Single-Cell RNA-Seq Mapping of Human Thymopoiesis Reveals Lineage Specification Trajectories and a Commitment Spectrum in T Cell Development.

The challenges in recapitulating in vivo human T cell development in laboratory models have posed a barrier to understanding human thymopoiesis. Here, we used single-cell RNA sequencing (sRNA-seq) to interrogate the rare CD34+ progenitor and the more differentiated CD34- fractions in the human postnatal thymus. CD34+ thymic progenitors were comprised of a spectrum of specification and commitment states characterized by multilineage priming followed by gradual T cell commitment. The earliest progenitors in the differentiation trajectory were CD7- and expressed a stem-cell-like transcriptional profile, but had also initiated T cell priming. Clustering analysis identified a CD34+ subpopulation primed for the plasmacytoid dendritic lineage, suggesting an intrathymic dendritic specification pathway. CD2 expression defined T cell commitment stages where loss of B cell potential preceded that of myeloid potential. These datasets delineate gene expression profiles spanning key differentiation events in human thymopoiesis and provide a resource for the further study of human T cell development.

Author Response: Emphasizing Patient-centered Outcomes and Improved Exclusion Criteria in Randomized Control Trials for Clinical Nutrition in ICU.

How to cite this article: Govil D, Chandrasekaran A, Pachisia AV, Harne R, Patel SJ, Pal D. Author Response: Emphasizing Patient-centered Outcomes and Improved Exclusion Criteria in Randomized Control Trials for Clinical Nutrition in ICU. Indian J Crit Care Med 2024;28(8):806-807.

Protocolized Regional Citrate Anticoagulation during Continuous Renal Replacement Therapy: A Single Center Experience.

Background: Regional citrate anticoagulation (RCA) has emerged as a treatment modality that reduces bleeding risk and filter clotting. With initial experience of using RCA with continuous renal replacement therapy (CRRT), we have formulated a working protocol based on published literature. Objective: The study aimed to evaluate the protocol for routine use of RCA during CRRT requiring anticoagulation and evaluation of filter life. Methodology: It is a single-center, open-label, prospective, non-randomized, non-interventional, single-arm, observational study conducted at a tertiary care hospital between September 2022 and July 2023. All adult patients with acute kidney injury (AKI) or hyperammonemia requiring CRRT and necessitating the use of anticoagulation were enrolled in the study. The study used Prisma Flex M100 AN 69 dialyzer on Prisma Flex (Baxter) CRRT machines during continuous venovenous hemodiafiltration (CVVHDF). The targeted CRRT dose in all the study patients was 25-30 mL/kg/hour. Based on the published literature, we have developed a working protocol (Appendix 1) for managing patients on CRRT using RCA. Results: A total of 159 patients were analyzed for the study. The median [interquartile range (IQR)] filter life using RCA was 30 (12-55) hours. Filter clotting was observed in 33.3% of patients. Citrate accumulation was present in 52.25% of patients, but no CRRT was discontinued as citrate accumulation resolved after following the corrective steps in the protocol. None of the patients had citrate toxicity. Chronic liver disease (CLD) (p ≤ 0.001) and those who were post-living donor liver transplant recipients (p = 0.004) had a statistically significant increase in citrate accumulation. Also, patients who had higher lactate at baseline (6 hours post-CRRT initiation), had a higher chance of citrate accumulation. Conclusion: Our RCA protocol provides a safe approach to regional anticoagulation during CRRT in critically ill patients. How to cite this article: Pachisia AV, Kumar GP, Harne R, Jagadeesh KN, Patel SJ, Pal D, et al. Protocolized Regional Citrate Anticoagulation during Continuous Renal Replacement Therapy: A Single Center Experience. Indian J Crit Care Med 2024;28(9):859-865.

Comparison between Effect of Indirect Calorimetry vs Weight-based Equation (25 kcal/kg/day)-guided Nutrition on Quadriceps Muscle Thickness as Assessed by Bedside Ultrasonography in Medical Intensive Care Unit Patients: A Randomized Clinical Trial.

Aim and background: Sarcopenia is a substantial contributor to intensive care unit (ICU)-acquired weakness and is associated with significant short- and long-term outcomes. It can, however, be mitigated by providing appropriate nutrition. Indirect calorimetry (IC) is believed to be the gold standard in determining caloric targets in the dynamic environment of critical illness. We conducted this study to compare the effect of IC vs weight-based (25 kcal/kg/day) feeding on quadriceps muscle thickness (QMT) by ultrasound in critically ill patients. Materials and methods: A prospective study was conducted on 60 mechanically ventilated patients randomized to two groups [weight-based equation (WBE) group or the IC group] in medical ICU after obtaining institutional ethics committee approval, and fed accordingly. The right QMT measurement using ultrasound and caloric targets were documented on day 1, 3 and 7 and analyzed statistically. The IC readings were obtained from the metabolic cart E-COVX ModuleTM. Results: The baseline demographics, APACHE-II, NUTRIC score, and SOFA scores on day 1, 3, and 7 were comparable between the two groups. The resting energy expenditure (REE) obtained in the IC group was significantly less than the WBE energy targets and the former were fed with significantly less calories. A significantly less percent reduction of QMT in the IC group compared with the WBE group was observed from day 1 to day 3, day 3 to day 7, and day 1 to day 7. Conclusion: From our study, we conclude that IC-REE-based nutrition is associated with lesser reduction in QMT and lesser calories fed in critically ill mechanically ventilated patients compared from WBE. CTRI registration-CTRI/2023/01/049119. How to cite this article: Chandrasekaran A, Pal D, Harne R, Patel SJ, Jagadeesh KN, Pachisia AV, et al. Comparison between Effect of Indirect Calorimetry vs Weight-based Equation (25 kcal/kg/day)-guided Nutrition on Quadriceps Muscle Thickness as Assessed by Bedside Ultrasonography in Medical Intensive Care Unit Patients: A Randomized Clinical Trial. Indian J Crit Care Med 2024;28(6):587-594.

Evaluation of the management of PARP inhibitor toxicities in ovarian and endometrial cancer within a multi-institution health-system.

INTRODUCTION: Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have become a cornerstone of therapy in the management ovarian cancer and other cancers. PARPi are associated with significant toxicities and management strategies are primarily founded on clinical trial experience. This study aimed to provide an evaluation of patients receiving PARPi therapy within an academic health-system. METHODS: A retrospective, observational study of adult patients with gynecologic malignancy was conducted at the University of Pennsylvania Health System. Data was collected on patients prescribed a PARPi between December 2014 and October 2019. The primary endpoint was the status of PARPi therapy at the end of the study period. Key secondary endpoints included toxicity management strategies, time to discontinuation due to toxicity, progression free survival (PFS), and overall survival (OS). RESULTS: Of the 85 patients included, 45 (53%) received olaparib, 24 (28%) niraparib, and 16 (19%) rucaparib. Twenty-nine patients (34%) continued on therapy, 15 (18%) discontinued due to toxicity, and 41 (48%) discontinued due to progression. Fifty-one percent of patients required a dose reduction due to toxicities. The median time to discontinuation due to toxicity was 69 days (9-353). Median PFS was 181 days (9-365) and median OS was 338 days (9-365). CONCLUSION: PARPi therapy is associated with numerous toxicities that are best managed through a multi-modal approach. Importantly, about half the patients in the current study required a dose reduction. Overall, this observational study outlines the incidence of PARPi toxicities and reviews potential management strategies, further guiding practitioners in an area with limited real-world experience.

Colonic Microflora Protagonist of Liver Metabolism and Gut Permeability: Study on Mice Model.

Alteration of gut microflora results in a metabolic imbalance in the liver. In the present study, we investigate the reversal potential of alteration of the colonic microflora via improving metabolism balance and regulating the altered tight junction of the intestinal tract. Animals were fed with high sugar diet to mimic the onset of the pathophysiological conditions of diabetes. Following induction, animals were divided into two reversal groups i.e., crude cefdinir and colon-specific formulated cefdinir, to alter the gut microflora. In the present study, we have tried to quantify the microbial content via metagenome analysis to provide an actual picture of the alteration and subsequent reversal. Expression of mRNA of junctional protein and parameters involved in liver metabolism was determined using qPCR. Results indicated direct effect of altered composition of gut microflora on the gut permeability and metabolic alteration. Metagenomic analysis showed least evenness and richness in the HSD group whereas antibiotic-treated groups showed reversal of microflora towards control group with increased richness, evenness and decreased distance on PCoA plot. This changes in gut microflora composition changes expression of metabolic markers and thus insulin sensitivity. Targeting colonic microflora to have a reversal effect on T2D pathogenesis, found to have a positive impact on liver metabolic state with improved permeability markers of gut with SCFA alteration. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01032-x.

Competencies for Point-of-care Ultrasonography in ICU: An ISCCM Expert Panel Practice Recommendation.

How to cite this article: Srinivasan S, Kumar PG, Govil D, Gupta S, Kumar V, Pichamuthu K, et al. Competencies for Point-of-care Ultrasonography in ICU: An ISCCM Expert Panel Practice Recommendation. Indian J Crit Care Med 2022;26(S2):S7-S12.

Effect of Haemophilus influenzae Type b and 13-Valent Pneumococcal Conjugate Vaccines on Childhood Pneumonia Hospitalizations and Deaths in Botswana.

BACKGROUND: Globally, pneumonia is the leading cause of death among children. Few data exist regarding the effect of Haemophilus influenzae type b (Hib) vaccine and 13-valent pneumococcal conjugate vaccine (PCV-13) on the burden of childhood pneumonia in African settings. METHODS: We collected data on children aged 1 to 59 months at 3 hospitals in Botswana. Hib vaccine and PCV-13 were introduced in Botswana in November 2010 and July 2012, respectively. We compared pneumonia hospitalizations and deaths prevaccine (January 2009 to October 2010) with postvaccine (January 2013 to December 2017) using seasonally adjusted, interrupted time-series analyses. RESULTS: We identified 6943 pneumonia hospitalizations and 201 pneumonia deaths. In the prevaccine period, pneumonia hospitalizations and deaths increased by 24% (rate, 1.24; 95% CI, .94-1.64) and 59% (rate, 1.59; 95% CI, .87-2.90) per year, respectively. Vaccine introduction was associated with a 48% (95% CI, 29-62%) decrease in the number of pneumonia hospitalizations and a 50% (95% CI, 1-75%) decrease in the number of pneumonia deaths between the end of the prevaccine period (October 2010) and the beginning of the postvaccine period (January 2013). During the postvaccine period, pneumonia hospitalizations and deaths declined by 6% (rate, .94; 95% CI, .89-.99) and 22% (rate, .78; 95% CI, .67-.92) per year, respectively. CONCLUSIONS: Pneumonia hospitalizations and deaths among children declined sharply following introduction of Hib vaccine and PCV-13 in Botswana. This effect was sustained for more than 5 years after vaccine introduction, supporting the long-term effectiveness of these vaccines in preventing childhood pneumonia in Botswana.

Low persistence to rivaroxaban or warfarin among patients with new venous thromboembolism at a safety net academic medical center.

Recent guidelines recommend direct acting oral anticoagulants (DOAC) over vitamin-k antagonist (VKA) for acute venous thromboembolism (VTE). Non-adherence to anticoagulation has been associated with increased frequency of VTE or stroke. This study evaluated 90 day persistence among patients prescribed rivaroxaban or warfarin for the treatment of acute VTE at an academic safety net hospital. We conducted a single center, retrospective cohort study of 314 consecutive patients newly prescribed rivaroxaban or warfarin for acute VTE between January 2016 and July 2017. Primary outcome was 90 day persistence, and secondary outcomes included 90 day readmission and/or ED visit, time to 90 m day readmission and/or ED visits, and attendance of direct oral anticoagulant education class. Of 314 patients, 78 were prescribed warfarin and 236 rivaroxaban. Patients had a mean age of 52 years, 62% were men, and 96% were diagnosed with deep vein thrombosis and/or pulmonary embolism. Persistence at 90 days was 52.6% among patients prescribed warfarin compared to 45.3% for patients prescribed rivaroxaban (p = 0.2678). Persistencewas associated with decreased 90 day hospital or ED readmission. Among patients prescribed rivaroxaban, attending a pharmacist led educational class was associated with a 2.5 fold increase in persistence (p < 0.0001). Among patients with new onset venous thromboembolism, 90 day persistence with anticoagulation was similarly low with either rivaroxaban or warfarin therapy. Participation in a pharmacist led DOAC class was associated with a 2.5-fold increase in persistence on rivaroxaban.

Sequencing and analysis of the whole genome of Indian Gujarati male.

The article presents the analysis of whole genome sequence of a Gujarati Indian individual (IHGP01) that was sequenced at 23.05× coverage with a total of 74.93 Gb of sequence data generated using Illumina HiSeq 2000 platform. Variant analysis revealed over 3.9 million single nucleotide variants (SNVs) and about 393,000 small insertions and deletions (InDels) including novel variants. The known variants were analyzed for their health and disease relevance and pharmacogenomic profile. Mitochondrial and Y-chromosome haplogroup analysis clearly indicated arrival on the continent not more than 20,000-25,000 years ago, following the route out of Africa to central Europe, then into Asian continent and subsequent migration to West part of the Indian subcontinent. The current research has added 141,000 novel genetic variations to the human DNA database. Functional analysis and validation of these novel variations and revelation of their role in health and disease will add a newer dimension to understand people of this subcontinent.

Percutaneous Tracheostomy under Real-time Ultrasound Guidance in Coagulopathic Patients: A Single-center Experience.

OBJECTIVE: To examine the safety and complications associated with percutaneous tracheostomy (PT) in critically ill coagulopathic patients under real-time ultrasound guidance. MATERIALS AND METHODS: Coagulopathy was defined as international normalized ratio (INR) ≥1.5 or thrombocytopenia (platelet count ≤50,000/mm3). Neck anatomy was assessed for all patients before the procedure and was characterized as excellent, good, satisfactory, and unsatisfactory based on the number of vessels in the path of needle. Percutaneous tracheostomy was performed under real-time ultrasound (USG) guidance, with certain modifications to the technique, and patients in both groups were assessed for immediate complications including bleeding. RESULTS: Six hundred and fifty-two patients underwent USG-guided PT. Three hundred and forty-five (52.9%) were coagulopathic before the procedure. Ninety-nine patients (15.2%) had an excellent neck anatomy on USG scan, and 112 patients (62 in coagulopathy group vs 50 in noncoagulopathy group, p value 0.386) had an unsatisfactory neck anatomy for tracheostomy. A total of 42 events of immediate complications were noted in 37 patients (5.7%). No difference was seen in the rate of immediate complications in both groups (5.8% in coagulopathy group vs 5.5% in noncoagulopathy group, p value 0.886). The incidence of minor bleeding in coagulopathic patients was 14 patients (4.1%) and 7 (2.3%) in those without coagulopathy, and this difference was not statistically different (p value-0.199). In the subgroup analysis of patients with significant coagulopathy and unsatisfactory anatomy, no difference was observed in the incidence of immediate complications. CONCLUSION: This study shows the efficacy and safety of real-time ultrasound-guided PT, even in patients with coagulopathy. HOW TO CITE THIS ARTICLE: Kumar P, Govil D, Patel SJ, Jagadeesh KN, Gupta S, Srinivasan S, et al. Percutaneous Tracheostomy under Real-time Ultrasound Guidance in Coagulopathic Patients: A Single-center Experience. Indian J Crit Care Med 2020;24(2):122-127.

A case of syngeneic graft-versus-host disease.

Graft-versus-host disease has been reported to occur rarely in syngeneic hematopoietic stem cell transplant recipients. Clinical and histological changes consistent with graft-versus-host disease have been reported to occur in this patient population. We report a case of a 46-year-old Caucasian male with diffuse large B-cell lymphoma in complete remission who underwent a syngeneic hematopoietic stem cell transplant. He was diagnosed with grade III acute skin and gastrointestinal graft-versus-host disease requiring high-dose corticosteroids and immunosuppressive therapy and resulting in a complete response. Syngeneic graft-versus-host disease is an anomaly that needs to be considered as a differential diagnosis of patients experiencing dermatitis, gastroenteritis, or hepatitis after an identical twin hematopoietic stem cell transplant.

Know Your Numbers: Creation and implementation of a novel community health mobile application (app) by student pharmacists.

OBJECTIVES: A free mobile application (app), Know Your Numbers (KYN), was developed by student pharmacists to assist underserved community members to track their health numbers. The study objectives included creating a health app, implementing a pilot program, and analyzing the frequency of app use and perceptions of community members toward their health numbers, pharmacists, and health apps. SETTING: Student pharmacists recruited participants at the community clinics and health fairs organized in underserved communities of the Atlanta metropolitan area. PRACTICE DESCRIPTION: This study used a pre- and post-survey study design to compare perceptions before and after use of a health app. Eligible participants completed a 22-item pre-survey that assessed understanding of their health numbers, previous health app use, and perceptions of pharmacists. EVALUATION: Frequency of app use and change in perceptions of community members toward health numbers, pharmacists, and health apps before and after enrolling in KYN were analyzed with the use of descriptive statistics and Wilcoxon signed rank tests for matched pre- and post-surveys. RESULTS: Thirty-three participants were enrolled for 56 days. African American participants (93.9%) earned less than $25,000 annually (56.7%). On average, participants had 3.98 interactions per week. Before using the mobile health app, 84.8% of users felt comfortable using a health app, but only 9% used one regularly. The post-survey response rate was 27.2% (n = 9). More participants agreed that a health app helped them to meet their health goals after the program (24.4% to 100%; P = 0.0006). More than 90% of participants agreed in both surveys that it is important to check their health numbers regularly and that they trust pharmacists to provide accurate information. CONCLUSION: KYN is a novel mobile tool that promotes chronic disease self-management and the profession of pharmacy. These findings support the benefits of mobile health app's usability and its ability to assist in achieving personal health goals.

Epidemiological Analysis of Extended-Spectrum Beta-Lactamase-Producing Bacterial Infections in Adult Live Donor Liver Transplant Patients.

INTRODUCTION: Bacterial infections are a leading cause of morbidity and mortality in patients receiving solid-organ transplants. Extended-spectrum beta-lactamases (ESBL) pathogens are the most important pathogenic bacteria infecting these patients. AIM: This study aims to evaluate for the incidence and characteristics of ESBL-positive organism, to look for the clinical outcomes in ESBL-positive infected cases, and to evaluate and draft the antibiotic policy in posttransplant patients during the first 28 days posttransplant. MATERIALS AND METHODS: This is a retrospective data analysis of liver transplant recipients infected with ESBL culture-positive infections. All the culture sites such as blood, urine, and endotracheal tube aspirates were screened for the first ESBL infection they had and noted. This data were collected till day 28 posttransplant. The antibiotic susceptibility pattern and the most common organism were also noted. RESULTS: A total of 484 patients was screened and 116 patients had ESBL-positive cultures. Out of these, 54 patients had infections and 62 patients were ESBL colonizers. The primary infection site was abdominal fluid (40.7%), with Klebsiella accounting for most of the ESBL infections. Colistin was the most sensitive antibiotic followed by tigecycline. The overall mortality was 11.4% and 31 out of 54 ESBL-infected patients died. CONCLUSIONS: Infections with ESBL-producing organism in liver transplant recipients has a high mortality and very limited therapeutic options.

Prognostication of long-term outcomes after subarachnoid hemorrhage: The FRESH score.

OBJECTIVE: To create a multidimensional tool to prognosticate long-term functional, cognitive, and quality of life outcomes after spontaneous subarachnoid hemorrhage (SAH) using data up to 48 hours after admission. METHODS: Data were prospectively collected for 1,619 consecutive patients enrolled in the SAH outcome project July 1996 to March 2014. Linear models (LMs) were applied to identify factors associated with outcome in 1,526 patients with complete data. Twelve-month functional, cognitive, and quality of life outcomes were measured using the modified Rankin scale (mRS), Telephone Interview for Cognitive Status, and Sickness Impact Profile. Based on the LM residuals, we constructed the FRESH score (Functional Recovery Expected after Subarachnoid Hemorrhage). Score performance, discrimination, and internal validity were tested using the area under the receiver operating characteristic curve (AUC), Nagelkerke and Cox/Snell R(2) , and bootstrapping. For external validation, we used a control population of SAH patients from the CONSCIOUS-1 study (n = 413). RESULTS: The FRESH score was composed of Hunt & Hess and APACHE-II physiologic scores on admission, age, and aneurysmal rebleed within 48 hours. Separate scores to prognosticate 1-year cognition (FRESH-cog) and quality of life (FRESH-quol) were developed controlling for education and premorbid disability. Poor functional outcome (mRS = 4-6) for score levels 1 through 9 respectively was present in 3, 6, 12, 38, 61, 83, 92, 98, and 100% at 1-year follow-up. Performance of FRESH (AUC = 0.90), FRESH-cog (AUC = 0.80), and FRESH-quol (AUC = 0.78) was high. External validation of our cohort using mRS as endpoint showed satisfactory results (AUC = 0.77). To allow for convenient score calculation, we built a smartphone app available for free download. INTERPRETATION: FRESH is the first clinical tool to prognosticate long-term outcome after spontaneous SAH in a multidimensional manner. Ann Neurol 2016;80:46-58.

Optimizing finite resources: Pharmacist chart reviews in an outpatient kidney transplant clinic.

OBJECTIVE: To determine if a pharmacist-executed comprehensive chart review could serve as sufficient substitution for direct participation during outpatient clinic visits in the postdischarge follow-up treatment of kidney transplant recipients. DESIGN: Retrospective, longitudinal, cross-sectional study. SETTING: Acute and chronic transplant clinics at the Medical University of South Carolina, Charleston, SC. PARTICIPANTS: 219 individual kidney transplant recipients. MAIN OUTCOME MEASURES: Effectiveness of chart review assessments (with written notes) as compared with in-clinic assessments (with verbal communication with transplant providers followed by documentation by pharmacists). An independent transplant provider graded pharmacist recommendations by severity. All recommendations were compared with the provider's plan to determine if the recommendations were incorporated. RESULTS: During the 3-month study period, 170 pharmacist chart reviews were written and 175 clinic visits involved direct pharmacist participation. Providers accepted a greater percentage of recommendations that were delivered directly compared with recommendations presented via a note in the patient folder following chart review (92% vs. 28%, respectively; P <0.0001). Directly provided recommendations were also associated with higher severity scores. CONCLUSION: The results of this study suggest that comprehensive chart review by pharmacists prior to patient clinic visits may not be as effective as in-person consultation in communicating recommendations to providers. Further research is needed in similar clinic settings.

An Interdisciplinary Videoconference to Improve Transitions of Care and Reduce Readmission, Cost, and Post-Acute Length of Stay in a Teaching and Community Hospital.

OBJECTIVES: Coordination of care across health care settings is needed to ensure safe patient transfers. We examined the effects of the ECHO-Care Transitions program (ECHO-CT) on readmissions, skilled nursing facility (SNF) length of stay (LOS), and costs. DESIGN: This is a prospective cohort study evaluating the ECHO-CT program. The intervention consisted of weekly 90-minute teleconferences between hospital and SNF-based teams to discuss the care of recently discharged patients. SETTING AND PARTICIPANTS: The intervention occurred at one small community hospital and 7 affiliated SNFs and 1 large teaching hospital and 11 associated SNFs between March 23, 2019, and February 25, 2021. A total of 882 patients received the intervention. METHODS: We selected 13 hospitals and 172 SNFs as controls. Specific hospital-SNF pairings within the intervention and control groups are referred to as hospital-SNF dyads. Using Medicare claims data for more than 10,000 patients with transfers between these hospital-SNF dyads, we performed multivariable regression to evaluate differences in 30-day rehospitalization rates, SNF lengths of stay, and SNF costs between patients discharged to intervention and control hospital-SNF dyads. We split the post period into pre-COVID and COVID periods and ran models separately for the small community and large teaching hospitals. RESULTS: There was no significant difference-in-differences among intervention compared to control facilities during either post-acute care period for any of the outcomes. CONCLUSIONS AND IMPLICATIONS: Although video-communication of care plans between hospitalists and post-acute care clinicians makes good clinical sense, our analysis was unable to detect significant reductions in rehospitalizations, SNF lengths of stay, or SNF Medicare costs. Disruption of the usual processes of care by the COVID pandemic may have played a role in the null findings.