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1.
Ecol Evol ; 14(2): e10923, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38384820

ABSTRACT

Human disturbance including rapid urbanization and increased temperatures can have profound effects on the ecology of local populations. Eusocial insects, such as ants, have adapted to stressors of increasing temperature and urbanization; however, these evolutionary responses are not consistent among populations across geographic space. Here we asked how urbanization and incubation temperature influence critical thermal maximum (CTmax) and various ecologically relevant behaviors in three ant species in urban and rural locations in Worcester, MA, USA. We did this by incubating colonies of three species of cavity dwelling ant (Aphaenogaster picea, Tapinoma sessile, and Temnothorax longispinosus) from 2 habitat types (Rural and Urban), for 60-days at multiple temperatures. We found that incubation temperature, urbanization, and species of ant all significantly affected overall colony critical thermal maximum. We also found that recruitment time, colonization time, and defense response were significantly affected by incubation temperature and varied between species of ant, while recruitment and colonization time were additionally affected by urbanization. These variable changes in performance and competitive traits across species suggest that responses to urbanization and shifting temperatures are not universal across species. Changes in behavioral responses caused by urbanization may disrupt biodiversity, creating unusual competitive environments as a consequence of natural adaptations and cause both direct and indirect mechanisms for which human disturbance can lead to local species extinction.

2.
bioRxiv ; 2024 Mar 24.
Article in English | MEDLINE | ID: mdl-38077016

ABSTRACT

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

3.
BMJ Case Rep ; 16(11)2023 Nov 06.
Article in English | MEDLINE | ID: mdl-37931960

ABSTRACT

Vaping nicotine and marijuana have been increasing among adolescents in the past 5 years. Tetrahydrocannabinol is the psychoactive cannabinoid in marijuana. The COVID-19 pandemic created gaps in healthcare access and visits, making it difficult to collect accurate data on adolescent vaping, willingness to quit and methods used to quit. In addition, the literature lacks information regarding effective evidence-based treatment measures for adolescents who vape. In this report, we seek to address this using two patient cases and detailing the interventions a managed care organisation enacted during this timeframe. Our investigation revealed a relationship between social stressors and vaping among teens. Addressing these underlying stressors and eliciting and treating mental health symptoms and polysubstance use appears to be critical to curbing vaping.


Subject(s)
COVID-19 , Cannabis , Electronic Nicotine Delivery Systems , Vaping , Humans , Adolescent , Pandemics , Vaping/psychology , Nicotine , Disease Progression
4.
PLoS One ; 18(4): e0283962, 2023.
Article in English | MEDLINE | ID: mdl-37075049

ABSTRACT

The physical environment has been shown to affect the emotional states of patients receiving mental health treatment, yet it remains unknown whether physical space design may play a role in optimizing the delivery of mental health care. Principles of architectural design and human-centered co-design have been applied to enhance the patient experience of facility environments; however, little is known about how patients view the impact of physical spaces on their recovery. In this qualitative study, we aimed to understand patient perspectives of how physical environments contribute to mental wellbeing and personal experiences of recovery, in the context of informing future design efforts. Semi-structured telephone interviews were conducted with 13 participants receiving outpatient mental health treatment at the Kaiser Permanente San Jose Adult Psychiatry Clinic. Interviews were transcribed and themes were extracted that could inform future design concepts. The sample was comprised of nine female and three male participants, and one unidentified-gender participant, between the ages of 26-64, and across several self-reported racial/ethnic subgroups. We found four dimensions of physical environments that participants reported as impactful: 1) sensory design elements (colors, sounds, and textures), 2) engagement qualities (intensity of distracted activity such as crafting or commuting), 3) social relational aspects (privacy or connection), and 4) affective experiences evoked by being present in the space itself (feeling safe, calm, in control, self-aware, or creative was beneficial). Many of these elements were similarly noted across clinic and non-clinic environments. This study identifies key dimensions of physical environments that can serve as potential metrics of design success in supporting and facilitating mental health recovery. In the midst of the current COVID-19 pandemic, where mental health treatment has increasingly shifted outside of traditional clinics, our findings can support patients and clinicians seeking to harness potential in situ therapeutic benefits of physical environments.


Subject(s)
COVID-19 , Mental Health Recovery , Adult , Humans , Male , Female , Middle Aged , Outpatients , Pandemics , Environment , Qualitative Research
5.
Perm J ; 26(4): 39-48, 2022 12 19.
Article in English | MEDLINE | ID: mdl-36351884

ABSTRACT

Background Collaborative care is an evidence-based multidisciplinary model shown to improve patient depression and anxiety outcomes. Although there is robust literature showing the effectiveness of collaborative care on depression and anxiety symptoms, there is little published on outcomes of collaborative care implementation or the efficacy of collaborative care compared with psychiatric referrals. Reported here is a study protocol examining a novel depression and anxiety collaborative care program in a large, integrated health care system. Methods This is a mixed methods study of the Achieving Depression and Anxiety Patient-Centered Treatment (ADAPT) program as compared to outpatient psychiatric care at Kaiser Permanente Northern California, a large, integrated health care delivery system. The ADAPT program was designed using collaborative care principles, including measurement-based care, accurate diagnosis, and population management. Eligible participants will be ≥ 18 years old with mild to moderate-severe depressive symptoms as measured by the Patient Health Questionnaire-9. Exclusion criteria include acute suicide risk and serious mental health comorbidities. Implementation is examined using the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework and interviews with program stakeholders. Results Pending. Conclusion Study data will help inform future collaborative care efforts while expanding the literature base. The Achieving Depression and Anxiety Patient-Centered Treatment program may improve patient outcomes and access to quality depression and/or anxiety care.


Subject(s)
Delivery of Health Care, Integrated , Depression , Humans , Adolescent , Depression/therapy , Depression/diagnosis , Primary Health Care , Anxiety/therapy , Patient-Centered Care , Observational Studies as Topic
6.
Microbiol Resour Announc ; 11(6): e0016022, 2022 Jun 16.
Article in English | MEDLINE | ID: mdl-35536032

ABSTRACT

The mycobacteriophages InvictusManeo (K5 subcluster) and Netyap (L2 subcluster) were isolated from soils in Cullowhee Creek, Cullowhee, North Carolina. Both exhibit Siphoviridae morphology and infect Mycobacterium smegmatis mc2155. The InvictusManeo genome is 61,147 bp and contains 96 predicted protein-coding genes, whereas the Netyap genome is 76,366 bp with 131 predicted protein-coding genes.

8.
JAMA Psychiatry ; 78(12): 1319-1328, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34468724

ABSTRACT

Importance: Population-level reports of suicide-related emergency department (ED) encounters among youth during the COVID-19 pandemic are lacking, along with youth characteristics and preexisting psychiatric service use. Objective: To characterize population-level and relative change in suicide-related ED encounters among youth during the COVID-19 pandemic compared with 2019. Design, Setting, and Participants: This cross-sectional study evaluated ED encounters in 2019 and 2020 at Kaiser Permanente Northern California-a large, integrated, community-based health system. Youth aged 5 to 17 years who presented to the ED with suicidal thoughts or behaviors were included. Exposure: The COVID-19 pandemic. Main Outcomes and Measures: Population-level incidence rate ratios (IRRs) and percent relative effects for suicide-related ED encounters as defined by the US Centers for Disease Control and Prevention-recommended International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes in 4 periods in 2020 compared with the same periods in 2019. Results: There were 2123 youth with suicide-related ED encounters in 2020 compared with 2339 in 2019. In the 2020 group, 1483 individuals (69.9%) were female and 1798 (84.7%) were aged 13 to 17 years. In the 2019 group, 1542 (65.9%) were female, and 1998 (85.4%) were aged 13 to 17 years. Suicide-related ED encounter incidence rates were significantly lower in March through May 2020 compared with this period in 2019 (IRR, 0.57; 95% CI, 0.51-0.63; P < .001), then returned to prepandemic levels. However, suicide-related ED visits among female youth from June 1 to August 31, 2020, and September 1 through December 15, 2020, were significantly higher than in the corresponding months in 2019 (IRR, 1.19; 95% CI, 1.04-1.35; P = .04 and IRR, 1.22; 95% CI, 1.11-1.35; P < .001, respectively), while suicide-related ED visits for male youth decreased from September 1 through December 15, 2020 (IRR, 0.81; 95% CI, 0.69 to 0.94). Youth with no history of outpatient mental health or suicide encounters (129.4%; 95% CI, 41.0-217.8) and those with comorbid psychiatric conditions documented at the ED encounter (6.7%; 95% CI, 1.0-12.3) had a higher risk of presenting with suicide-related problems from September to December 2020 vs the same period in 2019. Conclusions and Relevance: In this cross-sectional study of youth experiencing suicidal thoughts and behaviors, suicide-related presentations to the ED initially decreased during the COVID-19 pandemic, likely owing to shelter-in-place orders, then were similar to 2019 levels. However, a greater number of female youth, youth with no psychiatric history, and youth with psychiatric diagnoses at the time of the ED encounter presented for suicide-related concerns during the pandemic, suggesting these may be vulnerable groups in need of further interventions. Adjustments in care may be warranted to accommodate these groups during periods of crisis.


Subject(s)
COVID-19/psychology , Emergency Service, Hospital/statistics & numerical data , Suicidal Ideation , Adolescent , California/epidemiology , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Male , Retrospective Studies , SARS-CoV-2
9.
J Clin Psychiatry ; 82(2)2021 03 03.
Article in English | MEDLINE | ID: mdl-33979485

ABSTRACT

OBJECTIVE: The early COVID-19 pandemic resulted in great psychosocial disruption and stress, raising speculation that psychiatric disorders may worsen. This study aimed to identify patients vulnerable to worsening mental health during the COVID-19 pandemic. METHODS: This retrospective observational study used electronic health records from March 9 to May 31 in 2019 (n = 94,720) and 2020 (n = 94,589) in a large, community-based health care system. Percent change analysis compared variables standardized to the average patient population for the respective time periods. RESULTS: Compared to 2019, psychiatric visits increased significantly (P < .0001) in 2020, with the majority being telephone/video-based (+264%). Psychiatric care volume increased overall (7%), with the greatest increases in addiction (+42%), behavioral health in primary care (+17%), and adult psychiatry (+5%) clinics. While patients seeking care with preexisting psychiatric diagnoses were mainly stable (−2%), new patients declined (−42%). Visits for substance use (+51%), adjustment (+15%), anxiety (+12%), bipolar (+9%), and psychotic (+6%) disorder diagnoses, and for patients aged 18­25 years (+4%) and 26­39 years (+4%), increased. Child/adolescent and older adult patient visits decreased (−22.7% and −5.5%, respectively), and fewer patients identifying as White (−3.8%) or male (−5.0) or with depression (−3%) or disorders of childhood (−2%) sought care. CONCLUSIONS: The early COVID-19 pandemic was associated with dramatic changes in psychiatric care facilitated by a rapid telehealth care transition. Patient volume, demographic, and diagnostic changes may reflect comfort with telehealth or navigating the psychiatric care system. These data can inform health system resource management and guide future work examining how care delivery changes impact psychiatric care quality and access.


Subject(s)
COVID-19 , Community Health Services/statistics & numerical data , Mental Disorders/epidemiology , Mental Disorders/therapy , Mental Health Services/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Primary Health Care/statistics & numerical data , Telemedicine/statistics & numerical data , Adolescent , Adult , Child , Electronic Health Records , Female , Humans , Male , Mental Disorders/diagnosis , Middle Aged , Retrospective Studies , Young Adult
10.
Lancet Reg Health Am ; 4: 100078, 2021 Dec.
Article in English | MEDLINE | ID: mdl-36776704

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) pandemic resulted in widespread psychosocial disruption, which may impact suicidal thoughts and behaviours. This study characterizes adult suicide-related emergency department (ED) encounters and patient characteristics during the COVID-19 pandemic in 2020 compared to the year prior. Methods: Retrospective cross-sectional study in a large, integrated, community-based health system of adults (≥18-years-old) with suicide-related ED encounters (defined by the Centres for Disease Control-recommended International Statistical Classification of Diseases [ICD-10-CM] codes) during the COVID-19 pandemic compared to the same period in 2019. Population-level incidence rate ratios (IRRs) compared suicide-related ED encounters in 2020 to 2019. Patient characteristics for the first suicide-related ED visit for each period were used to calculate percent relative change comparing 2020 to 2019. Findings: Of 10,651 suicide-related ED encounters in 2020 and 11,476 in 2019, 49.6% and 51.6% were for females and the mean age was 38±17 and 38±16 years-old, respectively. Suicide-related ED encounters significantly declined in each month of 2020 (IRR 0.71-0.91, p<.05), but were equivalent to 2019 levels June-August. Adults in 2020 were more likely to have co-occurring substance use disorders (+15•7%; 95% CI 7•0-24•4%) or have no mental health or suicide diagnosis associated with an outpatient visit in the last year (+21•1%, 95% CI: 12•5-29•6) compared to 2019. Interpretation: Adults with suicidal thoughts and behaviours during the COVID-19 pandemic in 2020 had distinct social and psychiatric characteristics compared to patients in the prior year. These findings can help inform health system responses to mental health needs.

11.
Perm J ; 242020.
Article in English | MEDLINE | ID: mdl-32240081

ABSTRACT

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric conditions in youth. This disorder can persist into adulthood, with an estimated prevalence of 4.4% to 5.2% in the US. OBJECTIVE: To review adult ADHD diagnostic criteria, adult clinical presentation, and resulting impairments in function and to describe our adult psychiatry clinic's pharmacist-comanaged ADHD medication management program as a model to provide safe and effective care that is accessible, efficient, and well monitored. METHODS: The program consists of 1) screening (urine toxicology, diagnostic evaluation, data collection) by physicians, 2) program participation and treatment agreement with establishment of care goals, and 3) patient maintenance and monitoring. Pharmacists in the Department of Psychiatry manage refills, distributing the clinical caseload among a broader clinician base. RESULTS: This program created a standardized protocol for assessment, referral, and follow-up of adult patients with ADHD, with close monitoring and titration of controlled medications, systematic use of screening measures, and a stimulant treatment contract. DISCUSSION: Development of this program and workflow model could increase care delivery efficiency, potentially improving patient satisfaction and outcomes. There is a great need to use alternative patient management strategies such as this to maintain access to high-quality care while there is a nationwide need for more psychiatric clinicians. CONCLUSION: We believe this program offers a solution to a component of this growing problem, and other clinical sites would benefit from such a program. Next steps include analysis and publication of results of implementation, including patient outcomes, engagement in treatment, and satisfaction.


Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Central Nervous System Stimulants/therapeutic use , Medication Therapy Management/organization & administration , Pharmacists/organization & administration , Drug Monitoring , Humans , Patient Care Planning , Referral and Consultation
12.
Perm J ; 25: 1, 2020 12.
Article in English | MEDLINE | ID: mdl-33635764

ABSTRACT

INTRODUCTION: E-cigarette/vaping use in adolescents has increased 77.8% among high schoolers and 48.5% among middle schoolers in 2017-2018. As such, there is need for an effective workflow for screening for vaping. We aimed to increase screening rates of e-cigarette/vaping users from less than 1% to at least 50% in 6 months. METHODS: Screening for vaping in youth was implemented in a pediatric clinic in Northern California beginning in the summer of 2019 for 6 months. Depending on comorbidity, severity, and readiness to quit, patients were referred to treatment. Outcomes included screening rates, process measure included positive screening rates, and balancing measure was provider time. RESULTS: The clinic completed 1414 physicals with an average screening rate of 76% and a positive rate of 7.9%. The average age of patients was 15 (standard deviation = 1.3), 48% were female and 29% were Asian/Pacific Islander, 23% Hispanic, and 23% White. After 6 months, we met our goal in all but 1 plan-do-study-act (PDSA) cycle. DISCUSSION: We created a standardized workflow that identified teens who vaped. When compared to other studies, the positive rate for this study was low which is likely due to misinterpretation by staff of screening questions as well as the fact that data were collected during a clinic visit. CONCLUSIONS: It is important to find ways in which providers can mitigate this epidemic given the alarming increase in e-cigarette/vaping use among adolescents. This study furthers the effort to develop a screening method that is simple and brief, allowing physicians to intervene if necessary.


Subject(s)
Electronic Nicotine Delivery Systems , Epidemics , Pediatrics , Vaping , Adolescent , Child , Female , Humans , Research
13.
Pain Med ; 21(3): 595-603, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31309970

ABSTRACT

OBJECTIVE: Among Veterans Health Administration (VHA) patients who undergo total knee arthroplasty (TKA) nationally, what are the underlying readmission rates and associations with perioperative opioid use, and are there associations with other factors such as preoperative health care utilization? METHODS: We retrospectively examined the records of 5,514 TKA patients (primary N = 4,955, 89.9%; revision N = 559, 10.1%) over one fiscal year (October 1, 2010-September 30, 2011) across VHA hospitals nationwide. Opioid use was classified into no opioids, tramadol only, short-acting only, or any long-acting. We measured readmission within 30 days and the number of days to readmission within 30 days. Extended Cox regression models were developed. RESULTS: The overall 30-day hospital readmission rate was 9.6% (N = 531; primary 9.5%, revision 11.1%). Both readmitted patients and the overall sample were similar on types of preoperative opioid use. Relative to patients without opioids, patients in the short-acting opioids only tier had the highest risk for 30-day hospital readmission (hazard ratio = 1.38, 95% confidence interval = 1.14-1.67). Preoperative opioid status was not associated with 30-day readmission. Other risk factors for 30-day readmission included older age (≥66 years), higher comorbidity and diagnosis-related group weights, greater preoperative health care utilization, an urban location, and use of preoperative anticonvulsants. CONCLUSIONS: Given the current opioid epidemic, the routine prescribing of short-acting opioids after surgery should be carefully considered to avoid increasing risks of 30-day hospital readmissions and other negative outcomes, particularly in the context of other predisposing factors.


Subject(s)
Analgesics, Opioid/adverse effects , Arthroplasty, Replacement, Knee , Pain Management/methods , Patient Readmission/statistics & numerical data , Practice Patterns, Physicians' , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Pain Management/adverse effects , Pain, Postoperative/drug therapy , Perioperative Period , Retrospective Studies , Risk Factors , United States , United States Department of Veterans Affairs , Veterans
14.
Pain Med ; 20(5): 1020-1031, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30137452

ABSTRACT

OBJECTIVE: To determine an association between opioid use upon hospital discharge (ongoing and newly started) in surgical patients and risks of opioid overdose and delirium for the first year. DESIGN: Retrospective, cohort study. SETTING: Population-level study of Veterans Health Administration patients. SUBJECTS: All Veterans Health Administration patients (N = 64,391) who underwent surgery in 2011, discharged after one or more days, and without a diagnosis of opioid overdose or delirium from 90 days before admission through 30 days postdischarge (to account for additional opioid dosing in the context of chronic use). METHODS: Patients' opioid use was categorized as 1) no opioids, 2) tramadol only, 3) short-acting only, 4) long-acting only, 5) short- and long-acting. We calculated unadjusted incidence rates and the incidence rate ratio (IRR) for opioid overdose and drug delirium for two time intervals: postdischarge days 0-30 and days 31-365. We then modeled outcomes of opioid overdose and delirium for postdischarge days 31-365 using a multivariable extended Cox regression model. Sensitivity analysis examined risk factors for overdose for postdischarge days 0-30. RESULTS: Incidence of overdose was 11-fold greater from postdischarge days 0-30 than days 31-365: 26.3 events/person-year (N = 68) vs 2.4 events/person-year (N = 476; IRR = 10.80, 95% confidence interval [CI] = 8.37-13.92). Higher-intensity opioid use was associated with increasing risk of overdose for the year after surgery, with the highest risk for the short- and long-acting group (hazard ratio = 4.84, 95% CI = 3.28-7.14). Delirium (IRR = 10.66, 95% CI = 7.96-14.29) was also associated with higher opioid intensity. CONCLUSIONS: Surgical patients should be treated with the lowest effective intensity of opioids and be monitored to prevent opioid-related adverse events.


Subject(s)
Analgesics, Opioid/therapeutic use , Drug Overdose/epidemiology , Adult , Aged , Chronic Pain/epidemiology , Cohort Studies , Female , Humans , Incidence , Male , Middle Aged , Pain, Postoperative/drug therapy , Patient Discharge , Retrospective Studies , Risk Factors , Veterans
15.
J Vis Exp ; (133)2018 03 14.
Article in English | MEDLINE | ID: mdl-29608153

ABSTRACT

Reciprocal social behavior (RSB), an early-emerging capacity to engage in social contingency-which is foundational for both social learning and social competency-is hypothesized to be disrupted in autism spectrum disorder (ASD). The ability to quantify the full range of RSB during the toddler period, when core symptoms of ASD often arise, is pivotal for evaluating early risk for ASD, characterizing social development, and tracking response to early interventions. However, important parameters of variation in RSB-especially prior to the development of verbal language-can be nuanced and difficult to characterize using questionnaire-based methods. To address this challenge, we developed a system for measuring quantitative variation in RSB in toddlers (ages 18 - 30 months) that incorporated not only standard questionnaire data from caregivers but also a novel set of video-referenced items, through which a respondent compares the behavior of a subject to that observed in a short video of a young child manifesting a highly competent level of social communication. Testing of this measure in a general population sample of twins confirmed that both the video-referenced items and the RSB Total Score (video-referenced items plus non-video-referenced items) displayed unimodal, continuous distributions, strong internal consistency, marked preservation of individual differences, and extremely high heritability. In addition, video-referenced items were particularly sensitive to quantifying incremental changes in social communication, a major element of RSB, over the course of early childhood development. Scores on the vrRSB clearly differentiated children with and without ASD and these data comprise an initial validation of this promising method for quantifying early RSB-cross-sectionally, over time, and as a function of early intervention.


Subject(s)
Child Development/physiology , Communication , Social Behavior , Videotape Recording/methods , Child, Preschool , Female , Humans , Infant , Male , Surveys and Questionnaires
16.
Ann Am Thorac Soc ; 12(1): 46-56, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25496487

ABSTRACT

RATIONALE: Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. OBJECTIVES: To use existing serum samples from the phase 1 clinical trial of l-carnitine treatment for severe sepsis to metabolically phenotype l-carnitine responders and nonresponders. METHODS: Serum samples collected before (T0) and after completion of the infusion (T24, T48) from patients randomized to either l-carnitine (12 g) or placebo for the treatment of vasopressor-dependent septic shock were assayed by untargeted (1)H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of l-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. MEASUREMENTS AND MAIN RESULTS: Thirty-eight metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in l-carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating l-carnitine treatment response. Analysis of all patients based on pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 µM), patients were categorized as either high or low ketone. l-Carnitine-treated low-ketone patients had greater use of carnitine as evidenced by lower post-treatment l-carnitine levels. The l-carnitine responders also had faster resolution of vasopressor requirement and a trend toward a greater improvement in mortality at 1 year (P = 0.038) compared with patients with higher 3-hydroxybutyrate. CONCLUSIONS: The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of l-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing l-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study.


Subject(s)
Carnitine/pharmacokinetics , Metabolomics/methods , Shock, Septic/drug therapy , 3-Hydroxybutyric Acid/blood , Acetoacetates/blood , Aged , Female , Humans , Magnetic Resonance Spectroscopy , Male , Middle Aged , Phenotype , Shock, Septic/metabolism , Treatment Outcome , Valerates/blood , Vitamin B Complex/pharmacokinetics , Vitamin B Complex/therapeutic use
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