Managing Modern Antiretroviral Therapy in the Intensive Care Unit: Overcoming Challenges for Critically Ill People With Human Immunodeficiency Virus.

People with human immunodeficiency virus (HIV) have a 50% excess risk for intensive care unit (ICU) admission, often for non-HIV-related conditions. Despite this, clear guidance for managing antiretroviral therapy (ART) in this setting is lacking. Selecting appropriate ART in the ICU is complex due to drug interactions, absorption issues, and dosing adjustments. Continuing ART in the ICU can be challenging due to organ dysfunction, drug interactions, and formulary limitations. However, with careful consideration, continuation is often feasible through dose adjustments or alternative administration methods. Temporary discontinuation of ART may be beneficial depending on the clinical scenario. Clinicians should actively seek resources and support to mitigate adverse events and drug interactions in critically ill people with HIV. Navigating challenges in the ICU can optimize ART and improve care and outcomes for critically ill people with HIV. This review aims to identify strategies for addressing the challenges associated with the use of modern ART in the ICU.

Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy.

OBJECTIVE: To provide updates on the epidemiology and recommendations for management of candidemia in patients with critical illness. DATA SOURCES: A literature search using the PubMed database (inception to March 2023) was conducted using the search terms "invasive candidiasis," "candidemia," "critically ill," "azoles," "echinocandin," "antifungal agents," "rapid diagnostics," "antifungal susceptibility testing," "therapeutic drug monitoring," "antifungal dosing," "persistent candidemia," and "Candida biofilm." STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Ongoing trials were identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 109 articles were reviewed including 25 pharmacokinetic/pharmacodynamic studies and 30 studies including patient data, 13 of which were randomized controlled clinical trials. The remaining 54 articles included fungal surveillance data, in vitro studies, review articles, and survey data. The current 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Management of Candidiasis provides recommendations for selecting empiric and definitive antifungal therapies for candidemia, but data are limited regarding optimized dosing strategies in critically ill patients with dynamic pharmacokinetic changes or persistent candidemia complicated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Outcomes due to candidemia remain poor despite improved diagnostic platforms, antifungal susceptibility testing, and antifungal therapy selection for candidemia in critically ill patients. Earlier detection and identification of the species causing candidemia combined with recognition of patient-specific factors leading to dosing discrepancies are crucial to improving outcomes in critically ill patients with candidemia. CONCLUSIONS: Treatment of candidemia in critically ill patients must account for the incidence of non-albicans Candida species and trends in antifungal resistance as well as overcome the complex pathophysiologic changes to avoid suboptimal antifungal exposure.

Kimyrsa and Orbactiv - A Tale of Two Formulations.

Kimyrsa is a new formulation (NF) of the original formulation of oritavancin ([OF] Orbactiv). Comparatively, the obvious benefit with this product is the shortened infusion time and flexibility with solution compatibility, but otherwise maintains a similar pharmacokinetic and microbiologic profile. At present, the NF lacks significant real-world experience relative to other available lipoglycopeptides and thus its place in therapy remains difficult to predict but would not be expected to be significantly different than its OF.

IL-6 evoked biochemical changes in prostate cancer cells.

The pro-inflammatory cytokine IL-6 has been associated with the progression of PCa to a castration-resistant phenotype. In this work, we characterized the biochemical changes evoked by IL-6 in three different models of PCa cells, including LNCaP, C4-2, and PC3. The effect of IL-6 on PCa cells was compared with the effect obtained by co-stimulation with the cAMP-inducing agent forskolin (FSK). Stimulation of LNCaP cells with IL-6 or IL-6 + FSK evoked increased expression of the neuroendocrine marker tubulin IIIß and Cav3.2 T-type Ca2+ channel subunit. PC3 cells, representing a more advanced state of PCa, had high levels of tubulin IIIß expression without any further changes observed by treatment with IL-6 or IL-6 + FSK. Elevated expression of the glucocorticoid receptor was observed in PC3, but not in LNCaP or C4-2 cells. Glucocorticoid receptor expression was not regulated by IL-6 stimulation of LNCaP or C4-2 cells. IL-6 acting alone or together with FSK evoked a significant reduction in the expression of the transcription factor REST and retinoblastoma tumor suppressor protein Rb1. In LNCaP cells, IL-6 acting alone or together with FSK had no effect on the expression of several biological markers of advanced PCa, including Aurora kinase A, valosin-containing protein, calcium-sensing receptor, calreticulin, S100A protein, and Protein S. In PC3 cells, co-treatment with IL-6 + FSK evoked increased expression of REST and S100A proteins, as well as a reduction in Protein S levels. These findings reveal a complex pattern of biochemical changes in PCa cells under the influence of IL-6.

Characteristics and Outcomes of Cryptococcosis among Patients with and without COVID-19.

The effect of COVID-19 on the risk and prognosis of cryptococcosis is unclear. We compared the characteristics and outcomes of cryptococcosis in patients with and without COVID-19. Patients 18 years and older with cryptococcosis were identified from TriNetX and separated into two cohorts based on a diagnosis of COVID-19 within 3 months of the index diagnosis of cryptococcosis. Differences examined between groups included comorbidities, immunosuppressive medications, ED visits, hospitalizations, ICU admissions, mechanical ventilation, and deaths. The propensity score matching was performed based on demographics and comorbidities. Of the 6998 patients with cryptococcosis included, 4.4% (n = 306) had COVID-19 prior to cryptococcosis. Mortality was higher in patients with COVID-19 compared to those without COVID-19 (14% vs. 11%, p = 0.032). Additionally, those with COVID-19 were older (55.2 ± 14.4 vs. 51.9 ± 15.2 years, p < 0.001) with higher rates of transplant (29% vs. 13%, p < 0.001), neoplastic disease (37% vs. 21%, p < 0.001), chronic kidney disease (42% vs. 18%, p < 0.001), or diabetes (35% vs. 19%, p < 0.001) but not HIV (30% vs. 31%, p = 0.618). Glucocorticoid use was more common in those with COVID-19 (52% vs. 27%, p < 0.001). More patients with COVID-19 required ED visits (29% vs. 23%, p = 0.025) and ICU admission (18% vs. 11%, p < 0.001). After propensity score matching, patients with COVID-19 had higher rates of neoplastic disease, heart failure, chronic kidney disease, and glucocorticoid use but did not experience worse outcomes compared to those without COVID-19. Patients with COVID-19 who developed cryptococcosis had independently higher rates of comorbidities and glucocorticoid use but similar outcomes, including death, versus those without COVID-19.

Cryptococcosis in a patient with multiple myeloma receiving pomalidomide: a case report and literature review.

While overall survival with multiple myeloma (MM) has improved, patients suffer from overwhelming tumor burden, MM-associated comorbidities, and frequent relapses requiring administration of salvage therapies. As a result, this vicious cycle is often characterized by cumulative immunodeficiency stemming from a combination of disease- and treatment-related factors leading to neutropenia, T-cell deficiency, and hypogammaglobulinemia. Infectious etiologies differ based on the duration of MM and treatment-related factors, such as number of previous treatments and cumulative dose of corticosteroids. Herein, we present the case of a patient who was receiving pomalidomide without concomitant corticosteroids for MM and was later found to have cryptococcosis, as well as findings from a literature review. Most cases of cryptococcosis are reported in patients with late-stage MM, as well as those receiving novel anti-myeloma agents, such as pomalidomide, in combination with corticosteroids or following transplantation. However, it is likely cryptococcosis may be underdiagnosed in this population. Due to the cumulative immunodeficiency present in patients with MM, clinicians must be suspicious of cryptococcosis at any stage of MM.

Cryptococcosis among hospitalised patients with COVID-19: A multicentre research network study.

It is unclear if there is an association between COVID-19 and cryptococcosis. Therefore, this study aimed to describe the clinical features, risk factors, and outcomes associated with cryptococcosis in hospitalised patients with COVID-19. The objectives of this study were to determine the incidence of and examine factors associated with cryptococcosis after a diagnosis of COVID-19. We used TriNetX to identify and sort patients 18 years and older hospitalised with COVID-19 into two cohorts based on the presence or absence of a diagnosis of cryptococcosis following diagnosis of COVID-19. Outcomes of interest included the incidence of cryptococcosis following the diagnosis of COVID-19 as well as the proportion of patients in each group who had underlying comorbidities, received immunomodulatory therapy, required ICU admission or mechanical ventilation (MV), or died. Propensity score matching was used to adjust for confounding. Among 212,479 hospitalised patients with COVID-19, 65 developed cryptococcosis. The incidence of cryptococcosis following COVID-19 was 0.022%. Patients with cryptococcosis were more likely to be male and have underlying comorbidities. Among cases, 32% were people with HIV. Patients with cryptococcosis were more likely to have received tocilizumab (p < .0001) or baricitinib (p < .0001), but not dexamethasone (p = .0840). ICU admission (38% vs 29%), MV (23% vs 11%), and mortality (36% vs 14%) were significantly higher among patients with cryptococcosis. Mortality remained elevated after adjusted propensity score matching. Cryptococcosis occurred most often in hospitalised patients with COVID-19 who had traditional risk factors, comparable to findings in patients without COVID-19. Cryptococcosis was associated with increased ICU admission, MV, and mortality.

Cervical ripening with laminaria tents prior to second trimester induction of labor.

BACKGROUND: Induction abortion in the second trimester may be favored in some instances, such as in women with compounding medical conditions or when skilled providers are not available. Various methods of pre-induction cervical preparation have been used to shorten the length of induction and decrease the risk of complications. The benefits of cervical preparation with laminaria before D&E have been well studied, but the benefits of laminaria before medical induction are less clear. OBJECTIVE: To determine if overnight cervical preparation with laminaria tents shortens delivery interval in women undergoing 2nd trimester induction of labor (IOL) with misoprostol. STUDY DESIGN: This was a retrospective cohort study comparing overnight intracervical laminaria placement followed by misoprostol to misoprostol alone for 2nd trimester IOL between 1/2000 and 12/2010. Women were excluded if the reason for IOL was preterm labor or preterm premature rupture of membranes or if misoprostol was not used as the primary induction agent. The primary outcome was time from misoprostol administration to delivery. RESULTS: 126 women were analyzed including 36 (29%) who received laminaria + misoprostol and 90 (71%) who received misoprostol alone. Women in the laminaria + misoprostol group were significantly older (30 yrs [14-44] vs. 27 yrs [17-43], p = .029). Induction for fetal anomaly (92% vs. 34%, p ≤ .001) and the use of feticide (56% vs. 13%, p ≤ .001) were more common in the laminaria + misoprostol group. The mean time to delivery in the laminaria + misoprostol group was 6 h longer compared to the misoprostol only group; 19 ± 8 h compared to 13 ± 12hrs (p = .007). There was no difference in fetal to placental delivery time (p = .329), total misoprostol dose (p = .182), or length of hospitalization (p = .144) however, significantly more women completed abortion at 24 hrs in the misoprostol alone group (90% vs. 61%, p ≤ .001). CONCLUSIONS: The use of laminaria tents for overnight cervical preparation does not expedite delivery times in patients undergoing 2nd trimester IOL with misoprostol.

Incidence and utility of follow-up blood cultures in cancer patients with gram-negative bacteremia.

Benefit of follow-up blood cultures (FUBC) in cancer patients with gram-negative bacteremia (GNB) is unknown. Multicenter, retrospective review was performed in adult cancer patients with GNB between January and December 2018. Primary outcome was FUBC incidence. Chi-square, t-tests/Wilcoxon rank-sum, and bivariate regression (logistic/Poisson) analyses compared secondary outcomes (catheter removal, ID consultation, antibiotic duration, length stay, mortality) between patients with versus without FUBC. Of 52 patients with GNB, majority (35/52; 67%) received ≥1 FUBC (mean per patient 3.6, SD 4.3, range 0-29). Majority FUBC had no growth (157/173; 90.8%). Rates of catheter removal and ID consultation were similar between groups (P > 0.05). Patients with FUBC had greater LOS (mean 21 vs 15 days; coefficient = 0.31, CI 0.17-0.45), longer duration of antibiotics (mean 13 vs 11 days, coefficient 0.19, P = 0.013), but no mortality difference (P = 1). FUBC are frequently performed yet infrequently positive in cancer patients with GNB, but were associated with increased LOS and antibiotic duration.

The cellular antioxidant and anti-glycation capacities of phenolics from Georgia peaches.

Plant-based polyphenolics have been reported to bestow health benefits when consumed, which are partially ascribed to their antioxidant activity. Yet, many current in vitro chemical assays to characterize antioxidant potential do not truly reflect the physiological properties of food antioxidants in vivo. The present study employed biological approaches, including a cellular antioxidant activity (CAA) and protein glycation assays, to offer an improved picture of antioxidant potential of phenolic extracts from Georgia peach cultivars. The phenolic extracts from two peach varieties, showing contrasting antioxidant capacities according to hydrophilic-oxygen radical absorbance capacity (H-ORACFL) and ferric reducing antioxidant power (FRAP) assays, exhibited significant differences in two biological tests when the assays were performed on a fresh weight basis. The procyanidins fraction displayed notable antioxidant capacity, when compared to other phenolic classes in the peach extract, in these two biologically relevant assays.

Interchanging Breast Pump Kit Brands Alters Breast Pump Suction Pressure.

Background: Postpartum mothers express and store breast milk using a hospital-grade pump and manufacturer-specific kit (flanges, bottles, tubing, valves, and membranes). After hospital discharge, mothers may attempt to interchange kits from different manufacturers. The objective of this study is to determine whether pump performance is affected by the use of a different manufacturer's kit. Materials and Methods: Suction pressure was tested using kits and six pumps from three manufacturers (Ameda, Medela, and Spectra). Pump settings (speed and vacuum strength) simulated maximum, minimum, and commonly used median settings. Suction pressure (mmHg) was measured using an analog gauge and repeated six times for each pump-kit combination. Measurements were compared using repeated measures analysis of covariance (ANCOVA) to determine whether kit was an independent predictor of suction pressure. Results: The kit type was a significant independent predictor (p < 0.05) of suction pressure for all at medium vacuum strength and many at maximum and minimum vacuum strengths. Upon further analysis interchanging kits resulted in both significantly increased and decreased suction pressures compared to the manufacturer-specific kit. Conclusion: Breast pump kits generate variable suction pressures when interchanged between pumps from different manufacturers. Interchanging combinations of kits and breast pumps could potentially lead to low milk expression due to ineffective suction pressure or increased discomfort from excessive pressure. The results of this study emphasize the importance of maternal education regarding the use of manufacturer-specific kits and breast pumps.

Human Milk Retains Important Immunologic Properties After Defatting.

BACKGROUND: In neonatal chylothorax, thoracic lymphatic drainage is ineffective. The resultant effusions often require drainage, leading to a loss of immune components. Affected infants can be managed with formula or defatted human milk feedings low in long-chain triglycerides to decrease lymph production. We hypothesized that there is no significant difference in the immunological profile or antibacterial effect of full-fat and defatted human milk. METHODS: Milk from lactating mothers was divided into 1 aliquot that was defatted via centrifugation with the full-fat aliquot as control. Macronutrient content was analyzed with mid-infrared spectroscopy. Flow cytometry was used to measure immune cell populations. Lactoferrin, lysozyme, immunoglobulin (Ig)A, and IgG values were determined using enzyme-linked immunosorbent assay. The antibacterial properties were determined by inoculating paired full-fat and defatted milk samples with Escherichia coli or Streptococcus pneumoniae bacteria and performing colony counts. RESULTS: Compared with full-fat milk, defatted milk demonstrated decreased total energy and fat and increased carbohydrate concentrations. Defatted milk demonstrated a significant decrease in all immune cell populations. There was no difference in IgA, IgG, lysozyme, or lactoferrin concentrations. Both aliquots demonstrated equivalent growth inhibition of E. coli and S. pneumoniae. CONCLUSIONS: Unexpectedly, defatted human milk contained significantly less leukocytes than full-fat milk. IgA, IgG, lysozyme, and lactoferrin concentrations were preserved. The ability of defatted milk to inhibit bacterial growth was unaffected, suggesting that the antibacterial benefits of human milk remain after the defatting process. Further investigation regarding the clinical effect of leukocyte loss in defatted milk is warranted.

Recruitment Techniques and Strategies in a Community-Based Colorectal Cancer Screening Study of Men and Women of African Ancestry.

BACKGROUND: Recruiting ethnically diverse Black participants to an innovative, community-based research study to reduce colorectal cancer screening disparities requires multipronged recruitment techniques. OBJECTIVES: This article describes active, passive, and snowball recruitment techniques, and challenges and lessons learned in recruiting a diverse sample of Black participants. METHODS: For each of the three recruitment techniques, data were collected on strategies, enrollment efficiency (participants enrolled/participants evaluated), and reasons for ineligibility. RESULTS: Five hundred sixty individuals were evaluated, and 330 individuals were enrolled. Active recruitment yielded the highest number of enrolled participants, followed by passive and snowball. Snowball recruitment was the most efficient technique, with enrollment efficiency of 72.4%, followed by passive (58.1%) and active (55.7%) techniques. There were significant differences in gender, education, country of origin, health insurance, and having a regular physician by recruitment technique (p < .05). DISCUSSION: Multipronged recruitment techniques should be employed to increase reach, diversity, and study participation rates among Blacks. Although each recruitment technique had a variable enrollment efficiency, the use of multipronged recruitment techniques can lead to successful enrollment of diverse Blacks into cancer prevention and control interventions.

Long-acting protein drugs for the treatment of ocular diseases.

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3-4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3-4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.

Fetal intracardiac potassium chloride injection to expedite second-trimester dilation and evacuation.

OBJECTIVE: To determine whether potassium chloride (KCl)-induced feticide prior to termination by dilation and evacuation (D&E) improves surgical outcome. METHODS: We conducted a retrospective study of women who underwent second-trimester (13 0/7 to 23 6/7 weeks) D&E at an urban university-based hospital between January 2000 and July 2010. Women were divided into 3 cohorts: (1) D&E for termination of pregnancy after feticide, (2) D&E without feticide, and (3) D&E for spontaneous pregnancy loss. We compared maternal characteristics, various perioperative variables, and surgical outcomes for all 3 groups. Anesthesia time was used as a surrogate for operative time in the primary outcome. RESULTS: We analyzed 128 pregnancies (group 1: n = 23, group 2: n = 53, group 3: n = 52). Baseline maternal characteristics did not differ among the 3 groups. Anesthesia time was longest in the termination with KCl group (group 1: 116.9 min vs. group 2: 94.5 min and group 3: 90.3 min, p = 0.004), however, the effect was mitigated after controlling for fetal size (p = 0.176). There was no difference in blood loss (p = 0.968). Complications were uncommon, however, cervical lacerations were more common in the termination with KCl group (2 vs. 0 and 0, p = 0.010). CONCLUSION: Presurgical feticide with KCl was not associated with shorter anesthesia time. The decision to perform feticide should be based on other considerations, such as patient preference.

Structural basis for sirtuin function: what we know and what we don't.

The sirtuin (silent information regulator 2) proteins are NAD(+)-dependent deacetylases that are implicated in diverse biological processes including DNA regulation, metabolism, and longevity. Homologues of the prototypic yeast Sir2p have been identified in all three kingdoms of life, and while bacteria and archaea typically contain one to two sirtuins, eukaryotic organisms contain multiple members. Sirtuins are regulated in part by the cellular concentrations of the noncompetitive inhibitor, nicotinamide, and several synthetic modulators of these enzymes have been identified. The x-ray crystal structures of several sirtuin proteins in various liganded forms have been determined. This wealth of structural information, together with related biochemical studies, have provided important insights into the catalytic mechanism, substrate specificity, and inhibitory mechanism of sirtuin proteins. Implications for future structural studies to address outstanding questions in the field are also discussed.

Identification and characterization of novel sirtuin inhibitor scaffolds.

The sirtuin proteins are broadly conserved NAD(+)-dependent deacetylases that are implicated in diverse biological processes including DNA recombination and repair, transcriptional silencing, longevity, apoptosis, axonal protection, insulin signaling, and fat mobilization. Because of these associations, the identification of small molecule sirtuin modulators has been of significant interest. Here we report on high throughput screening against the yeast sirtuin, Hst2, leading to the identification of four unique inhibitor scaffolds that also inhibit the human sirtuins, SIRT1-3, and are able to inhibit telomeric silencing of yeast Sir2 in vivo. The identified inhibitor scaffolds range in potency from IC(50) values of 6.5-130 microM against Hst2. Each of the inhibitor scaffolds binds reversibly to the enzyme, and kinetic analysis reveals that each of the inhibitors is non-competitive with respect to both acetyl-lysine and NAD(+) binding. Limited SAR analysis of the scaffolds also identifies which functional groups may be important for inhibition. These sirtuin inhibitors are low molecular weight and well-suited for lead molecule optimization, making them useful chemical probes to study the mechanism and biological roles of sirtuins and potential starting points for optimization into therapeutics.

Ocular changes after photodynamic therapy.

PURPOSE: The aim of this study was to identify the changes in the primate visual system after a single session of photodynamic therapy (PDT) in an intact nonhuman primate retina. METHODS: As part of a larger study, PDT (wavelength 689 nm, 50 J/cm2, 600 mW/cm2, 83 seconds, 4-mm spot size) with verteporfin (6 mg/m2 intravenous infusion) was performed in one eye each of two cynomolgus monkeys. Fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), and multifocal electroretinography (mfERG) were performed at baseline and 12 time points (1-283 days) after PDT. In addition, retinal histopathologic findings were evaluated at 9 months. RESULTS: Various morphologic changes, including whitening of the treated area, RPE proliferation, closure of the choroidal vasculature, and subretinal edema (followed by foveolar thinning) were observed. Most of the changes persisted and were detectable in histopathologic evaluation at 9 months. Reductions of the mfERG amplitude, followed by varying degrees of recovery from the treated and the border regions, were observed. This was accompanied by progressive delay of P1 peak time up to 3 months after treatment, followed by complete recovery at 9 months. In addition, the nontreated area showed amplitude and timing mfERG deficits, which underwent gradual (but not complete) recovery. CONCLUSIONS: In a primate model, under standard clinical parameters, a single PDT treatment resulted in various dynamic morphologic and functional retinal changes detectable for up to 9 months after treatment. The significance of the observed changes and possible ways of pharmacologic interference with PDT adverse effects are discussed.