Adjuvant Modified FOLFIRINOX for Resected Pancreatic Adenocarcinoma (PDAC): Clinical Insights and Genomic Features from a Large Contemporary Cohort.

BACKGROUND: Adjuvant mFOLFIRINOX (mFFX) is standard of care for fit individuals with resected pancreatic ductal adenocarcinoma (PDAC). There are limited data on adjuvant mFFX outcomes outside clinical trials. METHODS: Institutional databases queried to identify patients with resected PDAC who received ≥1 dose adjuvant mFFX. Primary endpoints: recurrence free survival (RFS), overall survival (OS). Secondary endpoints: clinical factors, genomic features associated with outcomes. RFS and OS were estimated with Kaplan-Meier. Cox proportional hazards regression model was used to associate clinico-genomic features correlated with survival outcomes. RESULTS: N = 147 identified between 01/2015-01/2023. Median age: 67 years; N = 57 (39%) >70 years. Unfavorable prognostic features: N = 52 (36%) N2 nodal status, N = 115 (78%) lymphovascular invasion), and N = 133 (90%) perineural invasion. Median time from surgery to start mFFX: 1.78 months (m) (IQR 1.45, 2.12). N = 124 (84%) completed 12 doses; N = 98 (67%) stopped oxaliplatin early for neuropathy (median 10 doses; range 4-12). Further dosing characteristics are summarized in Supplementary Table 3. With median follow up of 35.1 m, median RFS (mRFS) 26 m (95% CI 19, 39) and median OS (mOS) not reached. For >70 cohort, mRFS 23 m (95% CI 14, NR) and mOS 51 m (95% CI 37, NR). mFFX started <8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p = .033) and OS (HR 0.53; 95% CI 0.3, 0.94; p = .030). KRAS mutation and whole genome doubling trended to shorter RFS and OS. Homologous recombination deficiency status did not confer improved survival outcomes. CONCLUSIONS: Adjuvant mFFX is effective and tolerable in resected PDAC in a non-trial setting, including for patients >70 years.

Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis.

Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior-posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, ß, or γ) and retinoid X receptors (RXRα, ß, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation. Mutations in DHRS3 can result in embryonic lethality and congenital defects. This study shows that mouse Dhrs3 expression is responsive to vitamin A status and is directly regulated by the RAR/RXR complex through cis-regulatory elements. This highlights a negative feedback mechanism that ensures retinoic acid homeostasis.

Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer.

Importance: Microsatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)-associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown. Objective: To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods. Design, Setting, and Participants: This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant. Main Outcomes and Measures: Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed. Results: Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%. Conclusion: The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.

Precision medicine for pancreatic cancer: characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease.

BACKGROUND: Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. METHODS: Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. RESULTS: Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. CONCLUSION: Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.

Swiping right on PrEP: a qualitative study of MSM preferences for PrEP public health messaging on dating apps.

Men who have sex with men (MSM) are disproportionately affected by HIV. Given that over 70% of MSM meet sexual partners via dating apps, such apps may be an effective platform for promoting HIV pre-exposure prophylaxis (PrEP) use. We aimed to describe preferences among MSM for PrEP advertisements displayed on dating apps. We conducted individual in-depth interviews with 16 MSM recruited from a mobile sexual health unit in Boston, Massachusetts. Two focus groups were also held: one with mobile unit staff (N = 3) and one with mobile unit users (N = 3). Content analysis was used to identify themes related to advertisement content and integration with app use. Mean participant age was 28 (SD 6.8); 37% identified as White and 63% as Latinx. 21% of interviews were conducted in Spanish. Preferences were organized around four themes: (1) relevant and relatable advertisements, (2) expansion of target audiences to promote access, (3) concise and captivating advertisements, and (4) PrEP advertisements and services as options, not obligations. MSM are supportive of receiving information about PrEP on dating apps, but feel that existing advertisements require modification to better engage viewers. Dating apps may be an underutilized tool for increasing PrEP awareness and knowledge among MSM.

Chlamydia retesting remains low among young women in Australia: an observational study using sentinel surveillance data, 2018-2022.

BACKGROUND: Chlamydia remains the most notified bacterial sexually transmissible infection in Australia with guidelines recommending testing for re-infection at 3months post treatment. This paper aimed to determine chlamydia retesting and repeat positivity rates within 2-4months among young women in Australia, and to evaluate what factors increase or decrease the likelihood of retesting. METHODS: Chlamydia retesting rates among 16-29-year-old women were analysed from Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of sexually transmissible infection and bloodborne virus (ACCESS) sentinel surveillance data (n =62 sites). Among women with at least one positive test between 1 January 2018 and 31 August 2022, retesting counts and proportions within 2-4months were calculated. Logistic regression was performed to assess factors associated with retesting within 2-4months. RESULTS: Among 8758 women who were positive before 31 August 2022 to allow time for follow up, 1423 (16.2%) were retested within 2-4months, of whom 179 (12.6%) tested positive. The odds of retesting within 2-4months were 25% lower if tested in a coronavirus disease 2019 (COVID-9) pandemic year (2020-2022) (aOR=0.75; 95% CI 0.59-0.95). Among 9140 women with a positive test before 30 November 2022, 397 (4.3%) were retested too early (within 7days to 1month) and 81 (20.4%) of those were positive. CONCLUSIONS: Chlamydia retesting rates remain low with around a sixth of women retested within 2-4months in line with guidelines. Re-infection is common with around one in eight retesting positive. An increase in retesting is required to reduce the risk of reproductive complications and onward transmission.

Harnessing Patient Life Stories to Engage Medical Trainees in Strengthening Veteran-Provider Relationships.

Introduction: Medical trainees do not have many opportunities to develop communication skills with patients. We established the voluntary "My Life, My Story" (MLMS) program at the Clement J. Zablocki VAMC in Milwaukee, WI, to determine if this pilot narrative medicine program enhanced trainee interpersonal skills and improved patient-centered care. Methods: Trainees at the Medical College of Wisconsin conducted in-person or virtual interviews of Veterans receiving care at the Milwaukee VAMC about their meaningful life experiences. Post-interview, trainees wrote a short first-person narrative in the Veteran's voice, which, after the Veteran's approval, was added to the electronic medical record and made available to the patient's care team. Trainees, Veterans, and health professionals completed post-interview surveys, from which we conducted descriptive statistics and qualitatively analyzed the text-based feedback. Results: Between 2020 and 2021, 24 medical trainees participated in our pilot implementation of the MLMS program, conducting a total of 32 interviews. All trainees reported a meaningful personal impact and found the pilot to be "valuable" and "rewarding." Both trainees and health professionals believed that the MLMS program improved "rapport building" with Veterans. Nearly all Veterans (n = 25, 93%) believed that their medical care team would be able to provide better care after reading their life story. Conclusions: Narrative medicine initiatives like the MLMS program may enable value-added education for trainees. Future research will allow us to better understand and maximize specific educational gains, while further enhancing patient care. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01854-4.

Pancreatic Cancer: BRCA Targeted Therapy and Beyond.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.

"That was our afterparty": a qualitative study of mobile, venue-based PrEP for MSM.

BACKGROUND: HIV preexposure prophylaxis (PrEP) uptake among men who have sex with men (MSM), a group disproportionately impacted by HIV, is not commensurate with need. Settings which reduce or remove barriers to accessing care are promising venues to support PrEP uptake. PrEP provision at mobile clinics represents a novel strategy to increase PrEP access; however, the acceptability and feasibility of this approach have not been well studied. METHODS: Our objective was to understand patient and staff experiences of a mobile clinic van offering PrEP and sexual health services in Boston, Massachusetts, USA. We interviewed mobile unit users and conducted focus groups with mobile unit staff and users. Data were organized using Dedoose software, and content analysis was used to identify themes of access, community, and stigma. RESULTS: Nineteen individuals (16 patients and 3 staff members) participated in interviews (N = 13) or focus groups (N = 6). All patients identified as MSM, 63% were Hispanic or Latino, and 21% of patient interviews were conducted in Spanish. Logistical and psychological convenience facilitated service use, while the community-oriented environment improved satisfaction with care. Overall, participants supported expansion of mobile unit services and recommended changes to improve access to longitudinal care. However, some barriers to PrEP persisted, including low HIV risk perception and stigma about sexual behavior. CONCLUSIONS: Mobile units can promote sexual health and PrEP uptake, particularly for populations facing social and logistical barriers to care in traditional settings.

Renal impairment associated with tenofovir disoproxil fumarate for antiretroviral therapy and HIV pre-exposure prophylaxis: An observational cohort study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is associated with adverse renal outcomes when prescribed for HIV infection. There are few data concerning real-world renal outcomes amongst patients prescribed TDF for pre-exposure prophylaxis (PrEP). METHODS AND FINDINGS: Data were extracted from 52 sexual health clinics across Australia from 2009-2019. All patients prescribed TDF-containing antiretroviral therapy and PrEP were included. Rates of renal impairment (a fall in eGFR to <60 ml/min/1·73m2) were calculated for people living with HIV (PLWHIV) prescribed TDF and HIV negative PrEP-users. Risk factors were assessed using Cox-proportional hazards models. Sensitivity analysis of risk using 1:1 propensity-score matching to adjust for potential imbalance in HIV and PrEP cohorts was conducted. 5,973 patients on PrEP and 1,973 PLWHIV were included. There were 39 (0.7%) instances of renal impairment in the PrEP group and 81 (4.1%) in the PLWHIV cohort (hazard ratio [HR]:0.35 95% confidence interval [CI]: 0.22-0.56). Rates of renal impairment were 4.01/1000 person-years (95%CI:2.93-5.48) in the PrEP cohort and 16.18/1000 person-years (95%CI:13.01-20.11) in the PLWHIV cohort (p<0.001). Predictors of renal impairment were: older age (40-49 years (HR:5.09 95%CI: 2.12-12.17) and 50-82 years (HR:13.69 95%CI: 5.92-31.67) (compared with 30-39 years) and baseline eGFR<90ml/min (HR:61.19 95%CI: 19.27-194.30). After adjusting for age and baseline eGFR the rate of renal impairment remained lower in the PrEP cohort (aHR:0.62 95%CI: 0.40-0.94, p = 0.023). In propensity-matched analysis using 1,622 patients per cohort the risk of renal impairment remained higher in the PLWHIV cohort (log-rank p = 0.001). CONCLUSION: Patients prescribed TDF-based PrEP had lower rates of renal impairment than patients prescribed TDF for HIV infection. In propensity analysis, after matching for some risk factors, rates of renal impairment remained higher amongst patients with HIV.

Is sex lost in translation? Linguistic and conceptual issues in the translation of sexual and reproductive health surveys.

Translated questionnaires are increasingly used in population health research. Nevertheless, translation is often not conducted with the same rigour as the process of survey development in the original language. This has serious limitations and may introduce bias in question relevance and meaning. This article describes and reflects on the process of translating a large and complex sexual and reproductive health survey from English into Simplified Chinese. We interrogated assumptions embedded in taken-for-granted translation practice to locate the sociocultural origins of these assumptions. We discuss how terminology and expression related to sexual and reproductive health may lose their conceptual or linguistic significance during translation in three different ways. Firstly, meanings can be lost in the negotiation of meanings associated with linguacultural and geographical variations of terminology. Secondly, meanings can be lost in the clash between everyday and professional sexual and reproductive health discourses. Thirdly, meanings can be lost due to the design of the source questionnaire and the intended mode of survey administration. We discuss ways to help overcome the unavoidable translation challenges that arise in the process of translating English sexual and reproductive health surveys for migrants from non-English speaking backgrounds.

Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice.

PURPOSE: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. RESULTS: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3-not reached (NR)], 27.1 months (95% CI: 22.7-NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9-NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2-29) relative to breast (18, 3-55) or ovarian (25, 3-56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. CONCLUSIONS: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

Mechanisms of Feedback Regulation of Vitamin A Metabolism.

Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.

Using Videoconferencing Focus Groups in Sexual and Reproductive Health Research With Chinese Im/Migrants in Australia.

Videoconferencing focus groups have emerged as a popular method for collecting qualitative data. However, its use in sexual and reproductive health research is still very much in its infancy. Based on participants' feedback and researchers' reflections on using videoconferencing focus groups to collect sexual and reproductive health data with 39 heterosexual and non-heterosexual Chinese im/migrants in Australia, we discuss some of the key lessons learned, and considerations involved in shifting from face-to-face to online focus groups. Overall, videoconferencing focus groups appeared to be a highly feasible and acceptable way to discuss "sensitive" topics with Chinese im/migrants. Importantly, researchers need to be both creative and reflexive during the research process and must not forget that the success of a study lies not only in troubleshooting technical issues but also in cultivating and maintaining a trusting relationship with research participants.

Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes.

BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

Renal impairment in a large-scale HIV preexposure prophylaxis implementation cohort.

BACKGROUND: HIV preexposure prophylaxis (PrEP) with fixed-dose tenofovir disoproxil fumarate (TDF) and emtricitabine has been associated with low rates of renal impairment in clinical trials. Large-scale PrEP implementation may result in higher rates, as the prevalence of associated risk factors may be higher than in trial populations. METHODS: A posthoc analysis of EPIC-NSW, a large Australian multicentre PrEP implementation trial for patients at high risk of HIV infection. Participants were eligible for inclusion if they commenced PrEP between 1 March 2016 and 30 April 2018, and had renal function assessed at baseline and at least once more before the censor date. The primary outcome was new-onset renal impairment, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. RESULTS: A total of 6808 participants were eligible for inclusion. Almost all were male (99%), with a median age of 35 years [interquartile range (IQR): 28-44]. Approximately one-quarter (26%) had a baseline eGFR <90 ml/min per 1.73 m2. Over a median follow-up period of 1.2 years (IQR: 0.6-1.7), the rate of renal impairment was 5.8 episodes per 1000 person-years [95% confidence interval (CI): 4.0-7.8]. In multivariable Cox regression, there was a higher risk of renal impairment in participants aged ≥50 years [hazard ratio (HR) 14.7, 95% CI: 5.0-43.3, P < 0.001] and those with an eGFR <90 ml/min per 1.73 m2 (HR 28.9, 95% CI: 6.9-121.9) at baseline. CONCLUSION: In a large-scale implementation study, TDF-containing PrEP was associated with a low risk of renal impairment overall, whereas older patients and those with preexisting renal dysfunction were at substantially increased risk.

Leptomeningeal disease in pancreas ductal adenocarcinoma: A manifestation of longevity.

BACKGROUND: /Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated. METHODS: Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed. RESULTS: Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months). CONCLUSIONS: LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.

Human-to-Human Transmission of Monkeypox Virus, United Kingdom, October 2018.

In September 2018, monkeypox virus was transmitted from a patient to a healthcare worker in the United Kingdom. Transmission was probably through contact with contaminated bedding. Infection control precautions for contacts (vaccination, daily monitoring, staying home from work) were implemented. Of 134 potential contacts, 4 became ill; all patients survived.

Two Distinct Gonorrhea Trends and Risk Factors Among Women in Australia.

BACKGROUND: In recent years, gonorrhea notifications have increased in women in Australia and other countries. We measured trends over time and risk factors among Australian Aboriginal and Torres Strait Islander ("Aboriginal") and non-Aboriginal women. METHODS: We conducted a cross-sectional analysis of data from 41 sexual health clinics. Gonorrhea positivity at each patient's first visit (first-test positivity) during the period 2009 to 2016 was calculated. Univariate and multivariate analyses assessed risk factors for first-test positivity in Aboriginal and non-Aboriginal women. RESULTS: Gonorrhea positivity decreased among Aboriginal women (7.1% in 2009 to 5.2% in 2016, P < 0.001) and increased among non-Aboriginal women (0.6%-2.9%, P < 0.001). Among Aboriginal women, first-test positivity was independently associated with living in a regional or remote area (adjusted odds ratio [aOR], 4.29; 95% confidence interval [CI], 2.52-7.31; P < 0.01) and chlamydia infection (aOR, 4.20; 95% CI,3.22-5.47; P < 0.01). Among non-Aboriginal women, first-test positivity was independently associated with greater socioeconomic disadvantage (second quartile: aOR, 1.68 [95% CI, 1.31-2.16; P < 0.01]; third quartile: aOR, 1.54 [95% CI, 1.25-1.89; P < 0.01]) compared with least disadvantaged quartile: recent sex work (aOR, 1.69; 95% CI, 1.37-2.08; P < 0.01), recent injecting drug use (aOR, 1.85; 95% CI, 1.34-2.57; P < 0.01), and chlamydia infection (aOR, 2.35; 95% CI, 1.90-2.91; P < 0.01). For non-Aboriginal women, being aged 16 to 19 years (aOR, 0.62; 95% CI, 0.49-0.80; P < 0.01) compared with those ≥30 years was a protective factor. CONCLUSIONS: These findings highlight 2 different epidemics and risk factors for Aboriginal and non-Aboriginal women, which can inform appropriate health promotion and clinical strategies.

Renal function change after switching tenofovir disoproxil fumarate for tenofovir alafenamide in the HIV-positive patients of a metropolitan sexual health service.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is widely used in the management of HIV-infection, but has been associated with renal impairment in a small proportion of patients. Tenofovir alafenamide (TAF), a novel prodrug of tenofovir, causes less renal impairment and can improve renal function in patients switched from TDF. The factors which predict improved renal function in patients switching from TDF to TAF have yet to be described. AIM: To determine which patient factors are associated with an improvement in renal function following the switch from a TDF- to a TAF-based HIV antiretroviral regimen. METHODS: A retrospective analysis was performed of a cohort from a publicly funded sexual health clinic in Sydney, Australia. All HIV-positive clinic patients switched from a TDF- to TAF-containing regimen between January 2016 and August 2018 were eligible for inclusion. Laboratory results were obtained from patients' electronic medical records. The statistical significance of differences between pre- and post-switch means was determined by paired t-tests, adjusted for baseline values, and associations between continuous variables by univariate linear regression. RESULTS: 79 patients met inclusion criteria. The majority were male (89%), with a median age of 44 years (IQR: 34.5 to 53). Patients had a mean pre-switch estimated glomerular filtration rate (eGFR) of 95 ± 2 mL/min/1.73 m2, and there was no significant change post-switch (p = 0.062). Pre-switch eGFR was a significant predictor of the magnitude of eGFR change after the switch (p < 0.001), but there was no significant association with age (p = 0.189), cumulative TDF exposure (p = 0.454) or baseline urinary protein to creatinine ratio (p = 0.814). CONCLUSION: While there was no significant difference in mean eGFR, in patients switched from TDF to TAF, baseline eGFR was a significant predictor of the change in eGFR. This suggests that patients on TDF with poorer baseline renal function would benefit more from switching to TAF. Further study to explore this association is warranted.