Correction: The contribution of drug import to the cost of tuberculosis treatment: A cost analysis of longer, shorter, and short drug regimens for Karakalpakstan, Uzbekistan.

[This corrects the article DOI: 10.1371/journal.pgph.0000567.].

Ultrasound-Derived Fat Fraction for Hepatic Steatosis Assessment: Prospective Study of Agreement With MRI PDFF and Sources of Variability in a Heterogeneous Population.

Background: Metabolic dysfunction-associated steatotic liver disease is a growing global public health concern. Quantitative ultrasound measurements, such as ultrasound-derived fat fraction (UDFF), could provide noninvasive, cost-effective, and portable steatosis evaluation. Objective: To evaluate utility of UDFF for steatosis assessment using PDFF as reference in patients undergoing liver MRI for heterogeneous indications, and to assess UDFF variability. Methods: This prospective study included a primary analysis of 187 patients (mean age, 53.8 years; 112 men, 75 women) who underwent 3-T liver MRI for any clinical indication from December 2020 to July 2021. Patients underwent investigational proton-density fat fraction (PDFF) measurement using MR spectroscopy, and investigational ultrasound with UDFF calculation (mean of 5 intercostal measurements) within 1 hour after MRI. In a subanalysis, 21 of these patients underwent additional UDFF measurements 1, 3, and 5 hours after meal consumption. The study also included repeatability and reproducibility (R&R) analysis of 30 patients (mean age, 26.3 years; 11 men, 20 women) who underwent clinical abdominal ultrasound between November 2022 and January 2023; in these patients, three operators sequentially performed UDFF measurements. Results: In primary analysis, UDFF and PDFF showed intraclass correlation coefficient (ICC) of 0.79. In Bland-Altmananalysis, UDFF and PDFF showed mean difference of 1.5% (95% CI, 0.6-2.4%), with 95% limits of agreement from -11.0% to 14.0%. UDFF exhibited AUC for detecting PDFF at historic thresholds of ≥6.5%, ≥17.4%, and ≥22.1% of 0.90, 0.95, and 0.95, respectively. In subanalysis, mean UDFF was not significantly different across time points with respect to meal consumption (p=.21). In R&R analysis, ICC for intraoperator repeatability ranged from 0.98 to 0.99, and for interoperator reproducibility from 0.90 to 0.96. Visual assessment of patient-level data plots indicated increasing variability of mean UDFF measurements across operators, and of intercostal measurements within individual patients, with increasing steatosis. Conclusion: UDFF showed robust agreement with PDFF, diagnostic performance for steatosis grades, as well as intraoperator repeatability and interoperator reproducibility. Nonetheless, UDFF exhibited bias toward slightly larger values versus PDFF, intraoperator and interoperator variation increased with increasing steatosis. Clinical Impact: UDFF shows promise for steatosis assessment across diverse populations, although continued optimization remains warranted.

An Approach to Intersectionally Target Mature Enteroendocrine Cells in the Small Intestine of Mice.

Enteroendocrine cells (EECs) constitute only a small proportion of Villin-1 (Vil1)-expressing intestinal epithelial cells (IECs) of the gastrointestinal tract; yet, in sum, they build the largest endocrine organ of the body, with each of them storing and releasing a distinct set of peptides for the control of feeding behavior, glucose metabolism, and gastrointestinal motility. Like all IEC types, EECs are continuously renewed from intestinal stem cells in the crypt base and terminally differentiate into mature subtypes while moving up the crypt-villus axis. Interestingly, EECs adjust their hormonal secretion according to their migration state as EECs receive altering differentiation signals along the crypt-villus axis and thus undergo functional readaptation. Cell-specific targeting of mature EEC subtypes by specific promoters is challenging because the expression of EEC-derived peptides and their precursors is not limited to EECs but are also found in other organs, such as the brain (e.g., Cck and Sst) as well as in the pancreas (e.g., Sst and Gcg). Here, we describe an intersectional genetic approach that enables cell type-specific targeting of functionally distinct EEC subtypes by combining a newly generated Dre-recombinase expressing mouse line (Vil1-2A-DD-Dre) with multiple existing Cre-recombinase mice and mouse strains with rox and loxP sites flanked stop cassettes for transgene expression. We found that transgene expression in triple-transgenic mice is highly specific in I but not D and L cells in the terminal villi of the small intestine. The targeting of EECs only in terminal villi is due to the integration of a defective 2A separating peptide that, combined with low EEC intrinsic Vil1 expression, restricts our Vil1-2A-DD-Dre mouse line and the intersectional genetic approach described here only applicable for the investigation of mature EEC subpopulations.

Determinants of Subjective Mental and Functional Health of Critical Illness Survivors: Comparing Pre-ICU and Post-ICU Status.

OBJECTIVES: To compare ICU survivors' subjective mental and functional health before ICU admission and after discharge and to assess determinants of subjective health decline or improvement. DESIGN: Secondary analysis of the multicenter cluster-randomized Enhanced Recovery after Intensive Care trial ( ClinicalTrials.gov : NCT03671447). SETTING: Ten ICU clusters in Germany. PATIENTS: Eight hundred fifty-five patients with 1478 follow-up assessments. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At two patient follow-ups scheduled 3 and 6 months after ICU discharge, patients rated their subjective mental and functional/physical health on two separate visual analog scales from 0 (worst) to 10 (best) in the previous week and before ICU admission. We compared pre-ICU and post-ICU subjective health and used mixed-effects regression to assess determinants of a health decline or improvement. At the first follow-up, 20% ( n = 165/841) and 30% ( n = 256/849) of patients reported a decline in subjective mental and functional health of at least three points, respectively; 16% ( n = 133/841 and n = 137/849) outlined improvements of mental and functional health. For 65% ( n = 543/841) and 54% ( n = 456/849), mental and functional health did not change three points or more at the first follow-up. Multivariable mixed-effects logistic regressions revealed that the ICU length of stay was a predictor of mental (adjusted odds ratio [OR] per ICU day, 1.04; 95% CI, 1.00-1.09; p = 0.038) and functional health (adjusted OR per ICU day, 1.06; 95% CI, 1.01-1.12; p = 0.026) decline. The odds of a mental health decline decreased with age (adjusted OR per year, 0.98; 95% CI, 0.96-0.99; p = 0.003) and the odds of a functional health decline decreased with time after discharge (adjusted OR per month, 0.86; 95% CI, 0.79-0.94; p = 0.001). CONCLUSIONS: The majority of ICU survivors did not experience substantial changes in their subjective health status, but patients with long ICU stays were prone to subjective mental and functional health decline. Hence, post-ICU care in post-ICU clinics could focus on these patients.

Enhancing European Management of Analgesia, Sedation, and Delirium: A Multinational, Prospective, Interventional Before-After Trial.

BACKGROUND: The objective of this study was to analyze the impact of a structured educational intervention on the implementation of guideline-recommended pain, agitation, and delirium (PAD) assessment. METHODS: This was a prospective, multinational, interventional before-after trial conducted at 12 intensive care units from 10 centers in Germany, Austria, Switzerland, and the UK. Intensive care units underwent a 6-week structured educational program, comprising online lectures, instructional videos, educational handouts, and bedside teaching. Patient-level PAD assessment data were collected in three 1-day point-prevalence assessments before (T1), 6 weeks after (T2), and 1 year after (T3) the educational program. RESULTS: A total of 430 patients were included. The rate of patients who received all three PAD assessments changed from 55% (107/195) at T1 to 53% (68/129) at T2, but increased to 73% (77/106) at T3 (p = 0.003). The delirium screening rate increased from 64% (124/195) at T1 to 65% (84/129) at T2 and 77% (82/106) at T3 (p = 0.041). The pain assessment rate increased from 87% (170/195) at T1 to 92% (119/129) at T2 and 98% (104/106) at T3 (p = 0.005). The rate of sedation assessment showed no signficiant change. The proportion of patients who received nonpharmacological delirium prevention measures increased from 58% (114/195) at T1 to 80% (103/129) at T2 and 91% (96/106) at T3 (p < 0.001). Multivariable regression revealed that at T3, patients were more likely to receive a delirium assessment (odds ratio [OR] 2.138, 95% confidence interval [CI] 1.206-3.790; p = 0.009), sedation assessment (OR 4.131, 95% CI 1.372-12.438; p = 0.012), or all three PAD assessments (OR 2.295, 95% CI 1.349-3.903; p = 0.002) compared with T1. CONCLUSIONS: In routine care, many patients were not assessed for PAD. Assessment rates increased significantly 1 year after the intervention. Clinical trial registration ClinicalTrials.gov: NCT03553719.

Effect of ICU care bundles on long-term patient-relevant outcomes: a scoping review.

OBJECTIVE: Care bundles are considered a key tool to improve bedside quality of care in the intensive care unit (ICU). We explored their effect on long-term patient-relevant outcomes. DESIGN: Systematic literature search and scoping review. DATA SOURCES: We searched PubMed, Embase, CINAHL, APA PsycInfo, Web of Science, CDSR and CENTRAL for keywords of intensive care, care bundles, patient-relevant outcomes, and follow-up studies. ELIGIBILITY CRITERIA: Original articles with patients admitted to adult ICUs assessing bundle implementations and measuring long-term (ie, ICU discharge or later) patient-relevant outcomes (ie, mortality, health-related quality of life (HrQoL), post-intensive care syndrome (PICS), care-related outcomes, adverse events, and social health). DATA EXTRACTION AND SYNTHESIS: After dual, independent, two-stage selection and charting, eligible records were critically appraised and assessed for bundle type, implementation strategies, and effects on long-term patient-relevant outcomes. RESULTS: Of 2012 records, 38 met inclusion criteria; 55% (n=21) were before-after studies, 21% (n=8) observational cohort studies, 13% (n=5) randomised controlled trials, and 11% (n=4) had other designs. Bundles pertained to sepsis (n=11), neurocognition (n=6), communication (n=4), early rehabilitation (n=3), pharmacological discontinuation (n=3), ventilation (n=2) or combined bundles (n=9). Almost two-thirds of the studies reported on survival (n=24), 45% (n=17) on care-related outcomes (eg, discharge disposition), and 13% (n=5) of studies on HrQoL. Regarding PICS, 24% (n=9) assessed cognition, 13% (n=5) physical health, and 11% (n=4) mental health, up to 1 year after discharge. The effects of bundles on long-term patient-relevant outcomes was inconclusive, except for a positive effect of sepsis bundles on survival. The inconclusive effects may have been due to the high risk of bias in included studies and the variability in implementation strategies, instruments, and follow-up times. CONCLUSIONS: There is a need to explore the long-term effects of ICU bundles on HrQoL and PICS. Closing this knowledge gap appears vital to determine if there is long-term patient value of ICU bundles.

Effectiveness of an intensive care telehealth programme to improve process quality (ERIC): a multicentre stepped wedge cluster randomised controlled trial.

PURPOSE: Supporting the provision of intensive care medicine through telehealth potentially improves process quality. This may improve patient recovery and long-term outcomes. We investigated the effectiveness of a multifaceted telemedical programme on the adherence to German quality indicators (QIs) in a regional network of intensive care units (ICUs) in Germany. METHODS: We conducted an investigator-initiated, large-scale, open-label, stepped-wedge cluster randomised controlled trial enrolling adult ICU patients with an expected ICU stay of ≥ 24 h. Twelve ICU clusters in Berlin and Brandenburg were randomly assigned to three sequence groups to transition from control (standard care) to the intervention condition (telemedicine). The quality improvement intervention consisted of daily telemedical rounds guided by eight German acute ICU care QIs and expert consultations. Co-primary effectiveness outcomes were patient-specific daily adherence (fulfilled yes/no) to QIs, assessed by a central end point adjudication committee. Analyses used mixed-effects logistic modelling adjusted for time. This study is completed and registered with ClinicalTrials.gov (NCT03671447). RESULTS: Between September 4, 2018, and March 31, 2020, 1463 patients (414 treated on control, 1049 on intervention condition) were enrolled at ten clusters, resulting in 14,783 evaluated days. Two randomised clusters recruited no patients (one withdrew informed consent; one dropped out). The intervention, as implemented, significantly increased QI performance for "sedation, analgesia and delirium" (adjusted odds ratio (99.375% confidence interval [CI]) 5.328, 3.395-8.358), "ventilation" (OR 2.248, 1.198-4.217), "weaning from ventilation" (OR 9.049, 2.707-30.247), "infection management" (OR 4.397, 1.482-13.037), "enteral nutrition" (OR 1.579, 1.032-2.416), "patient and family communication" (OR 6.787, 3.976-11.589), and "early mobilisation" (OR 3.161, 2.160-4.624). No evidence for a difference in adherence to "daily multi-professional and interdisciplinary clinical visits" between both conditions was found (OR 1.606, 0.780-3.309). Temporal trends related and unrelated to the intervention were detected. 149 patients died during their index ICU stay (45 treated on control, 104 on intervention condition). CONCLUSION: A telemedical quality improvement program increased adherence to seven evidence-based German performance indicators in acute ICU care. These results need further confirmation in a broader setting of regional, non-academic community hospitals and other healthcare systems.

Subjective Ratings of Mental and Physical Health Correlate With EQ-5D-5L Index Values in Survivors of Critical Illness: A Construct Validity Study.

OBJECTIVES: Survivors of critical illness commonly show impaired health-related quality of life (HrQoL). We investigated if HrQoL can be approximated by brief, easily applicable items to be used in primary care. DESIGN: Secondary analysis of data from the multicenter, cluster-randomized controlled Enhanced Recovery after Intensive Care trial ( ClinicalTrials.gov : NCT03671447) and construct validity study. SETTING: Ten participating clusters of ICUs in the metropolitan area of Berlin, Germany. PATIENTS: Eight hundred fifty ICU survivors enrolled in a mixed, medical or surgical ICU when they had an expected ICU length of stay of at least 24 hours, were at least 18 years old, and had statutory health insurance coverage. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients received follow-ups scheduled 3 and 6 months after ICU discharge. HrQoL was assessed with the EuroQol 5-Dimension 5-Level (EQ-5D-5L), and patients were asked to rate their current mental and physical health state from 0 (worst) to 10 (best). We fitted prediction models for the EQ-5D-5L index value using these two items and additional covariates, applying stepwise regression and adaptive lasso. Subjective mental health (Spearman: 0.59) and subjective physical health (Spearman: 0.68) correlated with EQ-5D-5L index values and were better predictors of EQ-5D-5L index values in the two-item regression (normalized root mean squared error [nRMSE] 0.164; normalized mean absolute error [nMAE] 0.118; R2adj 0.43) than the EQ-5D Visual Analog Scale (nRMSE 0.175; nMAE 0.124; R2adj 0.35). Stepwise regression with additional covariates further increased prediction performance (nRMSE 0.133; nMAE 0.1; R2adj 0.51). CONCLUSIONS: Asking patients to rate their subjective mental and physical health can be an easily applicable tool for a first impression of the HrQoL in primary care settings.

Out-of-pocket Expenses and Time Spent on Clinic Visits Among HIV Pre-exposure Prophylaxis Users and Other Clinic Attendees in Eswatini.

User costs constitute a barrier to the uptake of HIV pre-exposure prophylaxis (PrEP), but their magnitude appears rarely assessed. In this prospective observational study, we assessed self-reported out-of-pocket expenses (OOPE) and time spent on clinic visits during a PrEP demonstration project in Eswatini. At six public primary care clinics, 240 PrEP users and other clinic attendees were interviewed after a clinic visit. Among the 79.2% of clinic attendees reporting any medical OOPE (e.g., expenses for consultations or drugs) and/or non-medical OOPE (e.g., expenses for transport, food, or phone use), the median total OOPE was $1.36 (IQR 0.91-1.96). Non-medical OOPE occurred mostly due to transport expenses. The median travel time for a clinic visit was 1.0 h (IQR 0.67-2.0). The median time spent in the clinic was 2.0 h (IQR 1.15-3.0). The median opportunity cost of a clinic visit was $7.54 (IQR 5.42-11) when valuing time spent on a clinic visit with Eswatini's per-capita gross domestic product. Our findings can guide measures to reduce the user costs of PrEP in Eswatini and other contexts in which oral PrEP is provided through health care facilities.

RESUMEN: Los costes de los usuarios constituyen un obstáculo para la adopción de la profilaxis previa a la exposición al VIH (PrEP), pero su magnitud rara vez se evalúa. En este estudio observacional prospectivo, evaluamos los gastos de bolsillo (OOPE) declarados por los propios usuarios y el tiempo dedicado a las visitas clínicas durante un proyecto de demostración de la PrEP en Eswatini. En seis clínicas públicas de atención primaria, se entrevistó a 240 usuarios de la PrEP y a otros asistentes a la clínica después de una visita a la misma. Entre el 79,2% de los asistentes a las clínicas que declararon algún OOPE médico (por ejemplo, gastos por consultas o medicamentos) y/o OOPE no médico (por ejemplo, gastos de transporte, comida o uso del teléfono), la mediana del OOPE total fue de 1,36 dólares (IQR: 0,91­1,96). Los gastos no médicos se debieron principalmente a los gastos de transporte. La mediana del tiempo de viaje para una visita a la clínica fue de 1,0 horas (IQR 0,67­2,0). La mediana del tiempo empleado en la clínica fue de 2 horas (IQR 1,15­3,0). La mediana del coste de oportunidad de una visita a la clínica fue de 7,65 dólares (IQR 5,55­11) al valorar el tiempo dedicado a una visita a la clínica con el producto interior bruto per cápita de Eswatini. Nuestros resultados pueden orientar las medidas para reducir los costes de uso de la PrEP en Eswatini y en otros contextos en los que se suministra la PrEP oral a través de los centros de salud.

[Health and Professional Satisfaction of Freelance and Employed Midwives: Results of a Survey of Midwives in Baden-Wuerttemberg]. / Gesundheit und berufliche Zufriedenheit von freiberuflichen und angestellten Hebammen: Ergebnisse einer Hebammenbefragung in Baden-Württemberg.

BACKGROUND: A shortage of midwives has been the subject of discussion in Germany in recent years. In this study, we asked midwives in Baden-Wuerttemberg about their health and professional satisfaction. METHOD: In collaboration with the Baden-Wuerttemberg Midwives Association, an online midwives survey was conducted from October 16 to December 10, 2017. Using a visual analog scale (0-100 points), the WHO-5 questionnaire (0-100 points) and the Copenhagen Burnout Inventory (0-100 points), data on health, well-being and burnout were collected. Job satisfaction was assessed on a 7-point Likert scale. Seven hundred and twenty-two midwives participated in the survey. For this study, 545 to 608 data sets were analyzed. RESULTS: Of the studied midwives, 78.1% rated their health as good or very good (≥60 points). No statistically significant difference was observed between freelance midwives, employed midwives, and midwives who worked in both occupation forms (P=0.12). Midwives who were exclusively (15.0%) or partially (12.6%) employed were more likely to have very low well-being (≤25 points) than freelance midwives (7.3%; P=0.023). In addition, midwives who were exclusively (41.5%) or partially (39.4%) employed were more likely to have a moderate or high risk of burnout (≥50 points) than freelance midwives (20.6%; P<0.001). A lower health rating, lower well-being or higher burnout risk were associated with higher professional dissatisfaction in one or more domains. In multivariable analyses, higher burnout risk in particular was associated with higher job dissatisfaction in various domains. CONCLUSIONS: A large proportion of midwives in our study showed symptoms of depression and/or burnout. On average, the health status of midwives seems to be above the health status of women from the general population in Germany, but the well-being of midwives below. We recommend further investigation of how the stress of midwives can be reduced in the course of advancing midwifery and obstetric care structures.

Costs and import costs of past, present, and future TB drug regimens: a case study for Karakalpakstan, Uzbekistan.

BACKGROUND: Tuberculosis (TB) drugs and their import are costly. We assessed how shorter TB drug regimens, which were non-inferior or superior in recent TB trials, can affect the costs for purchasing and importing TB drugs. METHODS: We estimated the drug costs and import costs of 39 longer and shorter TB drug regimens using TB drug prices from the Global Drug Facility and import cost estimates for a TB program in Karakalpakstan, Uzbekistan. Drug regimens from recent TB trials were compared with TB drug regimens following present or past World Health Organization recommendations. RESULTS: We estimated an import cost of $4.19 and a drug cost of $43 per standard 6-month drug-sensitive (DS)-TB regimen. A new 17-week DS-TB regimen from the TBTC Study 31 currently requires more tablets and is more expensive to import ($6.08) and purchase ($233). The TB program can substantially decrease import costs ($2.26-14) and drug costs ($391-2308) per multidrug-resistant (MDR)-TB regimen when using new 6-month or shorter drug regimens from the Nix-TB, NExT, TB PRACTECAL, ZeNix, or BEAT TB trials instead of 9-20-month regimens with import costs of $9.96-507 and drug costs of $354-15 028. For a commonly used 20-month all-oral, bedaquiline-containing MDR-TB regimen, we estimated costs of $41 for drug import and $1773 for drug purchase. CONCLUSIONS: The implementation of a new and shorter DS-TB regimen may increase the costs for drug purchase and import. The implementation of new and shorter MDR-TB regimens may decrease the costs for drug purchase and/or drug import.

Post-Intensive Care Syndrome after Critical Illness: An Imperative for Effective Prevention.

Over the last decades, the importance of intensive care has considerably increased [...].

Human resource needs and costs for HIV pre-exposure prophylaxis provision in nurse-led primary care in Eswatini and opportunities for task sharing.

BACKGROUND: The global expansion of HIV pre-exposure prophylaxis (PrEP) includes health systems that face a shortage of skilled health care workers (HCWs). We estimated the human resource needs and costs for providing PrEP in nurse-led primary care clinics in Eswatini. Furthermore, we assessed potential cost savings from task sharing between nurses and other HCW cadres. METHODS: We conducted a time-and-motion and costing study in a PrEP demonstration project between August 2017 and January 2019. A form for recording time and performed activities ("motion") was filled by HCWs of six primary care clinics. To estimate the human resource needs for specific PrEP activities, we allocated recorded times to performed PrEP activities using linear regression with and without adjusting for a workflow interruption, that is, if a client was seen by different HCWs or by the same HCW at different times. We assessed a base case in which a nurse provides all PrEP activities and five task shifting scenarios, of which four include workflow interruptions due to task sharing between different HCW cadres. RESULTS: On average, PrEP initiation required 29 min (95% CI 25-32) of HCW time and PrEP follow-up 16 min (95% CI 14-18). The HCW time cost $4.55 (uncertainty interval [UI] 1.52-9.69) for PrEP initiation and $2.54 (UI 1.07-4.64) for PrEP follow-up when all activities were performed by a nurse. Time costs were $2.30-4.25 (UI 0.62-9.19) for PrEP initiation and $1.06-2.60 (UI 0.30-5.44) for PrEP follow-up when nurses shared tasks with HCWs from lower cadres. Interruptions of the workflow added, on average, 3.4 min (95% CI 0.69-6.0) to the time HCWs needed for a given number of PrEP activities. The cost of an interrupted workflow was estimated at $0.048-0.87 (UI 0.0098-1.63) depending on whose time need increased. CONCLUSIONS: A global shortage of skilled HCWs could slow the expansion of PrEP. Task shifting to lower-cadre HCW in nurse-led PrEP provision can free up nurse time and reduce the cost of PrEP provision even if interruptions associated with task sharing increase the overall human resource need.

Burnout among midwives and attitudes toward midwifery: A cross-sectional study from Baden-Württemberg, Germany.

INTRODUCTION: Midwifery services are a cornerstone of maternal care, but the mental health of midwives is at risk in many work settings. The aim of this study was to assess burnout and attitudes toward midwifery among midwives in Baden-Württemberg, Germany. METHODS: A cross-sectional online survey among midwives was conducted from 16 October to 10 December 2017. Burnout was assessed using the Copenhagen Burnout Inventory (CBI). RESULTS: A total of 602 survey respondents were studied; 48.3%, 38.2%, and 23.3% of midwives reported moderate or high (CBI score ≥50) levels of personal burnout, work-related burnout, and client-related burnout, respectively. Midwives with moderate or high burnout in at least one CBI dimension worked more weekly hours, were more commonly employed, and worked more frequently in the hospital. In turn, midwives with low burnout levels worked fewer weekly hours, more commonly freelance, and more frequently community based (all p<0.001). Moderate or high burnout levels were associated with a reduced likelihood to recommend midwifery as a profession (OR=0.34; 95% CI: 0.23-0.49) and an increased likelihood to intent leaving the profession (OR=3.39; 95% CI: 2.0-5.9) in a multivariable regression adjusting for midwife characteristics and work practices. CONCLUSIONS: Burnout symptoms were common among midwives. Burnout could be a health risk for midwives and a challenge to the profession by discouraging present and future midwives from practicing midwifery.

Programme costs of longer and shorter tuberculosis drug regimens and drug import: a modelling study for Karakalpakstan, Uzbekistan.

Background: The introduction of new and often shorter tuberculosis (TB) drug regimens affects the cost of TB programmes. Methods: We modelled drug purchase and import costs for 20-month, 9-month and 4- to 6-month TB drug regimens based on 2016-2020 treatment numbers from a TB programme in Karakalpakstan, Uzbekistan, and 2021 Global Drug Facility prices. Results: On average, 2225±374 (±sd) people per year started TB treatment, 30±2.1% of whom were diagnosed with drug-resistant forms of TB. Transitioning from a 6-month to a 4-month drug-susceptible (DS)-TB drug regimen increased the TB programme's annual DS-TB drug cost from USD 65±10 K to USD 357±56 K (p<0.001) and its drug import cost from USD 6.4±1.0 K to USD 9.3±1.4 K (p=0.008). Transitioning from a 20-month all-oral multidrug-resistant (MDR)-TB drug regimen to a 9-month MDR-TB drug regimen with an injectable antibiotic decreased the TB programme's annual MDR-TB drug cost from USD 1336±265 K to USD 266±53 K (p<0.001) and had no significant effect on the drug import cost (USD 28±5.5 K versus USD 27±5.4 K; p=0.88). Purchasing (USD 577±114 K) and importing (USD 3.0±0.59 K) the 6-month all-oral MDR-TB drug regimen cost more than procuring the 9-month MDR-TB drug regimen but less than the 20-month all-oral MDR-TB drug regimen (both p<0.01). Conclusion: Introducing new and shorter TB drug regimens could increase the cost of TB programmes with low drug resistance rates and decrease the cost of TB programmes with high drug resistance rates.

A Decade of Post-Intensive Care Syndrome: A Bibliometric Network Analysis.

Background and Objectives: In 2012, the umbrella term post-intensive care syndrome (PICS) was introduced to capture functional long-term impairments of survivors of critical illness. We present a bibliometric network analysis of the PICS research field. Materials and Methods: The Web of Science core database was searched for articles published in 2012 or later using 'post-intensive care syndrome' and variant spellings. Using VOSviewer, we computed co-authorship networks of countries, institutions, and authors, as well as keyword co-occurrence networks. We determined each country's relative research effort and Category Normalized Citation Index over time and analyzed the 100 most-cited articles with respect to article type, country of origin, and publishing journal. Results: Our search yielded 379 articles, of which 373 were analyzed. Annual PICS research output increased from 11 (2012) to 95 articles (2020). Most PICS research originates from the US, followed by England, Australia, the Netherlands, and Germany. We found various collaborations between countries, institutions, and authors, with recent collaborative networks of English and Australian institutions. Article keywords cover aspects of cognitive, mental health, and physical impairments, and more recently, COVID-19. Only a few keywords and articles pertained to PICS prevention and treatment. Conclusions: Our analysis of Web of Science-indexed PICS articles highlights the stark increase in PICS research output in recent years, primarily originating from US- and Europe-based authors and institutions. Despite the research field's growth, knowledge gaps with respect to PICS prevention and treatment remain.

Use of patient-relevant outcome measures to assess the long-term effects of care bundles in the ICU: a scoping review protocol.

INTRODUCTION: There is only moderate adherence to evidence-based practice in critical care. Care bundles can be used to increase adherence to best clinical practice. Components of bundle interventions, bundle implementation rates, barriers and facilitators of bundle implementation, and the effect of care bundles on short-term patient outcomes such as intensive care unit (ICU) mortality all appear to be regularly studied. However, over the last years, critical care research has turned towards long-term patient-relevant outcomes after discharge from the ICU. To our knowledge, there is no systematic overview on the long-term effect of care bundle implementation on patient-relevant outcomes. We present a protocol for a scoping review of the available literature on the effect of the implementation of care bundles in the ICU on long-term patient-relevant outcomes. METHODS AND ANALYSIS: This scoping review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines and the Arksey and O'Malley framework. The recommendations of the Joanna Briggs Institute for Scoping Reviews will also be followed. A systematic literature research will be performed using electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, CDSR and CENTRAL). A preliminary search has been conducted on 1 September 2021, yielding 1929 entries. The main search, data extraction and charting has not been started yet. This scoping review will provide an overview of the long-term patient-relevant outcomes that have been used to assess the implementation of care bundles in the ICU. It will be the first study to summarise the long-term impact of care bundles for critically ill patients and identify research gaps to inform future research. ETHICS AND DISSEMINATION: Due to the utilisation of already published primary studies, ethical approval is dispensable. Results of this work will be published in a peer-reviewed journal.

Influence of Patient-Specific Covariates on Test Validity of Two Delirium Screening Instruments in Neurocritical Care Patients (DEMON-ICU).

BACKGROUND: Delirium screening instruments (DSIs) should be used to detect delirium, but they only show moderate sensitivity in patients with neurocritical illness. We explored whether, for these patients, DSI validity is impacted by patient-specific covariates. METHODS: Data were prospectively collected in a single-center quality improvement project. Patients were screened for delirium once daily using the Intensive Care Delirium Screening Checklist (ICDSC) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Reference was the daily assessment using criteria from the Diagnostic and Statistical Manual, 4th Edition, Text Revision (DSM-IV-TR). In a two-step receiver operating characteristics regression analysis adjusting for repeated measurements, the impact of acute diagnosis of stroke or transient ischemic attack (TIA), neurosurgical intervention, Richmond Agitation Sedation Scale, and ventilation status on test validity was determined. RESULTS: Of 181 patients screened, 101 went into final analysis. Delirium incidence according to DSM-IV-TR was 29.7%. For the first complete assessment series (CAM-ICU, ICDSC, and DSM-IV-TR), sensitivity for the CAM-ICU and the ICDSC was 73.3% and 66.7%, and specificity was 91.8% and 94.1%, respectively. Consideration of daily repeated measurements increased sensitivity for the CAM-ICU and ICDSC to 75.7% and 73.4%, and specificity to 97.3% and 98.9%, respectively. Receiver operating characteristics regression revealed that lower Richmond Agitation Sedation Scale levels significantly impaired validity of the ICDSC (p = 0.029) and the CAM-ICU in its severity scale version (p = 0.004). Neither acute diagnosis of stroke or TIA nor neurosurgical intervention or mechanical ventilation significantly influenced DSI validity. CONCLUSIONS: The CAM-ICU and ICDSC perform well in patients requiring neurocritical care, regardless of the presence of acute stroke, TIA, or neurosurgical interventions. Yet, even very light or moderate sedation can significantly impair DSI performance.

The contribution of drug import to the cost of tuberculosis treatment: A cost analysis of longer, shorter, and short drug regimens for Karakalpakstan, Uzbekistan.

Tuberculosis (TB) programs depend on a continuous supply of large amounts of high-quality TB drugs. When TB programs procure TB drugs from international suppliers, such as the Global Drug Facility, they can incur import costs for international transport, customs clearance, and national transport. We assessed the drug costs and import costs of 18 longer (≥18 months), 10 shorter (9-12 months), and 8 short (≤6 months) drug regimens for drug-sensitive (DS) and multidrug-resistant (MDR)-TB treatment. Costs per regimen were estimated by multiplying recommended drug amounts with 2021 Global Drug Facility prices and drug import costs of a TB program in Karakalpakstan, Uzbekistan. The standard short-course treatment of DS-TB requires taking 730 fixed-dose combination tablets, which weigh 0.79 kg and cause an import cost of $4.19 (9.8% of the regimen's drug cost of $43). A new 4-month DS-TB regimen requires taking 1358 tablets, which weigh 1.1 kg and cause an import cost of $6.07 (2.6% of the regimen's drug cost of $233). MDR-TB regimens that last between 24 weeks and 20 months involve 546-9368 tablets and injections. The drugs for these MDR-TB regimens were estimated to weigh 0.42-96 kg and cause an import cost of $2.26-507 per drug regimen (0.29-11% of a regimen's drug cost of $360-15,028). In a multivariable regression analysis, an additional treatment month increased the import cost of a drug regimen by $5.45 (95% CI: 1.65 to 9.26). Use of an injectable antibiotic in a regimen increased the import cost by $133 (95% CI: 47 to 219). The variable and potentially sizable import costs of TB regimens can affect the financial needs of TB programs. Drug regimens that are shorter and all-oral tend to reduce import costs compared to longer regimens and regimens including an injectable drug.

Outcomes in Critically Ill Patients Sedated with Intravenous Lormetazepam or Midazolam: A Retrospective Cohort Study.

The benzodiazepine, midazolam, is one of the most frequently used sedatives in intensive care medicine, but it has an unfavorable pharmacokinetic profile when continuously applied. As a consequence, patients are frequently prolonged and more deeply sedated than intended. Due to its distinct pharmacological features, including a cytochrome P450-independent metabolization, intravenous lormetazepam might be clinically advantageous compared to midazolam. In this retrospective cohort study, we compared patients who received either intravenous lormetazepam or midazolam with respect to their survival and sedation characteristics. The cohort included 3314 mechanically ventilated, critically ill patients that received one of the two drugs in a tertiary medical center in Germany between 2006 and 2018. A Cox proportional hazards model with mortality as outcome and APACHE II, age, gender, and admission mode as covariates revealed a hazard ratio of 1.75 [95% CI 1.46-2.09; p < 0.001] for in-hospital mortality associated with the use of midazolam. After additionally adjusting for sedation intensity, the HR became 1.04 [95% CI 0.83-1.31; p = 0.97]. Thus, we concluded that excessive sedation occurs more frequently in critically ill patients treated with midazolam than in patients treated with lormetazepam. These findings require further investigation in prospective trials to assess if lormetazepam, due to its ability to maintain light sedation, might be favorable over other benzodiazepines for sedation in the ICU.