Extended Postexposure Protection Against Vaginal Simian/Human Immunodeficiency Virus Infection With Tenofovir Alafenamide Fumarate/Elvitegravir Inserts in Macaques.

Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20 mg) and elvitegravir (EVG, 16 mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.

Comprehensive, long-term evaluation of pancreatic exocrine insufficiency after pancreatoduodenectomy.

AIMS: Treatment of pancreatic exocrine insufficiency (PEI) following pancreatoduodenectomy (PD) improves quality of life, clinical outcomes, and survival. However, diagnosing PEI following PD is challenging owing to the difficulties with current tests and often non-specific symptoms. This work aims to quantify the true rate of long-term PEI in patients following a PD. METHODS: Patients underwent a PEI screen approximately one to two years following PD for oncologic indication, including the 13C Mixed triglyceride breath test (13CMTGT), faecal elastase 1 (FE-1) and the PEI Questionnaire (PEI-Q). Four reviewers with expertise in PEI reviewed the results blinded to other decisions to classify PEI status; disagreements were resolved on consensus. RESULTS: 26 patients were recruited. Of those with valid test results, these were indicative of PEI based on pre-specified thresholds for 60 % (15/25) for the 13CMTGT, 82 % (18/22) for FE-1, and 88 % (22/25) for the PEI-Q. After discussion between reviewers, the consensus PEI prevalence was 81 % (95 % CI: 61-93 %; 21/26), with 50 % (N = 13) classified as having severe, 23 % (N = 6) moderate, and 8 % (N = 2) mild PEI. DISCUSSION: Since no ideal test exists for PEI, this collation of diagnostic modalities and blinded expert review was designed to ascertain the true rate of long-term PEI following PD. This required our cohort to survive a year, travel to hospital, and undergo a period of starvation and PERT hold, and therefore there is likely to be recruitment bias towards fitter, younger patients with less aggressive pathology. Despite this, over 80 % were deemed to have PEI, with over 90 % of these being considered moderate or severe.

Investigating misdiagnosis of suspected cancer among patients undergoing pancreatoduodenectomy: three decades of experience.

BACKGROUND: Diagnostic error can result in pancreatoduodenectomy (PD) being mistakenly performed for benign disease. The aims of this study were to observe the error rate in PD over three decades and identify characteristics of benign disease that can mimic malignancy. METHODS: Patients with a benign histological diagnosis after having PD performed for suspected malignancy between 1988 and 2019 were selected for review. Preoperative clinical features, imaging and pathological samples were reviewed alongside resection specimens to identify features that may have led to misdiagnosis. RESULTS: Over the study period, 1812 patients underwent PD for suspected malignancy and 97 (5.2 %) of these had a final benign diagnosis. The rate of benign cases reduced across the study period. Some 62 patients proceeded to surgery without a preoperative tissue diagnosis; the decision to operate was made upon clinical and radiologic features alone. There were six patients who had a preoperative pathological sample suspicious for malignancy, of which two had autoimmune pancreatitis in the postoperative histology specimen. DISCUSSION: Benign conditions, notably autoimmune and chronic pancreatitis, can mimic malignancy even with the use of EUS-FNA. The results of all available diagnostic modalities should be interpreted by a multidisciplinary team and honest discussions with the patient should follow.

Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy: meta-analysis.

BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.

Identification and optimization of a novel series of selective PIP5K inhibitors.

Phosphatidyl inositol (4,5)-bisphosphate (PI(4,5)P2) plays several key roles in human biology and the lipid kinase that produces PI(4,5)P2, PIP5K, has been hypothesized to provide a potential therapeutic target of interest in the treatment of cancers. To better understand and explore the role of PIP5K in human cancers there remains an urgent need for potent and specific PIP5K inhibitor molecules. Following a high throughput screen of the AstraZeneca collection, a novel, moderately potent and selective inhibitor of PIP5K, 1, was discovered. Detailed exploration of the SAR for this novel scaffold resulted in the considerable optimization of both potency for PIP5K, and selectivity over the closely related kinase PI3Kα, as well as identifying several opportunities for the continued optimization of drug-like properties. As a result, several high quality in vitro tool compounds were identified (8, 20 and 25) that demonstrate the desired biochemical and cellular profiles required to aid better understanding of this complex area of biology.

Long-term outcomes of delayed biliary strictures following cholecystectomy.

BACKGROUND: Delayed biliary strictures (DBS) after cholecystectomy are uncommon and little is known of their aetiology or long-term consequences. The aims of this study were to investigate the clinical and economic impact of DBS after cholecystectomy. METHODS: Patients who developed DBS after cholecystectomy were identified from a prospectively collected and maintained database. Risk factors for stricture development, quality of life (QoL) and long-term biliary complication rates were explored. Costs of treatment and follow up were determined. The same outcomes among patients with minor or major bile duct injury (BDI) were used as a comparison. RESULTS: Among 44 patients, a laparoscopic converted to open procedure or post cholecystectomy bile leak affected some 18 and 12 patients respectively. Most DBS required surgical treatment (40). Over a median follow-up of 8.9 years after DBS treatment, 16 (36%) patients developed biliary complications (similar to minor, 26%, and major BDI, 40%) and 1 patient died of causes related to the biliary stricture. Costs of treating DBS and its follow up (£14,309.26 per patient), were similar to previously reported costs for major BDI (£15,784). CONCLUSION: DBS typically occur after a technically and/or complicated cholecystectomy. Clinical, economic and QoL outcomes are similar to patients with major BDI.

Early oral feeding after pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: The effect of early oral feeding (EOF) after pancreatoduodenectomy (PD) upon perioperative complications and outcomes is unknown, therefore the aim of this systematic review and meta-analysis was to investigate the effect of EOF on clinical outcomes after PD, such as postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE) and length of stay (LOS). METHODS: A systematic review and meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance and assimilated evidence from studies reporting outcomes for patients who received EOF after PD compared to enteral tube feeding (EN) or parenteral nutrition (PN). RESULTS: Four studies reported outcomes after EOF compared to EN/PN after PD and included 553 patients. Meta-analyses showed no difference in rates of CR-POPF (OR 0.74; 95%CI 0.44-1.24; p = 0.25) or DGE (Grade B/C) (OR 0.83; 95%CI 0.31-2.21; p = 0.70). LOS was significantly shorter in the EOF group compared to the EN/PN group (Mean Difference -3.40 days; 95% -6.11-0.70 days; p = 0.01). CONCLUSION: Current available evidence suggests that EOF after PD is not associated with increased risk of DGE, does not exacerbate POPF and appears to reduce length of stay.

External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores. METHODS: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. RESULTS: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. CONCLUSION: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. . Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.

Primary Care Physician Perspectives on Recommending E-cigarettes to Smokers: a Best-Worst Discrete Choice Experiment.

BACKGROUND: Recent clinical trials suggest that e-cigarettes may be more effective for smoking cessation than traditional cessation aids, yet primary care physician (PCP) practices regarding e-cigarette recommendations for smokers have not been studied in-depth. OBJECTIVE: To identify factors influencing PCP recommendation of e-cigarettes for smoking cessation. DESIGN: Discrete choice experiment and survey. PARTICIPANTS: Florida PCPs. MEASURES: The survey included a discrete choice experiment in which PCPs indicated whether they would recommend e-cigarettes for each of 8 hypothetical patient profiles with the following contrasting characteristics: e-cigarette use, interest in approved cessation methods, smoking intensity, prior experience with approved cessation medications, quit intention, age, and comorbidity. Responses were summarized using descriptive statistics and standardized scores (SS). KEY RESULTS: The sample (n = 216) was predominately male (76%), white (66%), and non-Hispanic (78%), and most respondents had held their medical degree for 20+ years (77%). The response rate was 28.7%. Most PCPs thought e-cigarettes were at least somewhat effective for smoking cessation (66%) and lowering disease risk (65%); 31% perceived e-cigarettes to be equally/more effective than traditional cessation aids. PCPs were split regarding whether e-cigarettes were less (50%) or equally harmful (38%) as cigarettes. Yet, few were very confident in their ability to counsel patients on e-cigarettes risks (27%) or benefits (15%). PCPs recommended e-cigarettes in 27% of patient profiles they evaluated. The most important factors influencing the decision to recommend or not recommend e-cigarette were patients' prior use of nicotine replacement therapy with (SS = 0.22, 95% CI = 0.17-0.27) and without use of other medications for cessation (SS = 0.18, 95% CI = 0.13-0.23), and being middle age (50 years old) with chronic obstructive pulmonary disease (SS = 0.16, 95% CI = 0.10-0.23). CONCLUSIONS: Considering the increased patient use of e-cigarettes and increasing use for cessation, this study highlights the need for guidelines and education to aid PCPs' counseling of patients about e-cigarette use.

Patient Exposure from Radiologic and Nuclear Medicine Procedures in the United States: Procedure Volume and Effective Dose for the Period 2006-2016.

Background Comprehensive assessments of the frequency and associated doses from radiologic and nuclear medicine procedures are rarely conducted. The use of these procedures and the population-based radiation dose increased remarkably from 1980 to 2006. Purpose To determine the change in per capita radiation exposure in the United States from 2006 to 2016. Materials and Methods The U.S. National Council on Radiation Protection and Measurements conducted a retrospective assessment for 2016 and compared the results to previously published data for the year 2006. Effective dose values for procedures were obtained from the literature, and frequency data were obtained from commercial, governmental, and professional society data. Results In the United States in 2006, an estimated 377 million diagnostic and interventional radiologic examinations were performed. This value remained essentially the same for 2016 even though the U.S. population had increased by about 24 million people. The number of CT scans performed increased from 67 million to 84 million, but the number of other procedures (eg, diagnostic fluoroscopy) and nuclear medicine procedures decreased from 17 million to 13.5 million. The number of dental radiographic and dental CT examinations performed was estimated to be about 320 million in 2016. Using the tissue-weighting factors from Publication 60 of the International Commission on Radiological Protection, the U.S. annual individual (per capita) effective dose from diagnostic and interventional medical procedures was estimated to have been 2.9 mSv in 2006 and 2.3 mSv in 2016, with the collective doses being 885 000 and 755 000 person-sievert, respectively. Conclusion The trend from 1980 to 2006 of increasing dose from medical radiation has reversed. Estimated 2016 total collective effective dose and radiation dose per capita dose are lower than in 2006. © RSNA, 2020 See also the editorial by Einstein in this issue.

Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.

In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.

Does non-operative management of iatrogenic bile duct injury result in impaired quality of life? A systematic review.

BACKGROUND: Several studies have reported the effect of bile duct injury (BDI) on health-related quality of life (HRQOL) with conflicting results. This systematic review aims to study the impact of patient and treatment factors on HRQOL after BDI. METHODS: A search of the PubMed database was performed and studies were reviewed as per the PRISMA guidelines. Selected studies (n = 11) were then divided into two subgroups depending on whether they found HRQOL to be similar or worse between BDI and control groups. Pooled rates of surgical repair and major BDI were calculated for each of these subgroups. RESULTS: Surgical repair rates were 99% (95% CI: 96%-99%) in studies where the BDI patients had similar outcomes to controls, compared to 78% (40%-100%) where their outcomes were significantly worse (p = 0.091). The major BDI rate was 51% (95% CI: 42%-61%) in studies where the BDI patients had similar outcomes to controls, compared to 72% (41%-94%) where their outcomes were significantly worse (p = 0.322). Considerable heterogeneity was present within the two subgroups (I2: 68-99%). DISCUSSION: HRQOL may be adversely affected amongst patients with BDI who do not undergo surgical repair. Significant heterogeneity of data suggests the need for standardised HRQOL tools and injury severity systems when assessing outcomes after BDI.

A comprehensive evaluation of the long-term economic impact of major bile duct injury.

BACKGROUND: Complications and litigation after bile duct injury (BDI) result in clinical and economic burden. The aim of this study was to comprehensively evaluate the long-term clinical and economic impact of major BDI. METHOD: Patients with long-term follow-up after Strasberg E BDI were identified. Costs of treatment and litigation were the primary outcome. Relationships between these outcomes and repair factors, like timing of repair and surgeon expertise, were secondary outcomes. RESULTS: Among 139 patients with a median follow up of 10.7 years, 40% of patients developed biliary complications. Repairs by non-specialist surgeons had significantly higher follow up and treatment costs than those by specialists (£25,814 vs. £14,269, p < 0.001). Estimated litigation costs were higher in delayed than immediate repairs (£23,295 vs. £12,864). As such, the lowest average costs per BDI are after immediate specialist repair and the highest after delayed non-specialist repair (£27,133 vs. £49,109, ×1.81 more costly, p < 0.001). Repair by a non-specialist surgeon (HR: 4.00, p < 0.001) and vascular injury (HR: 2.35, p = 0.013) were significant independent predictors of increased complication rates. CONCLUSION: Costs of major BDI are considerable. They can be reduced by immediate on-table repair by specialist surgeons. This must therefore be considered the standard of care wherever possible.

Increases in Endogenous or Exogenous Progestins Promote Virus-Target Cell Interactions within the Non-human Primate Female Reproductive Tract.

Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels.

A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in Non-Human Primates.

PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring. RESULTS: In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528's EC90, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings. CONCLUSIONS: We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC90.

Repeated administration of high-dose depot medroxyprogesterone acetate does not alter SHIVSF162p3 viral kinetics and tenofovir pharmacokinetics when delivered via intravaginal rings.

BACKGROUND: Intravaginal rings (IVR) for HIV prevention will likely be used by women on depot medroxyprogesterone acetate (DMPA) hormonal contraception. We used pigtailed macaques to evaluate the effects of DMPA on tenofovir disoproxil fumarate (TDF) IVR pharmacokinetics and viral shedding. METHODS: Mucosal tenofovir (TFV) levels were compared in SHIVSF162p3 -negative DMPA-treated (n=4) and normally cycling (n=6) macaques receiving TDF IVRs. Plasma viremia and vaginal shedding were determined in groups of SHIVSF162p3 -positive DMPA-treated (n=6) and normally cycling (n=5) macaques. RESULTS: Similar median vaginal fluid TFV concentrations were observed in the DMPA-treated and cycling macaques over 4 weeks (1.2×105 and 1.1.×105  ng/mL, respectively). Median plasma viremia and vaginal shedding AUC of the DMPA-treated (2.73×107 and 8.15×104 copies/mL, respectively) and cycling macaques (3.98×107 and 1.47×103 copies/mL, respectively) were statistically similar. CONCLUSIONS: DMPA does not affect TDF IVR pharmacokinetics or SHIV shedding.

A comparative study of risk factors for pancreatic fistula after pancreatoduodenectomy or distal pancreatectomy.

BACKGROUND: Evidence associates various biometric and histological variables such as steatosis and absence of fibrosis as risk factors for post-operative pancreatic fistula (POPF) after pancreatoduodenectomy (PD). Following distal pancreatectomy (DP), the association between these factors and POPF is less clear. This study of patients, drawn from the same background population, undergoing PD or DP at a single centre is a comparative study of the risk factors for POPF after these two operations. METHODS: Associations between POPF and patient characteristics, pre-operative blood tests, data from pre-operative computed tomography (CT) imaging, assessment of histological steatosis and fibrosis were explored. RESULTS: 26/107 (24%) and 26/90 (29%) patients developed POPF after PD and DP respectively. Absence of fibrosis was associated with POPF (p < 0.001) after PD and its presence correlated with pancreatic duct width (p < 0.001). Steatosis was not associated with POPF (p = 0.910). Multivariable analysis showed pancreatic duct width (p = 0.016) and fibrosis (p = 0.025) to be independent predictors of POPF after PD. The only variable associated with POPF after DP was underlying pathology (p = 0.005). CONCLUSION: Pancreatic duct width is the most important variable related to POPF after PD and is correlated with fibrosis. Steatosis was not related to POPF. In contrast, after DP POPF appears to be related to the underlying disease.

Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis.

For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n = 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) µg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) µg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the in vitro 90% inhibitory concentration (IC90) of 0.146 µg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.