nerve and no hemiation. After harvesting from the dorsal iliac crest, there were no major complications. CONCLUSION: Bone graft harvesting from the posterior iliac crest should be preferred over harvesting from the anterior iliac crest beeause of the substantially reduced donor site morbidity. Harvesting from the ventral iliac crest should have a clear indication, synthetic bone substitutes should be taken into consideration.

Insulin restores GH responsiveness during lactation-induced negative energy balance in dairy cattle: effects on expression of IGF-I and GH receptor 1A.

Early lactation in dairy cattle is a period of severe negative energy balance (NEB) characterized by reduced blood glucose and insulin concentrations and elevated blood GH concentrations. The liver is refractory to GH during NEB and this uncoupling of the GH-IGF axis results in diminished plasma concentrations of IGF-I. Our objectives were to examine the effects of insulin administration during the immediate postpartum period on plasma IGF-I and GH concentrations and to examine the hepatic expression of total GH receptors (all GH receptor transcripts), GH receptor 1A (GHR 1A) and IGF-I. In addition, we examined adipose tissue for total GH receptor and IGF-I mRNA levels to establish the effects of chronic hyperinsulinemia on an insulin-responsive peripheral tissue. Holstein cows (n=14) were subjected to either a hyperinsulinemic-euglycemic clamp (insulin; INS) or saline infusion (control; CTL) for 96 h starting on day 10 postpartum. Insulin was infused i.v. (1 micro g/kg body weight per h), blood samples were collected hourly, and euglycemia was maintained by infusion of glucose. Insulin concentrations during the infusions were increased 8-fold in INS compared with CTL cows (2.33+/-0.14 vs 0.27+/-0.14 ng/ml (S.E.M.); P<0.001) while blood glucose concentrations were not different between treatments (45.3+/-2.2 vs 42.5+/-2.2 mg/dl; P>0.1). Plasma IGF-I increased continuously during the insulin infusion, and reached the highest concentrations at the end of the clamp, being almost 4-fold higher in INS compared with CTL cows (117+/-4 vs 30+/-4 ng/ml; P<0.001). Hepatic expression of GHR 1A and IGF-I mRNA was low in CTL cows, but was increased 3.6-fold (P<0.05) and 6.3-fold (P<0.001) respectively in INS cows. By contrast, in adipose tissue the changes in gene expression in response to insulin were reversed with decreases in both total GHR and IGF-I mRNA. The expressions of GHR 1A and IGF-I mRNA in liver tissue were correlated in INS (r=0.86; P<0.05), but not CTL cows (r=0.43; P>0.1). Insulin appears to be a key metabolic signal in coupling the GH-IGF axis, thus orchestrating a marked elevation in circulating IGF-I concentrations.

In vitro effects of 2-methoxyestradiol on canine tumour cells.

The in vitro antiproliferative, apoptotic and cell-cycle effects of 2-methoxyestradiol (2ME(2)), an endogenous oestrogen metabolite, were investigated using a variety of canine tumour cell lines. The cells were cultured under standard conditions and incubated with varying concentrations of 2ME(2). Inhibition of tumour cell proliferation was evaluated using a tetrazolium-based colorimetric assay. DNA content analysis was performed using propidium iodide staining and flow cytometry. Cytologic analysis with Leukostat staining solution and Hoechst 33342 staining and Annexin V-fluorescein isothiocyanate (FITC) fluorescence were used to quantify cell-cycle distribution and apoptosis induction. Tumour cell proliferation was inhibited by 50% at concentrations of 2ME(2) ranging from 0.88 to 7.67 microM, depending on the cell line tested. Profound G(2)/M phase arrest, an increase in binucleate cells and induction of apoptosis were observed in all cell lines tested, in a dose-dependent manner. Based on these results, this compound has potential as an agent for the treatment of canine cancer and warrants further investigation. The canine lymphoma cell line, 1771, was inhibited at concentrations that may be achievable in vivo.

Colorectal adenomas and diet: a case-control study. Colorectal Adenoma Study Group.

It has been postulated that high intakes of animal fat and protein and low intakes of fiber, calcium, and antioxidants increase the risk of colorectal cancer. Whether specific types of protein such as that from red meat are important, and whether vegetables might be key protective factors will also be considered in this study. Dietary intake over the past year was studied according to the diet history method by means of a case-control study in 184 cases and matched controls. After adjustment for energy, relative weight, and social class, no associations were found for fat or protein in comparison with either control group. Unexpectedly, carbohydrate intake was inversely related with adenoma risk, the RR being 0.29 (0.10-0.81) for quintile 5 versus 1 in comparison with hospital controls. None of the antioxidants showed a significant protective effect except beta-carotene intake in comparison with hospital controls, the RR being 0.24 (0.11-0.50) for the highest versus the lowest quintile. There was, however, a statistically significant positive association between adenomas and meat consumption with the RR for the highest versus the lowest quintile. There was, however, a statistically significant positive association between adenomas and meat consumption with the RR for the highest versus the lowest quintile of intake being 3.6 (1.7-7.5) in comparison with hospital controls and 4.4 (1.6-12.1) in comparison with population controls. Our data support the protective role for carbohydrate intake and of beta-carotene intake in the etiology of colorectal adenomas and show a strong increased risk for developing adenomas in those with high meat intake.

Relation of serum antioxidant vitamins to the risk of colorectal adenoma.

The relation between risk of colorectal adenoma and serum concentrations of vitamins A, C, E and carotene was examined in a population-based case-control study of 105 cases of colorectal adenoma and a similar number of hospital controls showing no polyps at colonoscopy and a second control group of population controls. There were no significant associations with serum concentrations of vitamins C and E and carotene. Serum concentrations of vitamin A were significantly inversely related to the risk of colorectal adenoma when cases were compared with both control groups. After adjustment for energy intake, smoking, alcohol, estrogen therapy, body-mass-index and social class the inverse association between vitamin A and colorectal adenoma was even more marked. For the highest versus the lowest quartile of serum levels the adjusted RR was 0.23 (0.07-0.73) in relation to hospital controls and 0.08 (0.02-0.25) in relation to population controls. These findings suggest that the risk of developing colorectal adenomas is reduced in those with high vitamin A levels.