Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Systemic antibiotics for Pseudomonas aeruginosa infection in outpatients with non-hospitalised exacerbations of pre-existing lung diseases: a randomised clinical trial.

BACKGROUND: The effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes. METHODS: Multicenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365. RESULTS: The trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27-0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6-1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3-4.5) in the control group, p = 0.037. CONCLUSIONS: Use of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03262142, registration date 2017-08-25.

Alcohol consumption and risk of psoriasis: Results from observational and genetic analyses in more than 100,000 individuals from the Danish general population.

Background: Psoriasis is associated with high alcohol consumption, but the causality of this relationship is unclear. Objective: We aimed to use a Mendelian randomization approach to investigate the causal effects of alcohol on incident psoriasis. Methods: We included 102,655 adults from the prospective Copenhagen studies. All participants filled out a questionnaire on alcohol consumption, were physically examined, and had blood drawn for biochemical and genetic analyses. We created a genetic instrument based on the number of fast-metabolizing alleles in alcohol dehydrogenase 1B and alcohol dehydrogenase 1C, known to be associated with alcohol consumption, to test whether alcohol consumption was causally associated with psoriasis. Results: Observationally, we found an increased risk of incident psoriasis among individuals with high alcohol consumption compared to those with low alcohol consumption with a hazard ratio of 1.30 (95% confidence interval 1.05-1.60) in the fully adjusted model. Using genetic data to predict alcohol consumption to avoid confounding and reverse causation, we found no association between number of fast-metabolizing alleles and risk of psoriasis. Limitations: Alcohol consumption was self-reported and psoriasis was defined using the International Classification of Diseases 10th revision and 8th revision codes. Conclusion: Alcohol consumption is observationally but not causally associated with incident psoriasis.

Risk of Mortality and Cardiovascular Events in Patients with Chronic Obstructive Pulmonary Disease Treated with Azithromycin, Roxithromycin, Clarithromycin, and Amoxicillin.

Background: Prior research has raised concerns regarding the use of macrolides and their association with an increased risk of cardiovascular events. Methods: We conducted a cohort study, where we explored the cardiovascular risks associated with the treatment of COPD patients using macrolide antibiotics-namely azithromycin, clarithromycin, and roxithromycin-with amoxicillin serving as a reference. The study focused on COPD patients in an outpatient setting and included a thorough 3-year follow-up. Patients were categorized into four groups based on their treatment. The primary analysis utilized an adjusted Cox model, supplemented by sensitivity analysis through inverse probability of treatment weighting. Results: No significant differences were found in major adverse cardiovascular events (MACE-stroke, acute myocardial infarction, cardiovascular death) between the macrolide groups, and the amoxicillin/hazard ratios (HR) were azithromycin HR = 1.01, clarithromycin HR = 0.99, and roxithromycin HR = 1.02. Similarly, sensitivity analysis showed no disparities in all-cause mortality and cardiovascular death among the groups. Conclusions: Overall, the study revealed no evidence of increased risk of MACE, all-cause mortality, or cardiovascular death in COPD patients treated with these macrolides compared to amoxicillin over a 3-year period.

Implementation of a rapid diagnostic assay package for cryptococcosis, histoplasmosis and tuberculosis in people living with HIV in Paraguay.

BACKGROUND: Opportunistic infections (OIs) are common causes of mortality among people living with HIV (PLHIV). We determined prevalence and 30-day mortality due to histoplasmosis, cryptococcosis, and TB in PLHIV with advanced HIV disease (AHD). METHODS: PLHIV 18 years and older, with a CD4 + T-cell count of less than 350 cells/mm3 newly diagnosed with HIV infection or re-engaged in care after being without ART for more than 90 days (Group A). The second group included symptomatic PLHIV regardless of ART status or CD4 + T-cell count (Group B); all followed for 30 days. Detection of Histoplasma Ag (HisAg) in urine was done by enzyme immunoassay (EIA), Cryptococcus antigen (CrAg) was detected in serum and cerebrospinal fluid (CSF) specimens by lateral flow assay (LFA), and lipoarabinomannan (LAM) detection in urine was by LFA (TB LAM) and in sputum by GeneXpert for diagnosis of Mycobacterium infections. RESULTS: From August 2021 to June 2022, 491 PLHIV were enrolled; 482 (98%) had a CD4 + T-cell result, and 381 patients (79%) were classified with AHD according to CD4 + T-cell count (< 200 CD4/mm3). Frequency of an OI was 38% (n = 145/381). Antigen test positivity rate was 16% (72/467) for TB-LAM, 9% (43/464) for HisAg, and 11% (51/484) for CrAg. Twenty-one of 34 (62%) patients receiving CSF CrAg tests were positive, confirming meningitis. Significant differences in 30-day mortality were observed in patients with an OI (16%) vs. no OI (7%) (p = 0.002). Mortality was highest in patients with histoplasmosis (25%), co-infection (22%), cryptococcosis (18% overall; 19% for cryptococcal meningitis), and TB (10%). CONCLUSIONS: TB and fungal OIs, including co-infection, were common in PLHIV in Paraguay and had high associated mortality. Laboratories and health facilities need access to CD4 + T-cell testing and rapid diagnostic assays.

Thrombelastography and Conventional Coagulation Markers in Chronic Obstructive Pulmonary Disease: A Prospective Paired-Measurements Study Comparing Exacerbation and Stable Phases.

Chronic Obstructive Pulmonary Disease (COPD) exacerbation is known for its substantial impact on morbidity and mortality among affected patients, creating a significant healthcare burden worldwide. Coagulation abnormalities have emerged as potential contributors to exacerbation pathogenesis, raising concerns about increased thrombotic events during exacerbation. The aim of this study was to explore the differences in thrombelastography (TEG) parameters and coagulation markers in COPD patients during admission with exacerbation and at a follow-up after discharge. This was a multi-center cohort study. COPD patients were enrolled within 72 h of hospitalization. The baseline assessments were Kaolin-TEG and blood samples. Statistical analysis involved using descriptive statistics; the main analysis was a paired t-test comparing coagulation parameters between exacerbation and follow-up. One hundred patients participated, 66% of whom were female, with a median age of 78.5 years and comorbidities including atrial fibrillation (18%) and essential arterial hypertension (45%), and sixty-five individuals completed a follow-up after discharge. No significant variations were observed in Kaolin-TEG or conventional coagulation markers between exacerbation and follow-up. The Activated Partial Thromboplastin Clotting Time (APTT) results were near-significant, with p = 0.08. In conclusion, TEG parameters displayed no significant alterations between exacerbation and follow-up.

The Nairobi Declaration 2023: A commitment to address deadly yet neglected fungal diseases in Africa.

On May 30th and 31st, 2023, delegates representing various African subregions, together with global representatives from the International Society of Human and Animal Mycology (ISHAM), the European Confederation of Medical Mycology (ECMM), the United States Centre for Disease Control and Prevention (CDC), and Global Action for Fungal Infections (GAFFI), convened in Nairobi, Kenya under the aegis of the Pan African Mycology Working Group, a working group of ISHAM. The meeting objectives were, amongst others, to deliberate on a continental response to the World Health Organisation Fungal Priority Pathogen List and facilitate interaction between global and regional leaders. Country delegates and international speakers addressed Africa's fungal disease burden; capacity for diagnosis and management; ongoing surveillance; knowledge gaps and trends in invasive fungal diseases such as Candida auris, mucormycosis, aspergillosis, and Acquired Immune Deficiency Syndrome (AIDS)-related mycoses; and current laboratory practice. During the technical sessions, expert panels deliberated on establishing and financing of national/regional surveillance networks for mycoses; establishing and sustaining African-led collaborations; expanding on existing laboratory and point-of-care diagnostic capacity as well as planning a mycology reference laboratory service and network in Africa. The meeting also highlighted successful African-led collaborations, capacity building, and clinical trial initiatives. The meeting conclusions informed the resolutions of the Nairobi Declaration calling for improved awareness; strong collaborations between clinical and laboratory teams across Africa; improved fungal disease surveillance within the continent; access to antifungals and diagnostics; and leveraging qualified human resources for mycology present within and outside Africa to facilitate trainings, collaborations, and exchanges.

This review presents the current state of the art in medical mycology in Africa discussed at the first scientific meeting of the Pan African Mycology Working Group, an affiliate of the International Society for Human and Animal Mycology (ISHAM) held in Nairobi, Kenya on May 30th and 31st, 2023.

Incidence of community-acquired pneumonia hospitalisation in persons with bronchiectasis during the COVID-19 lockdown in Denmark: a retrospective cohort study.

BACKGROUND: Persons with bronchiectasis have a high risk of community-acquired pneumonia. Social distancing measures, implemented to prevent the spreading of SARS-CoV-2, could potentially reduce the incidence of other infectious diseases. RESEARCH QUESTION: Was the COVID-19 lockdown period, along with accompanying social distancing measures, associated with reduced hospital admissions for community-acquired pneumonia and decreased overall mortality rates among individuals with bronchiectasis? METHODS: Social distancing measures were introduced in Denmark by 12 March 2020 and were preserved until 20 May 2020 (social distancing period), after which the measures were gradually dismissed. The study included all adults (≥18 years) with bronchiectasis residing in Denmark. Confirmed cases of SARS-CoV-2 infection were excluded. We retrospectively investigated the incidence of community-acquired pneumonia hospital admission, death of all causes and respiratory antibiotic treatment in the 10-week social distancing period in 2020, compared with the same dates in 2019. 9344 persons were included in the study. RESULTS: In the social distancing period, the incidence rate of pneumonia-hospitalisation per 10 000 person-weeks was 9.2 compared with 13.8 in the reference period. This reduction corresponds to an incidence rate ratio (IRR) of 0.67 (95% CI 0.51 to 0.88, p<0.01). Mortality was unchanged (IRR 0.90, 95% CI 0.61 to 1.32, p=0.58). Fewer persons received respiratory antibiotics (IRR 0.85, 95% CI 0.78 to 0.94, p<0.001). CONCLUSION: The social distancing period was associated with a lower incidence of community-acquired pneumonia hospitalisations and respiratory antibiotic treatments in persons with bronchiectasis while all-cause mortality remained unchanged.

Inhalation devices and inhaled corticosteroids particle size influence on severe pneumonia in patients with chronic obstructive pulmonary disease: a nationwide cohort study.

BACKGROUND: Inhaled corticosteroids (ICSs) are associated with an increased risk of pneumonia among patients with chronic obstructive pulmonary disease (COPD). The introduction of extrafine particle ICS has aimed to improve the distribution of medicine in the airways by altering deposition within the lungs, potentially affecting efficacy and side effects. It remains unclear if extrafine particle ICS administration alters the risk of pneumonia compared with standard particle size ICS. METHODS: An observational cohort study including all Danish COPD outpatients receiving ICS from 2010 to 2017. The primary outcome was pneumonia hospitalisation in the different ICS particle dosing regimens. The primary analysis was an adjusted Cox proportional hazards model. For sensitivity analysis, a subgroup analysis of patients receiving spray devices was done. Further, we created a propensity score matched cohort, in which we matched for the same covariates as adjusted for in the main analysis. RESULTS: A total of 35 691 patients were included of whom 1471 received extrafine particle ICS. Among these patients, 4657 were hospitalised due to pneumonia. Patients with COPD receiving extrafine particle ICS had a lower risk of hospitalisation due to pneumonia compared with patients receiving standard particle size ICS in our primary analysis (HR 0.75; 95% CI 0.63 to 0.89; p=0.002), subgroup analysis (HR 0.54; 95% CI 0.45 to 0.65; p<0.0001) and the propensity-matched population (HR 0.72; 95% CI 0.60 to 0.87; p=0.0006). INTERPRETATION: The use of extrafine particle ICS administration was associated with a lower risk of pneumonia hospitalisation in patients with COPD compared with those who received standard size treatment.

Public Health Research Priorities for Fungal Diseases: A Multidisciplinary Approach to Save Lives.

Fungal infections can cause severe disease and death and impose a substantial economic burden on healthcare systems. Public health research requires a multidisciplinary approach and is essential to help save lives and prevent disability from fungal diseases. In this manuscript, we outline the main public health research priorities for fungal diseases, including the measurement of the fungal disease burden and distribution and the need for improved diagnostics, therapeutics, and vaccines. Characterizing the public health, economic, health system, and individual burden caused by fungal diseases can provide critical insights to promote better prevention and treatment. The development and validation of fungal diagnostic tests that are rapid, accurate, and cost-effective can improve testing practices. Understanding best practices for antifungal prophylaxis can optimize prevention in at-risk populations, while research on antifungal resistance can improve patient outcomes. Investment in vaccines may eliminate certain fungal diseases or lower incidence and mortality. Public health research priorities and approaches may vary by fungal pathogen.

Cost-effectiveness evaluation of routine histoplasmosis screening among people living with advanced HIV disease in Latin America and the Caribbean.

Histoplasma antigen can be detected in people with advanced HIV disease (AHD), allowing for early and accurate diagnosis of histoplasmosis. The aim of this analysis was to assess the cost-effectiveness of routine histoplasmosis screening using antigen detection, among people with AHD. We developed a decision analytic model to evaluate Histoplasma antigen screening among people with AHD. The model estimated the costs, effectiveness, and cost-effectiveness of routine screening for Histoplasma antigen compared to the current practice of no routine Histoplasma antigen screening. The model includes stratification by symptoms of histoplasmosis, severity of presentation, and estimates of 30-day mortality. Data sources were taken from the Pan American Health Organization (PAHO) Strategic Fund databases on public purchases of medicines, and published literature on treatment outcomes. Outcome measures are life years saved (LYS), costs (US dollars), and incremental cost-effectiveness ratios (ICERs). Routine Histoplasma antigen screening avoids an estimated 17% of deaths in persons with advanced HIV disease, and is cost-effective compared to no histoplasmosis screening, with an ICER of $26/LYS. In sensitivity analysis assuming treatment for histoplasmosis with liposomal amphotericin, Histoplasma antigen screening remains cost-effective with an ICER of $607/LYS. Histoplasma antigen screening among people with AHD is a cost-effective strategy and could potentially avert 17% of AIDS-related deaths. Prospective evaluation of histoplasmosis screening is warranted to determine effectiveness and treatment outcomes with this strategy.

Calcium Channel Blockers and the Risk of Exacerbation in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Study of 48,488 Outpatients.

Patients with chronic obstructive pulmonary disease (COPD) are prone to developing arterial hypertension, and many patients are treated with the calcium channel blocker amlodipine. However, it remains unclear whether using this drug potentially affects the risk of acute severe exacerbations (AECOPD) and all-cause mortality in these patients. The data were collected from Danish national registries, containing complete information on health, prescriptions, hospital admissions, and outpatient clinic visits. The COPD patients (n = 48,488) were matched via propensity score on known predictors of the primary outcome in an active comparator design. One group was exposed to amlodipine treatment, and the other was exposed to bendroflumethiazide, since both of these drugs are considered to be the first choice for the treatment of arterial hypertension according to Danish guidelines. The use of amlodipine was associated with a reduced risk of death from all causes at the 1-year follow-up (hazard ratio 0.69, 95% confidence interval: 0.62-0.76) compared with the use of bendroflumethiazide in the matched patients. No difference in the risk of severe AECOPD was found. In the COPD patients, amlodipine use was associated with a lower risk of death from all causes compared with the use of bendroflumethiazide. Amlodipine seems to be a safe first choice for the treatment of arterial hypertension in COPD patients.

Time-Updated Phenotypic Guidance of Corticosteroids and Antibiotics in COPD: Rationale, Perspective and a Proposed Method.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with distinct phenotypes, each having distinct treatment needs. Eosinophilic airway inflammation is present in a subset of COPD patients in whom it can act as a driver of exacerbations. Blood eosinophil counts are a reliable way to identify patients with an eosinophilic phenotype, and these measurements have proven to be successful in guiding the use of corticosteroids in moderate and severe COPD exacerbations. Antibiotic use in COPD patients induces a risk of Clostridium difficile infection, diarrhea, and antibiotic resistance. Procalcitonin could possibly guide antibiotic treatment in patients admitted with AECOPD. Current studies in COPD patients were successful in reducing exposure to antibiotics with no changes in mortality or length of stay. Daily monitoring of blood eosinophils is a safe and effective way to reduce oral corticosteroid exposure and side effects for acute exacerbations. No evidence on time-updated treatment guidance for stable COPD exists yet, but a current trial is testing an eosinophil-guided approach on inhaled corticosteroid use. Procalcitonin-guided antibiotic treatment in AECOPD shows promising results in safely and substantially reducing antibiotic exposure both in time-independent and time-updated algorithms.

Phylourny: efficiently calculating elimination tournament win probabilities via phylogenetic methods.

The prediction of knockout tournaments represents an area of large public interest and active academic as well as industrial research. Here, we show how one can leverage the computational analogies between calculating the phylogenetic likelihood score used in the area of molecular evolution to efficiently calculate, instead of approximate via simulations, the exact per-team tournament win probabilities, given a pairwise win probability matrix between all teams. We implement and make available our method as open-source code and show that it is two orders of magnitude faster than simulations and two or more orders of magnitude faster than calculating the exact per-team win probabilities naïvely, without taking into account the substantial computational savings induced by the tournament tree structure. Furthermore, we showcase novel prediction approaches that now become feasible due to this order of magnitude improvement in calculating tournament win probabilities. We demonstrate how to quantify prediction uncertainty by calculating 100,000 distinct tournament win probabilities for a tournament with 16 teams under slight variations of a reasonable pairwise win probability matrix within one minute on a standard laptop. We also conduct an analogous analysis for a tournament with 64 teams. Supplementary Information: The online version contains supplementary material available at 10.1007/s11222-023-10246-y.

Psychiatric Adverse Effects of Montelukast-A Nationwide Cohort Study.

BACKGROUND: Recent observational studies suggest that the leukotriene receptor antagonist montelukast may have neuropsychiatric adverse effects; however, results are conflicting. OBJECTIVE: To assess whether montelukast exposure in adults with asthma is associated with onset of neuropsychiatric adverse events using data from the Danish nationwide health registers. METHODS: Individuals 18 years old or older with either 1 or more prescription redemption of inhaled corticosteroids or with at least 1 hospital contact with asthma as the main diagnosis between January 1, 2011, and December 31, 2018, were included. Montelukast exposure was assessed as a time-dependent variable. The 2 outcomes of interest were use of neuropsychiatric medicine including antidepressants, antipsychotics, anxiolytics, lithium, and medication used for attention-deficit/hyperactivity disorder (outcome 1), and hospital contacts with a neuropsychiatric diagnosis (outcome 2), within 90 days of exposure to montelukast. RESULTS: Initiation of montelukast was significantly associated with outcome 1: use of neuropsychiatric medicine (hazard ratio [95% confidence interval]) 1.14 [1.08-1.20]; P < .0001). In the assessment of outcome 2: hospital contacts with a neuropsychiatric diagnosis, a significant risk associated with montelukast initiation was found only in the youngest age groups (hazard ratio [95% confidence interval] 1.28 [1.12-1.47], P < .001 and 1.16 [1.02-1.31]; P < .05, for age group 18-29 y and 30-44 y, respectively). Age-stratified analyses showed that the risk of both outcomes increased with decreasing age, with the highest risk seen in patients aged 18 to 29 years. CONCLUSIONS: Among younger individuals, montelukast use was significantly associated with an increased risk of neuropsychiatric events such as use of neuropsychiatric medicine and hospital treatment. Clinicians should increase awareness of such adverse effects when prescribing montelukast.

A multicenter survey of asymptomatic cryptococcal antigenemia among patients with advanced HIV disease in Nigeria.

As of 2018, cryptococcal antigen (CrAg) screening in patients with advanced human immunodeficiency virus (HIV) disease (AHD) was not routinely implemented in Nigeria despite being recommended in the national HIV treatment guidelines. Our aim was to determine the prevalence and risk factors for asymptomatic cryptococcal antigenemia in adult people living with HIV (PLHIV) in Nigeria to advocate for the implementation of routine CrAg screening. A descriptive cross-sectional study and CrAg screening of consecutive adult PLHIV with CD4 counts ≤200 cells/µL was conducted from April 2018 to April 2019 at HIV clinics in eleven tertiary hospitals spread across Nigeria's six geopolitical regions. Prevalence of asymptomatic cryptococcal antigenemia was estimated by facility and geopolitical zone. Logistic regression was conducted to identify risk factors for cryptococcal antigenemia. In total, 1,114 patients with AHD were screened. The overall prevalence of asymptomatic cryptococcal antigenemia was 3.9% with wide variation across facilities (range: 0/75 [0%]- 15/122 [12.3%]) and geopolitical zones (range: 0/75 [0%]-19/279 [6.8%]). Prevalence of antigenemia was highest in the South-West (19/279 [6.8%]) and lowest in the North-East (0/75 [0%]). Prevalence was 5.2% (26/512) and 3.2% (18/561) in patients with CD4<100 and CD4 of 101-200, respectively. Of all patients with antigenemia, 50% were on antiretroviral therapy (ART) at the time of having a positive CrAg test. In adjusted analysis, cryptococcal antigenemia was significantly less in patients on ART and patients who had completed any formal education. The survey showed a high overall burden of cryptococcal antigenemia in Nigeria, with variable prevalence across geopolitical regions. We provided valuable evidence for implementing routine CrAg screening of AHD patients in Nigeria which has commenced in selected centres.

Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma.

The aggressive biology of pancreatic ductal adenocarcinoma (PDAC), along with its limited sensitivity to many systemic therapies, presents a major challenge in the management of patients with metastatic PDAC. Over the past decade, the incorporation of combinatorial cytotoxic chemotherapy regimens has improved patient outcomes. Despite these advances, resistance to cytotoxic chemotherapy inevitably occurs, and there is a great need for effective therapies. A major focus of research has been to identify molecularly defined subpopulations of patients with PDAC who may benefit from targeted therapies that are matched to their molecular profile. Recent successes include the demonstration of the efficacy of maintenance PARP inhibition in PDAC tumors harboring deleterious BRCA1, BRCA2, and PALB2 alterations. In addition, while therapeutic targeting of KRAS was long thought to be infeasible, emerging data on the efficacy of KRAS G12C inhibitors have increased optimism about next-generation KRAS-directed therapies in PDAC. Meanwhile, KRAS wild-type PDAC encompasses a unique molecular subpopulation of PDAC that is enriched for targetable genetic alterations, such as oncogenic BRAF alterations, mismatch repair deficiency, and FGFR2, ALK, NTRK, ROS1, NRG1, and RET rearrangements. As more molecularly targeted therapies are developed, precision medicine has the potential to revolutionize the treatment of patients with metastatic PDAC.

Investigation of a Prolonged and Large Outbreak of Healthcare-Associated Mucormycosis Cases in an Acute Care Hospital-Arkansas, June 2019-May 2021.

Background: Outbreaks of healthcare-associated mucormycosis (HCM), a life-threatening fungal infection, have been attributed to multiple sources, including contaminated healthcare linens. In 2020, staff at Hospital A in Arkansas alerted public health officials of a potential HCM outbreak. Methods: We collected data on patients at Hospital A who had invasive mucormycosis during January 2017-June 2021 and calculated annual incidence of HCM (defined as mucormycosis diagnosed within ≥7 days after hospital admission). We performed targeted environmental assessments, including linen sampling at the hospital, to identify potential sources of infection. Results: During the outbreak period (June 2019-June 2021), 16 patients had HCM; clinical features were similar between HCM patients and non-HCM patients. Hospital-wide HCM incidence (per 100 000 patient-days) increased from 0 in 2018 to 3 in 2019 and 6 in 2020. For the 16 HCM patients, the most common underlying medical conditions were hematologic malignancy (56%) and recent traumatic injury (38%); 38% of HCM patients died in-hospital. Healthcare-associated mucormycosis cases were not epidemiologically linked by common procedures, products, units, or rooms. At Hospital A and its contracted offsite laundry provider, suboptimal handling of laundered linens and inadequate environmental controls to prevent mucormycete contamination were observed. We detected Rhizopus on 9 (9%) of 98 linens sampled at the hospital, including on linens that had just arrived from the laundry facility. Conclusions: We describe the largest, single-center, HCM outbreak reported to date. Our findings underscore the importance of hospital-based monitoring for HCM and increased attention to the safe handling of laundered linens.