PI3K drives the de novo synthesis of coenzyme A from vitamin B5.

In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis1. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling2,3. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells4,5 and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate)6,7. We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT8. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK49 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K-PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.

The Use of Bacteriophages and Immunological Monitoring for the Treatment of a Case of Chronic Septicemic Cutaneous Ulcerative Disease in a Loggerhead Sea Turtle Caretta caretta.

In this case study, phage therapy was applied to treat a multidrug-resistant case of septicemic cutaneous ulcerative disease (SCUD) caused by Citrobacter freundii in a loggerhead sea turtle Caretta caretta. Phages were applied topically, intravenously, into the carapace, and into the exhibit water using various phage cocktails specific to the causative agent over an 8-month period. This was performed in conjunction with antimicrobial therapy. The animal was monitored through weekly cultures, photographs, and complete blood cell counts, as well as immune assays (phagocytosis, plasma lysozyme and superoxide dismutase activity, and plasma electrophoresis profiles). The animal, in comparison to an untreated, unaffected control, had elevated antibody titers to the administered phages, which persisted for at least 35 weeks. Although cultures were clear of C. freundii after phage treatment, the infection did return over time and immune assays confirmed deficiencies when compared to a healthy loggerhead sea turtle. Immune parameters with statistically significant changes over the study period included the following: decreased phagocytosis, increased alpha- and gamma-globulin protein components, and an increased albumin : globulin ratio. When C. freundii appeared again, the multidrug-resistant status had reverted back to normal susceptibility patterns. Although not completely known whether it was another subspecies of bacteria, the therapy did resolve the multidrug-resistant challenge. Phage therapy in combination with antimicrobial agents may be an effective treatment for sea turtles with normally functioning immune systems or less-severe infections. Additional research is needed to better understand and quantify sea turtle immunology.

An Exploratory Analysis of Sociodemographic Factors Associated With Physical Functional Impairment in ICU Survivors.

IMPORTANCE: Physical functional impairment is one of three components of postintensive care syndrome (PICS) that affects up to 60% of ICU survivors. OBJECTIVES: To explore the prevalence of objective physical functional impairment among a diverse cohort of ICU survivors, both at discharge and longitudinally, and to highlight sociodemographic factors that might be associated with the presence of objective physical functional impairment. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of 37 patients admitted to the ICU in New Orleans, Louisiana, and Denver, Colorado between 2016 and 2019 who survived with longitudinal follow-up data. MAIN OUTCOMES AND MEASURES: Our primary outcome of physical functional impairment was defined by handgrip strength and the short physical performance battery. We explored associations between functional impairment and sociodemographic factors that included race/ethnicity, sex, primary language, education status, and medical comorbidities. RESULTS: More than 75% of ICU survivors were affected by physical functional impairment at discharge and longitudinally at 3- to 6-month follow-up. We did not see a significant difference in the proportion of patients with physical functional impairment by race/ethnicity, primary language, or education status. Impairment was relatively higher in the follow-up period among women, compared with men, and those with comorbidities. Among 18 patients with scores at both time points, White patients demonstrated greater change in handgrip strength than non-White patients. Four non-White patients demonstrated diminished handgrip strength between discharge and follow-up. CONCLUSIONS AND RELEVANCE: In this exploratory analysis, we saw that the prevalence of objective physical functional impairment among ICU survivors was high and persisted after hospital discharge. Our findings suggest a possible relationship between race/ethnicity and physical functional impairment. These exploratory findings may inform future investigations to evaluate the impact of sociodemographic factors on functional recovery.

Prevalence of Alcohol Use Characterized by Phosphatidylethanol in Patients With Respiratory Failure Before and During the COVID-19 Pandemic.

BACKGROUND: Alcohol misuse is overlooked frequently in hospitalized patients, but is common among patients with pneumonia and acute hypoxic respiratory failure. Investigations in hospitalized patients rely heavily on self-report surveys or chart abstraction, which lack sensitivity. Therefore, our understanding of the prevalence of alcohol misuse before and during the COVID-19 pandemic is limited. RESEARCH QUESTION: In critically ill patients with respiratory failure, did the proportion of patients with alcohol misuse, defined by the direct biomarker phosphatidylethanol, vary over a period including the COVID-19 pandemic? STUDY DESIGN AND METHODS: Patients with acute hypoxic respiratory failure receiving mechanical ventilation were enrolled prospectively from 2015 through 2019 (before the pandemic) and from 2020 through 2022 (during the pandemic). Alcohol use data, including Alcohol Use Disorders Identification Test (AUDIT)-C scores, were collected from electronic health records, and phosphatidylethanol presence was assessed at ICU admission. The relationship between clinical variables and phosphatidylethanol values was examined using multivariable ordinal regression. Dichotomized phosphatidylethanol values (≥ 25 ng/mL) defining alcohol misuse were compared with AUDIT-C scores signifying misuse before and during the pandemic, and correlations between log-transformed phosphatidylethanol levels and AUDIT-C scores were evaluated and compared by era. Multiple imputation by chained equations was used to handle missing phosphatidylethanol data. RESULTS: Compared with patients enrolled before the pandemic (n = 144), patients in the pandemic cohort (n = 92) included a substantially higher proportion with phosphatidylethanol-defined alcohol misuse (38% vs 90%; P < .001). In adjusted models, absence of diabetes, positive results for COVID-19, and enrollment during the pandemic each were associated with higher phosphatidylethanol values. The correlation between health care worker-recorded AUDIT-C score and phosphatidylethanol level was significantly lower during the pandemic. INTERPRETATION: The higher prevalence of phosphatidylethanol-defined alcohol misuse during the pandemic suggests that alcohol consumption increased during this period, identifying alcohol misuse as a potential risk factor for severe COVID-19-associated respiratory failure. Results also suggest that AUDIT-C score may be less useful in characterizing alcohol consumption during high clinical capacity.

Parents' Experiences Caring for a Child after a Critical Illness: A Qualitative Study.

Objectives This article described parents' experience and identifies outcomes important to parents following their child's critical illness. Methods Semistructured interviews with 22 female and 4 male parents representing 26 critically ill children with predominately neurologic and respiratory diagnoses. Most children were younger than 5 years at discharge with a median (interquartile range) of 2 (2.0-3.0) years from discharge to interview. Results Many children returned home with life-altering physical and cognitive disabilities requiring months to years of rehabilitation. Parents remembered feeling unprepared and facing an intense, chaotic time when the child first returned home. They described how they suddenly had to center their daily activities around the child's needs amidst competing needs of siblings and partners, and in some cases, the medicalization of the home. They recounted negotiating adjustments almost daily with insurance agencies, medical doctors and therapists, employers, the child, and other family members to keep the family functioning. In the long term, families developed a new norm, choosing to focus on what the child could still do rather than what they could not. Even if the child returned to baseline, parents remembered the adjustments made to keep the child alive and the family functioning. Conclusion Heightened awareness of family experiences after pediatric critical illness will allow health care providers to improve family preparedness for the transition from hospital to home.

Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation.

More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines. A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068. Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of INY-05-040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.

Frontline professionals' use of and attitudes towards technology to support interventions for adolescents with depression symptoms: A mixed methods survey.

METHOD: Cross-sectional survey of a convenience sample of professionals in the UK (N = 115, including low intensity practitioners, GPs, education staff, school nurses). The survey included rating scales and free text boxes. Quantitative data were analysed descriptively, and we used reflexive thematic analysis for the qualitative data. RESULTS: Frontline professionals rate their technological competence as good and have favourable attitudes towards using technology to support adolescents with depression symptoms. They rated online resources as most useful with mild-moderate symptoms, compared to severe symptoms (t(110) = 14.54, p < .001, Cohen's d = 1.49). Technology was viewed as important to bridge the needs-access gap and professionals were interested in learning about online SSIs due to usefulness (r = .32, p < .001). CONCLUSION: Technology, such as SSIs, are of interest to mental health professionals and may be useful for supporting adolescents with depression. Future research should explore the use of SSIs for treating adolescent depression.

Supporting families during pediatric critical illness: Opportunities identified in a multicenter, qualitative study.

Critical illness resulting in a pediatric intensive care unit (PICU) admission is a profoundly stressful experience for a child and their family. Increasing evidence for emotional and behavioral sequelae post-PICU emphasizes a need to provide better support for families throughout this period of care and recovery. The aim of this qualitative investigation was to identify salient and modifiable aspects of a critical care experience that can be addressed to better support families of critically ill children. Individual semi-structured interviews were conducted with 26 caregivers of children who survived a PICU admission. Interviews were audio-recorded and transcribed verbatim; themes were identified via thematic analysis. Caregivers were enrolled using convenience sampling from seven tertiary care PICUs in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Themes from caregiver interviews were identified within two overarching categories containing three themes each. Advice for future PICU families: (1) Be intentional about caring for your own well-being, (2) speak up, ask questions, and challenge decisions you're not comfortable with, and (3) continue to engage with your child. Characteristics of a satisfactory PICU experience: (1) A caregiver-provider relationship of mutual trust established through clear communication and respectful collaboration, (2) hospital environments that provide physical and social supports to maintain humanity in healthcare, and (3) preparing families for care transitions. Targeted, interdisciplinary approaches to partner with families during critical care may improve their PICU experience and contribute to improved long-term outcomes for PICU survivors.

Determinants of Risk-Aligned Bladder Cancer Surveillance-Mixed-Methods Evaluation Using the Tailored Implementation for Chronic Diseases Framework.

PURPOSE: For many patients with cancer, the frequency of surveillance after primary treatment depends on the risk for cancer recurrence or progression. Lack of risk-aligned surveillance means too many unnecessary surveillance procedures for low-risk patients and not enough for high-risk patients. Using bladder cancer as an example, we examined whether practice determinants differ between Department of Veterans Affairs sites where risk-aligned surveillance was more (risk-aligned sites) or less common (need improvement sites). METHODS: We used our prior quantitative data to identify two risk-aligned sites and four need improvement sites. We performed semistructured interviews with 40 Veterans Affairs staff guided by the Tailored Implementation for Chronic Diseases framework that were deductively coded. We integrated quantitative data (risk-aligned site v need improvement site) and qualitative data from interviews, cross-tabulating salient determinants by site type. RESULTS: There were 14 participants from risk-aligned sites and 26 participants from need improvement sites. Irrespective of site type, we found a lack of knowledge on guideline recommendations. Additional salient determinants at need improvement sites were a lack of resources ("the next available without overbooking is probably seven to eight weeks out") and an absence of routines to incorporate risk-aligned surveillance ("I have my own guidelines that I've been using for 35 years"). CONCLUSION: Knowledge, resources, and lack of routines were salient barriers to risk-aligned bladder cancer surveillance. Implementation strategies addressing knowledge and resources can likely contribute to more risk-aligned surveillance. In addition, reminders for providers to incorporate risk into their surveillance plans may improve their routines.