Taxanes for the treatment of breast cancer during pregnancy: an international cohort study.

INTRODUCTION: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. METHODS: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. RESULTS: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). CONCLUSION: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated.

Implementation of robotic pancreaticoduodenectomy at a community tertiary care hospital utilizing a comprehensive curriculum.

BACKGROUND: We evaluated the outcomes of a robotic pancreaticoduodenectomy (RPD) program implemented at a community tertiary care hospital. METHODS: A retrospective review of 65 RPD cases compared surgical outcomes and performance to benchmark data. RESULTS: Postoperative complications occurred in 31% (20) of patients vs. ≤73% (variance -42), with grade IV complications in 3% (2) vs. ≤5% (variance -2). Postoperative pancreatic fistula type B frequency was 12% (8) vs. ≤15% (variance -3). One 90-day mortality occurred (1.5% vs. 1.6%). Failure to rescue rate was 7% vs. ≤9% (variance -2), and R1 resection rate was 2% vs. ≤39% (variance -37). There was a downward trend of operative time (rho â€‹= â€‹-0.600, P â€‹< â€‹0.001), with a learning curve of 27 cases. Median hospital length of stay was 6 days vs. ≤15 days (variance -9). CONCLUSION: Our comprehensive RPD training program resulted in improved operative performance and outcomes commensurate with benchmark thresholds.

The Psychosocial Impact of the COVID-19 Pandemic on Adolescent and Young Adult Cancer Survivors in the United States: An Integrative Review.

Adolescent and young adult cancer survivors (AYAs) are uniquely challenged with navigating health care systems during an important developmental phase of life. During the Coronavirus disease 2019 (COVID-19) pandemic, many people experienced social isolation, mental health symptoms, and schooling and employment changes, which may have affected vulnerable AYA cancer survivors. The purpose of this integrative review is to explore the psychosocial impact of the COVID-19 pandemic on AYA cancer survivors in the United States. A literature search was conducted in November 2022 using PubMed, Web of Science, and SCOPUS databases with the following search terms: distress*, depress*, lonel*, anx*, insomnia*, cancer*, neoplasm, COVID-19, coronavirus, young adult, AYA, teen*, and adolescen*. The initial search yielded 468 articles. Inclusion criteria required that studies were conducted in the United States, published in English, with a sample of patients diagnosed with cancer between ages 15 and 39. After review and appraisal of each relevant article, eight were included. Through comparative analysis of eight articles, including qualitative and quantitative studies, three themes emerged: mental health impact, health care impact, and financial impact. Mental health impact included increased anxiety, worsening depression and social isolation, and sleep disturbances. Changes in health care included delays in care, medical cost-coping and benefits of virtual care. Financial difficulties included employment changes and benefits of remote work. The COVID-19 pandemic had an immense impact on the psychosocial health of AYA cancer survivors. It is essential that oncology providers and health care teams consider specific interventions to best serve the psychosocial needs of their AYA patients.

Comparative antimicrobial use in coronavirus disease 2019 (COVID-19) and non-COVID-19 inpatients from 2019 to 2020: A multicenter ecological study.

OBJECTIVE: We sought to determine whether increased antimicrobial use (AU) at the onset of the coronavirus disease 2019 (COVID-19) pandemic was driven by greater AU in COVID-19 patients only, or whether AU also increased in non-COVID-19 patients. DESIGN: In this retrospective observational ecological study from 2019 to 2020, we stratified inpatients by COVID-19 status and determined relative percentage differences in median monthly AU in COVID-19 patients versus non-COVID-19 patients during the COVID-19 period (March-December 2020) and the pre-COVID-19 period (March-December 2019). We also determined relative percentage differences in median monthly AU in non-COVID-19 patients during the COVID-19 period versus the pre-COVID-19 period. Statistical significance was assessed using Wilcoxon signed-rank tests. SETTING: The study was conducted in 3 acute-care hospitals in Chicago, Illinois. PATIENTS: Hospitalized patients. RESULTS: Facility-wide AU for broad-spectrum antibacterial agents predominantly used for hospital-onset infections was significantly greater in COVID-19 patients versus non-COVID-19 patients during the COVID-19 period (with relative increases of 73%, 66%, and 91% for hospitals A, B, and C, respectively), and during the pre-COVID-19 period (with relative increases of 52%, 64%, and 66% for hospitals A, B, and C, respectively). In contrast, facility-wide AU for all antibacterial agents was significantly lower in non-COVID-19 patients during the COVID-19 period versus the pre-COVID-19 period (with relative decreases of 8%, 7%, and 8% in hospitals A, B, and C, respectively). CONCLUSIONS: AU for broad-spectrum antimicrobials was greater in COVID-19 patients compared to non-COVID-19 patients at the onset of the pandemic. AU for all antibacterial agents in non-COVID-19 patients decreased in the COVID-19 period compared to the pre-COVID-19 period.

Improvement in Post-traumatic Stress Symptoms Following an Internet-based Cognitive-Behavioral Intervention for Insomnia: An Open Trial among Rural Appalachian Women.

Appalachian women face significant health disparities and have limited access to health care. Mental health conditions and treatment-seeking are stigmatized in Appalachian communities. Appalachian women may benefit from web-based interventions targeting less stigmatized health complaints (e.g., insomnia), while simultaneously yielding benefit in associated mental health conditions including symptoms of post-traumatic stress disorder (PTSD). In this study, 37 trauma-exposed adult women aged 45 and older from rural Appalachian Kentucky completed a six-session online self-administered cognitive behavioral therapy for insomnia (CBT-I) intervention and completed measures of PTSD symptoms, insomnia, and depression at pre- and post-treatment. Participants reported a significant reduction in PTSD symptoms from pre- to post-intervention, and this remained significant after adjusting for severity of insomnia and depression pre-treatment. Pending replication in a randomized controlled trial, web-based CBT-I may offer an adjunctive mental health treatment option that circumvents cultural stigmas and reduces PTSD symptoms for trauma-exposed Appalachian women.

Validity of the Spanish-Language Patient Health Questionnaires 2 and 9: A Systematic Review and Meta-Analysis.

Importance: Reliable screening for major depressive disorder (MDD) relies on valid and accurate screening tools. Objective: To examine the validity, accuracy, and reliability of the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) to screen for MDD. Data Sources: PubMed, Web of Science, Embase, and PsycINFO from data initiation through February 27, 2023. Study Selection: English- and Spanish-language studies evaluating the validity of the Spanish-language PHQ-2 or PHQ-9 in screening adults for MDD compared with a standardized clinical interview (gold standard). Search terms included PHQ-2, PHQ-9, depression, and Spanish. Data Extraction and Synthesis: Two reviewers performed abstract and full-text reviews, data extraction, and quality assessment. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Random-effects meta-analyses of sensitivity, specificity, and area under the curve (AUC) were performed. Internal consistency was evaluated using Cronbach α and McDonald ψ. Main Outcomes and Measures: Test accuracy and internal consistency. The PHQ-2 is composed of the first 2 questions of the PHQ-9 (targeting core depression symptoms of depressed mood and anhedonia; a score of 3 or higher (score range, 0-6) is generally considered a positive depression screen. If a patient screens positive with the PHQ-2, a follow-up assessment with the PHQ-9 and a clinical diagnostic evaluation are recommended. Once depression is diagnosed, a PHQ-9 score of 10 or higher (score range, 0-27) is often considered an acceptable threshold for treating depression. Results: Ten cross-sectional studies involving 5164 Spanish-speaking adults (mean age range, 34.1-71.8 years) were included; most studies (n = 8) were in primary care settings. One study evaluated the PHQ-2, 7 evaluated the PHQ-9, and 2 evaluated both the PHQ-2 and PHQ-9. For the PHQ-2, optimal cutoff scores ranged from greater than or equal to 1 to greater than or equal to 2, with an overall pooled sensitivity of 0.89 (95% CI, 0.81-0.95), overall pooled specificity of 0.89 (95% CI, 0.81-0.95), and overall pooled AUC of 0.87 (95% CI, 0.83-0.90); Cronbach α was 0.71 to 0.75, and McDonald ψ was 0.71. For the PHQ-9, optimal cutoff scores ranged from greater than or equal to 5 to greater than or equal to 12, with an overall pooled sensitivity of 0.86 (95% CI, 0.82-0.90), overall pooled specificity of 0.80 (95% CI, 0.75-0.85), and overall pooled AUC of 0.88 (95% CI, 0.87-0.90); Cronbach α was 0.78 to 0.90, and McDonald ψ was 0.79 to 0.90. Four studies were considered to have low risk of bias; 6 studies had indeterminate risk of bias due to a lack of blinding information. Conclusions and Relevance: In this systematic review and meta-analysis, limited available evidence supported the use of the Spanish-language PHQ-2 and PHQ-9 in screening for MDD, but optimal cutoff scores varied greatly across studies, and few studies reported on blinding schemes. These results suggest that MDD should be considered in Spanish-speaking individuals with lower test scores. Given the widespread clinical use of the tools and the heterogeneity of existing evidence, further investigation is needed.

Quality of Life in Adult Cancer Patients With Underage Children: An Integrative Review.

As many as 24.7% of cancer patients are also parents to children younger than 18 years of age. This population faces unique challenges, and quality of life in parental cancer patients has not been well studied. This integrative review assessed parental cancer patients' quality of life. PubMed and Scopus were searched using the following terms: quality of life, distress, anxiety, coping, emotion, social support, employment, work, psychosocial, physical, function, parental cancer, and parents with cancer. English publications conducted within the past 15 years that used an objective instrument to measure quality of life in adult cancer patients with children 18 years of age or younger were included. Studies with an intervention focus were excluded. After review of 672 articles, nine studies met the criteria for inclusion. Several instruments were utilized to measure quality of life. Some parental cancer patients reported decreased quality of life when compared with other cancer patients and the general population at diagnosis and years after. Parental cancer patients may be at an increased risk of decreased quality of life. With this understanding, health-care providers should complete comprehensive assessments routinely so that these patients' unique needs may be more adequately addressed.

A new leadership frontier: Nurse practitioners and physician associates as inpatient medical directors.

ABSTRACT: Nurse practitioners and physician associates (NPs and PAs) have become an integral part of health care delivery in every clinical setting. Both NPs and PAs possess the knowledge and skills to deliver quality care to patients that may otherwise go without. There is a push to have NPs and PAs work to the top of their licenses and take on leadership roles as they help reshape health care delivery in the United States. However, high-level leadership positions for this group of clinicians are not abundant, and no specific pathway has been established to develop these skills. The aim of this report is to share the early experience of a small group of NPs and PAs, given the opportunity to function as inpatient medical directors (IMD) and the qualities that make them ideal for this novel leadership role.

An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele.

Carrying the apolipoprotein E (ApoE) Ɛ4 allele is associated with an increased risk of cerebral amyloidosis and late-onset Alzheimer's disease, but the degree to which apoE glycosylation affects its development is not clear. In a previous pilot study, we identified distinct total and secondary isoform-specific cerebral spinal fluid (CSF) apoE glycosylation profiles, with the E4 isoform having the lowest glycosylation percentage (E2 > E3 > E4). In this work, we extend the analysis to a larger cohort of individuals (n = 106), utilizing matched plasma and CSF samples with clinical measures of AD biomarkers. The results confirm the isoform-specific glycosylation of apoE in CSF, resulting from secondary CSF apoE glycosylation patterns. CSF apoE glycosylation percentages positively correlated with CSF Aß42 levels (r = 0.53, p < 0.0001). These correlations were not observed for plasma apoE glycosylation. CSF total and secondary apoE glycosylation percentages also correlated with the concentration of CSF small high-density lipoprotein particles (s-HDL-P), which we have previously shown to be correlated with CSF Aß42 levels and measures of cognitive function. Desialylation of apoE purified from CSF showed reduced Aß42 degradation in microglia with E4 > E3 and increased binding affinity to heparin. These results indicate that apoE glycosylation has a new and important role in influencing brain Aß metabolism and can be a potential target of treatment.

Acceptability of patient-centered, multi-disciplinary medication therapy management recommendations: results from the INCREASE randomized study.

BACKGROUND: Polypharmacy and inappropriate medications may be a modifiable risk factor for Alzheimer's Disease and Related Dementias (ADRD). Medication therapy management (MTM) interventions may mitigate medication-induced cognitive dysfunction and delay onset of symptomatic impairment. The objective of the current study is to describe an MTM protocol for a patient-centered team intervention (pharmacist and non-pharmacist clinician) in a randomized controlled trial (RCT) directed at delaying the symptomatic onset of ADRD. METHODS: Community dwelling adults 65 + years, non-demented, using ≥ 1 potentially inappropriate medications (PIM) were enrolled in an RCT to evaluate the effect of an MTM intervention on improving medication appropriateness and cognition (NCT02849639). The MTM intervention involved a three-step process: (1) pharmacist identified potential medication-related problems (MRPs) and made initial recommendations for prescribed and over-the-counter medications, vitamins, and supplements; (2) study team reviewed all initial recommendations together with the participants, allowing for revisions prior to the finalized recommendations; (3) participant responses to final recommendations were recorded. Here, we describe initial recommendations, changes during team engagement, and participant responses to final recommendations. RESULTS: Among the 90 participants, a mean 6.7 ± 3.6 MRPs per participant were reported. Of the 259 initial MTM recommendations made for the treatment group participants (N = 46), 40% percent underwent revisions in the second step. Participants reported willingness to adopt 46% of final recommendations and expressed need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications. CONCLUSION: The evaluation of modifications to MTM recommendations demonstrated that pharmacists' initial MTM recommendations often changed following the participation in the multidisciplinary decision-making process that incorporated patient preferences. The team was encouraged to see a correlation between engaging patients and a positive overall response towards participant acceptance of final MTM recommendations. TRIAL REGISTRATION: Study registration number: clinicaltrial.gov NCT02849639 registered on 29/07/2016.

Kappa opioid receptor agonists produce sexually dimorphic and prolactin-dependent hyperalgesic priming.

ABSTRACT: Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we hypothesized that repeated administration of KOR agonists might mimic, in part, stress-induced hyperalgesic priming. The potential contribution of circulating prolactin (PRL) and dysregulation of the expression of PRL receptor (PRLR) isoforms in sensory neurons after KOR agonist administration was also investigated. Mice received 3 daily doses of U-69593 or nalfurafine as a "first-hit" stimulus followed by assessment of periorbital tactile allodynia. Sixteen days after the first KOR agonist administration, animals received a subthreshold dose of inhalational umbellulone, a TRPA1 agonist, as the second-hit stimulus and periorbital allodynia was assessed. Cabergoline, a dopamine D2 receptor agonist, was used to inhibit circulating PRL in additional cohorts. Prolactin receptor isoforms were quantified in the V1 region of the trigeminal ganglion after repeated doses of U-69593. In both sexes, KOR agonists increased circulating PRL and produced allodynia that resolved within 14 days. Hyperalgesic priming, revealed by umbellulone-induced allodynia in animals previously treated with the KOR agonists, also occurred in both sexes. However, repeated U-69593 downregulated the PRLR long isoform in trigeminal neurons only in female mice. Umbellulone-induced allodynia was prevented by cabergoline co-treatment during priming with KOR agonists in female, but not male, mice. Hyperalgesic priming therefore occurs in both sexes after either biased or nonbiased KOR agonists. However, a PRL/PRLR-dependence is observed only in female nociceptors possibly contributing to pain in stress-related pain disorders in females.

The small HDL particle hypothesis of Alzheimer's disease.

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

Role of Preemptive Cytomegalovirus Hyperimmunoglobulin in Cytomegalovirus Viremia Following Stem Cell Transplant: An Integrative Review.

Introduction: Cytomegalovirus (CMV) is a major cause of morbidity and mortality in stem cell transplant (SCT) patients. Cytomegalovirus hyperimmunoglobulin (CMV-HIG) therapy has been described in the solid organ transplant setting. However, no review has focused on preemptive use of intravenous CMV immunoglobulins in the SCT setting. This review aims to consolidate findings regarding the preemptive use of CMV-HIG for CMV viremia in SCT patients. Methods: PubMed and Scopus were searched using specific search criteria for publications from 2011 to 2021. Search terms were: cytomegalovirus, CMV, immunoglobulins, immunoglobulin, IVIG, CMVIG, hematopoietic stem cell transplantation, and stem cell. Included studies discussed stem cell transplantation, immunoglobulins, and cytomegalovirus. 366 articles were identified from the search. Five articles met the inclusion and exclusion criteria. Results: Preemptive CMV-HIG resulted in an overall response in 65% to 100% of patients with a clearance time of 14 to 21 days. Early use of CMV-HIG may shorten clearance time. No treatment-related mortality or serious adverse events were associated. Conclusion: CMV-HIG is an effective treatment option in SCT patients that is as safe as antivirals alone. Preemptive CMV-HIG with antivirals may provide the added advantage of reduced time to viremia clearance without adding renal injury. Larger, prospective studies are needed to evaluate CMV-HIG's impact on time to viremia clearance and the effectiveness of preemptive CMV-HIG use with antivirals.

Timely Genetic Testing and Therapy Management in Patients With gBRCA-Mutated Metastatic Breast Cancer Receiving Talazoparib.

Talazoparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that has demonstrated strong efficacy with manageable side effects for patients with germline breast cancer susceptibility genes 1 or 2 (gBRCA1/2)- mutated, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer (mBC) in the EMBRACA and ABRAZO trials. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer recommend genetic testing for all patients with recurrent or metastatic BC to identify those with a gBRCA1/2 mutation who would benefit from treatment with a PARP inhibitor. However, many patients who meet these criteria do not receive genetic testing for a variety of reasons. Advanced practitioners (APs) can play a key role in the care of these patients by guiding them through the genetic testing process and explaining how the results impact treatment choices. A hypothetical case study highlighting a 42-year-old woman who received a diagnosis of triple-negative mBC provides an example of genetic testing strategies, as well as management considerations, with the use of talazoparib that can be implemented by APs. The efficacy and safety of talazoparib are reviewed along with practical guidance on its use (i.e., managing adverse events and drug interactions) to optimize patient outcomes. The patient case described in this publication is fictional and does not represent actual events or a response from an actual patient. The authors developed this fictional case for educational purposes only.

Computing antimicrobial use/antimicrobial resistance ratios: A novel way to assess inpatient antimicrobial utilization using current National Healthcare Safety Network metrics.

BACKGROUND: Current methods for benchmarking inpatient antimicrobial use (AU) could benefit from combining AU with antimicrobial resistance (AR) information to provide metrics benchmarked to microbiological data; this may yield more instructive and better risk-adjusted measurements than AU and AR in isolation. METHODS: In this retrospective single-center study, we computed facility-wide AU/AR ratios from 2019 to 2020 for specific antimicrobial agents and corresponding AR events, and compared median monthly AU/AR ratios between March 2019 through December 2019 (pre-COVID period) and March 2020 through December 2020 (COVID period). Aggregate AU was expressed as a ratio to aggregate AR events for antimicrobials that typically have activity against the AR organism and are frequently used to treat the AR organism in clinical practice. We also computed AU/AR ratios in our surgical intensive care unit in the pre-COVID period. RESULTS: High-median facility-wide monthly AU/AR ratios were observed for intravenous vancomycin/methicillin-resistant Staphylococcus aureus, with 130.0 in the pre-COVID period and 121.3 in the COVID period (p =.520). Decreases in facility-wide median monthly AU/AR ratios were observed between periods for meropenem/ESBL Enterobacterales (20.9 vs. 7.9, p < .001), linezolid/vancomycin-resistant Enterococcus (48.5 vs. 15.8, p =.004), and daptomycin/vancomycin-resistant Enterococcus (32.2 vs. 4.8, p = .002). Increases in facility-wide median monthly AU/AR ratios were observed between periods for ceftazidime-avibactam/carbapenem-resistant Enterobacterales (0.0 vs. 3.2, p = .020) and ceftazidime-avibactam/multidrug-resistant Pseudomonas aeruginosa (0.0 vs. 4.0, p = .017). The AU/AR ratio for intravenous vancomycin/methicillin-resistant S. aureus in the surgical intensive care unit was 191.5 in the pre-COVID period. CONCLUSIONS: AU/AR ratios may be used to supplement current AU and AR metrics. Future directions should include the development of more AU metrics benchmarked to microbiological information. AU metrics more specific to transplant infectious diseases should be developed.

Exploring the neurobiology of the premonitory phase of migraine preclinically - a role for hypothalamic kappa opioid receptors?

BACKGROUND: The migraine premonitory phase is characterized in part by increased thirst, urination and yawning. Imaging studies show that the hypothalamus is activated in the premonitory phase. Stress is a well know migraine initiation factor which was demonstrated to engage dynorphin/kappa opioid receptors (KOR) signaling in several brain regions, including the hypothalamus. This study proposes the exploration of the possible link between hypothalamic KOR and migraine premonitory symptoms in rodent models. METHODS: Rats were treated systemically with the KOR agonist U-69,593 followed by yawning and urination monitoring. Apomorphine, a dopamine D1/2 agonist, was used as a positive control for yawning behaviors. Urination and water consumption following systemic administration of U-69,593 was also assessed. To examine if KOR activation specifically in the hypothalamus can promote premonitory symptoms, AAV8-hSyn-DIO-hM4Di (Gi-DREADD)-mCherry viral vector was microinjected into the right arcuate nucleus (ARC) of female and male KORCRE or KORWT mice. Four weeks after the injection, clozapine N-oxide (CNO) was administered systemically followed by the assessment of urination, water consumption and tactile sensory response. RESULTS: Systemic administration of U-69,593 increased urination but did not produce yawning in rats. Systemic KOR agonist also increased urination in mice as well as water consumption. Cell specific Gi-DREADD activation (i.e., inhibition through Gi-coupled signaling) of KORCRE neurons in the ARC also increased water consumption and the total volume of urine in mice but did not affect tactile sensory responses. CONCLUSION: Our studies in rodents identified the KOR in a hypothalamic region as a mechanism that promotes behaviors consistent with clinically-observed premonitory symptoms of migraine, including increased thirst and urination but not yawning. Importantly, these behaviors occurred in the absence of pain responses, consistent with the emergence of the premonitory phase before the headache phase. Early intervention for preventive treatment even before the headache phase may be achievable by targeting the hypothalamic KOR.

Effect of the ABCA1 agonist CS-6253 on amyloid-ß and lipoprotein metabolism in cynomolgus monkeys.

BACKGROUND: Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer's disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-ß peptides (Aß) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans. METHODS: CS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aß were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models. RESULTS: Following CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aß42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aß42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids. CONCLUSIONS: Treatment with the ABCA1 agonist CS-6253 appears to favor Aß clearance from the brain.

Hospital-acquired coronavirus disease 2019 (COVID-19) among patients of two acute-care hospitals: Implications for surveillance.

OBJECTIVES: We quantified hospital-acquired coronavirus disease 2019 (COVID-19) during the early phases of the pandemic, and we evaluated solely temporal determinations of hospital acquisition. DESIGN: Retrospective observational study during early phases of the COVID-19 pandemic, March 1-November 30, 2020. We identified laboratory-detected severe acute respiratory coronavirus virus 2 (SARS-CoV-2) from 30 days before admission through discharge. All cases detected after hospital day 5 were categorized by chart review as community or unlikely hospital-acquired cases, or possible or probable hospital-acquired cases. SETTING: The study was conducted in 2 acute-care hospitals in Chicago, Illinois. PATIENTS: The study included all hospitalized patients including an inpatient rehabilitation unit. INTERVENTIONS: Each hospital implemented infection-control precautions soon after identifying COVID-19 cases, including patient and staff cohort protocols, universal masking, and restricted visitation policies. RESULTS: Among 2,667 patients with SARS-CoV-2, detection before hospital day 6 was most common (n = 2,612; 98%); detection during hospital days 6-14 was uncommon (n = 43; 1.6%); and detection after hospital day 14 was rare (n = 16; 0.6%). By chart review, most cases after day 5 were categorized as community acquired, usually because SARS-CoV-2 had been detected at a prior healthcare facility (68% of cases on days 6-14 and 53% of cases after day 14). The incidence rates of possible and probable hospital-acquired cases per 10,000 patient days were similar for ICU- and non-ICU patients at hospital A (1.2 vs 1.3 difference, 0.1; 95% CI, -2.8 to 3.0) and hospital B (2.8 vs 1.2 difference, 1.6; 95% CI, -0.1 to 4.0). CONCLUSIONS: Most patients were protected by early and sustained application of infection-control precautions modified to reduce SARS-CoV-2 transmission. Using solely temporal criteria to discriminate hospital versus community acquisition would have misclassified many "late onset" SARS-CoV-2-positive cases.