Management of CRE Infections: High Time for an RCT?

How to cite this article: Kundu R, Chowdhury SR. Management of CRE Infections: High Time for an RCT? Indian J Crit Care Med 2024;28(5):511.

Role of Alström syndrome 1 in the regulation of glomerular hemodynamics.

Inactivating mutations in the ALMS1 gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However, the role of ALMS1 in renal function and hemodynamics is unclear. We previously found that ALMS1 is expressed in thick ascending limbs, where it binds and decreases Na+-K+-2Cl- cotransporter activity. We hypothesized that ALMS1 is expressed in macula densa cells and that its deletion enhances tubuloglomerular feedback (TGF) and reduces glomerular filtration rate (GFR) in rats. To test this, homozygous ALMS1 knockout (KO) and littermate wild-type Dahl salt-sensitive rats were studied. TGF sensitivity was higher in ALMS1 KO rats as measured by in vivo renal micropuncture. Using confocal microscopy, we confirmed immunolabeling of ALMS1 in macula densa cells (nitric oxide synthase 1 positive), supporting a role for ALMS1 in TGF regulation. Baseline glomerular capillary pressure was higher in ALMS1 KO rats, as was mean arterial pressure. Renal interstitial hydrostatic pressure was lower in ALMS1 KO rats, which is linked to increased Na+ reabsorption and hypertension. GFR was reduced in ALMS1 KO rats. Seven-week-old ALMS1 KO rats were not proteinuric, but proteinuria was present in 18- to 22-wk-old ALMS1 KO rats. The glomerulosclerosis index was higher in 18-wk-old ALMS1 KO rats. In conclusion, ALMS1 is involved in the control of glomerular hemodynamics in part by enhancing TGF sensitivity, and this may contribute to decreased GFR. Increased TGF sensitivity, enhanced glomerular capillary pressure, and hypertension may lead to glomerular damage in ALMS1 KO rats. These are the first data supporting the role of ALMS1 in TGF and glomerular hemodynamics.NEW & NOTEWORTHY ALMS1 is a novel protein involved in regulating tubuloglomerular feedback (TGF) sensitivity, glomerular capillary pressure, and blood pressure, and its dysfunction may reduce renal function and cause glomerular damage.

Effects of a Province-wide Triaging System for TIA: The ASPIRE Intervention.

BACKGROUND AND OBJECTIVES: Urgent transient ischemic attack (TIA) management to reduce stroke recurrence is challenging, particularly in rural and remote areas. In Alberta, Canada, despite an organized stroke system, data from 1999 to 2000 suggested that stroke recurrence after TIA was as high as 9.5% at 90 days. Our objective was to determine whether a multifaceted population-based intervention resulted in a reduction in recurrent stroke after TIA. METHODS: In this quasi-experimental health services research intervention study, we implemented a TIA management algorithm across the entire province, centered around a 24-hour physician's TIA hotline and public and health provider education on TIA. From administrative databases, we linked emergency department discharge abstracts to hospital discharge abstracts to identify incident TIAs and recurrent strokes at 90 days across a single payer system with validation of recurrent stroke events. The primary outcome was recurrent stroke; with a secondary composite outcome of recurrent stroke, acute coronary syndrome, and all-cause death. We used an interrupted time series regression analysis of age-adjusted and sex-adjusted stroke recurrence rates after TIA, incorporating a 2-year preimplementation period (2007-2009), a 15-month implementation period, and a 2-year postimplementation period (2010-2012). Logistic regression was used to examine outcomes that did not fit the time series model. RESULTS: We assessed 6,715 patients preimplementation and 6,956 patients postimplementation. The 90-day stroke recurrence rate in the pre-Alberta Stroke Prevention in TIA and mild Strokes (ASPIRE) period was 4.5% compared with 5.3% during the post-ASPIRE period. There was neither a step change (estimate 0.38; p = 0.65) nor slope change (parameter estimate 0.30; p = 0.12) in recurrent stroke rates associated with the ASPIRE intervention implementation period. Adjusted all-cause mortality (odds ratio 0.71, 95% CI 0.56-0.89) was significantly lower after the ASPIRE intervention. DISCUSSION: The ASPIRE TIA triaging and management interventions did not further reduce stroke recurrence in the context of an organized stroke system. The apparent lower mortality postintervention may be related to improved surveillance after events identified as TIAs, but secular trends cannot be excluded. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a standardized population-wide algorithmic triage system for patients with TIA did not reduce recurrent stroke rate.

Cultural Knowledge in Context - People Aged 50 Years and Over Make Sense of a First Fracture and Osteoporosis.

Catch a Break (CaB) is a secondary fracture prevention program that uses medical understandings of osteoporosis to assess first fractures and determine appropriateness for secondary fracture prevention. In this study, we interviewed CaB program participants to identify the understandings that patients themselves used to make sense of first fractures and the osteoporosis suggestion as cause. Semi-structured interviews were conducted with female and male participants of the CaB program in Canada. An interpretive practice approach was used to analyze the data. A random sample of 20 individuals, 12 women, and eight men all aged 50 years and over participated. First fractures were produced as meaningful in the context of osteoporosis only for seniors of very advanced age, and for people of any age with poor nutrition. The trauma events that led to a first fracture were produced as meaningful only if perceived as accidents, and having an active lifestyle was produced as beneficial only for mental health and well-being unrelated to osteoporosis. Cultural knowledge shapes, but does not determine, how individuals make sense of their health and illness experiences. Risk prevention program designers should include patients on the design team and be more aware of the presumptive knowledge used to identify individuals at risk of disease.

Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol.

Background: In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. Methods: In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Results: Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. Conclusions: TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

Looking for a Silver Lining to the Dark Cloud: A Google Trends Analysis of Contraceptive Interest in the United States Post Roe vs. Wade Verdict.

Background In the wake of the recent Roe vs. Wade judgment, we performed a Google Trends analysis to identify the impact of this decision on the interests regarding contraceptive choices in the United States. Methods A Google Trends search between April 6 and July 5, 2022, with the United States as the area of interest, was performed using the five most popular contraception choices. In addition, a second trend search was performed using oral and injectable hormonal birth control measures. Results Trends showed a spike in interest regarding various contraceptive methods immediately following the verdict. The highest increase in interest was noted for "vasectomy," followed by "tubal ligation." With respect to oral and injectable birth control measures, "morning after pill" showed a marked spike in interest. Conclusion This verdict has triggered increased interest in contraceptive practices, which can be translated into better reproductive health with proper public health initiatives.

Assessment of role of inferior vena cava collapsibility index and variations in carotid artery peak systolic velocity in prediction of post-spinal anaesthesia hypotension in spontaneously breathing patients: An observational study.

Background and Aims: Post-spinal anaesthesia hypotension (PSH) is common and can lead to significant morbidity and mortality. The inferior vena cava collapsibility index (IVCCI) and carotid artery peak systolic velocity variations (CAPVV) are two widely used parameters for assessing the volume status of critically ill patients which have also been investigated as predictors of PSH and hypotension after induction of general anaesthesia. In this study, we evaluated the diagnostic accuracy of IVCCI and CAPVV as predictors of PSH. Methods: A total of 50 patients aged between 18 and 65 years undergoing elective lower abdominal surgeries under spinal anaesthesia were included. The IVCCI and CAPVV were measured using ultrasound pre-operatively. After administering spinal anaesthesia, haemodynamic data were collected till 15 min. Our primary objective was to evaluate the role of IVCCI and CAPVV to predict PSH. The secondary objectives were to compare the predictive efficacy of these two parameters and to detect other parameters for predicting PSH. We constructed the receiver operator characteristic (ROC) curves for IVCCI and CAPVV and obtained the best cut-off values. Results: The PSH occurred in 34% of the patients. IVCCI >21.15 could predict PSH with 58.8% sensitivity and 69.7% specificity. CAPVV >18.33 predicted PSH with 70.6% sensitivity and 54.6% specificity and IVC max/IVCCI >60 could predict PSH with 58.8% sensitivity and 54.5% specificity. A composite model comprising IVCmax (maximum IVC diameter), CAPVV, and baseline mean blood pressure was able to predict PSH. Conclusion: Both IVCCI and CAPVV have poor diagnostic accuracy in predicting PSH in adult patients undergoing elective infra-umbilical surgery.

Decreased tubuloglomerular feedback response in high-fat diet-induced obesity.

Obesity increases the risk of renal damage, but the mechanisms are not clear. Normally, kidneys autoregulate to keep the glomerular capillary pressure (PGC), renal blood flow, and glomerular filtration rate in a steady state. However, in obesity, higher PGC, renal blood flow, and glomerular filtration rate are noted. Together, these may lead to glomerular damage. PGC is controlled mainly by afferent arteriole resistance, which, in turn, is regulated by tubuloglomerular feedback (TGF), a vasoconstrictor mechanism. High fat-induced obesity causes renal damage, and this may be related to increased PGC. However, there are no studies as to whether high-fat diet (HFD)-induced obesity affects TGF. We hypothesized that TGF would be attenuated in obesity caused by HFD feeding (60% fat) in Sprague-Dawley rats. Sprague-Dawley rats fed a normal-fat diet (NFD; 12% fat) served as the control. We studied 4 and 16 wk of HFD feeding using in vivo renal micropuncture of individual rat nephrons. We did not observe significant differences in body weight, TGF response, and mean arterial pressure at 4 wk of HFD feeding, but after 16 wk of HFD, rats were heavier and hypertensive. The maximal TGF response was smaller in HFD-fed rats than in NFD-fed rats, indicating an attenuation of TGF in HFD-induced obesity. Baseline PGC was higher in HFD-fed rats than in NFD-fed rats and was associated with higher glomerulosclerosis. We conclude that attenuated TGF and higher PGC along with hypertension in HFD-fed obese Sprague-Dawley rats could explain the higher propensity of glomerular damage observed in obesity.NEW & NOTEWORTHY Reduced tubuloglomerular feedback, higher glomerular capillary pressure, and hypertension in combination may explain the higher glomerular damage observed in high-fat diet-induced obesity.

Choriocapillaris: Fundamentals and advancements.

The choriocapillaris is the innermost structure of the choroid that directly nourishes the retinal pigment epithelium and photoreceptors. This article provides an overview of its hemovasculogenesis development to achieve its final architecture as a lobular vasculature, and also summarizes the current histological and molecular knowledge about choriocapillaris and its dysfunction. After describing the existing state-of-the-art tools to image the choriocapillaris, we report the findings in the choriocapillaris encountered in the most frequent retinochoroidal diseases including vascular diseases, inflammatory diseases, myopia, pachychoroid disease spectrum disorders, and glaucoma. The final section focuses on the development of imaging technology to optimize visualization of the choriocapillaris as well as current treatments of retinochoroidal disorders that specifically target the choriocapillaris. We conclude the article with pertinent unanswered questions and future directions in research for the choriocapillaris.

Accounts of health risk assessment survey administration in the Catch a Break Program: the social construction of osteoporosis risk identification and need for intervention.

Catch a Break staff conducting the organizational work of delivering secondary fracture prevention screening conversations drew on cultural and organizational resources to determine eligibility of individuals. They encountered and navigated their way through interactional troubles as they requested participation, assessed trauma risk, and provided lifestyle information. PURPOSE: We investigated delivery of a population-based type C fracture liaison service for non-hip fractures. The purpose of this study was to examine accounts of how osteoporosis health risk screening interactions were delivered. METHODS: A pre-determined sample of 5 organizational representatives (program staff) were interviewed by telephone. We analyzed the qualitative data through the lens of interpretive inquiry, informed by discourse analysis, to examine staff's "talk" about conducting the program risk screening conversations. RESULTS: A dominant finding emerging from CAB staff's accounts of program delivery was the conversational work required to include only those individuals deemed appropriate for the program while managing the survey interaction. Staff talked about specific examples of interactional troubles they experienced as barriers to the smooth and successful risk screening conversation. They drew on cultural and organizational resources as interpretive frameworks to make decisions about individuals and groups at risk and in need of further investigation. They drew on larger ideas about ageism and genderism, judging as inappropriate for participation the oldest old adults, men involved in high risk occupations, and adults aged 50 to 70. Staff also employed interactional resources useful in managing problems in the conversation during the request to participate, trauma risk assessment, and lifestyle/health information provision sequences of the risk screening call. CONCLUSION: We uncovered areas in the screening interaction that were talked about by staff as problematic to achieving the program objective of identifying and enrolling individuals in the secondary fracture prevention program. By highlighting areas for improvement in program delivery, this study may help to reduce the interactional troubles staff negotiate as they deliver this type of program.

The predictive ability of EQ-5D-3L compared to the LACE index and its association with 30-day post-hospitalization outcomes.

PURPOSE: To examine whether the EQ-5D-3L at the time of discharge from hospital provides additional prognostic information above the LACE index for 30-day post-discharge hospital readmission and to explore the association of EQ-5D-3L with readmissions, emergency department (ED) visits, and death within the same period. METHODS: Using data (n = 495; mean age 62.9 years (SD 18.6), 50.5% female) from a prospective cohort study of patients discharged from medical wards at two university hospitals, the prognostic ability of EQ-5D-3L was examined using C-statistic, Integrated Discrimination Improvement (IDI) Index, and Akaike's Information Criterion (AIC). The associations between EQ-5D-3L dimensions, total sum, index and VAS scores at the time of discharge and 30-day post-discharge ED visits, readmission, and readmission/death were examined using multivariate logistic regression. RESULTS: At the time of discharge, 58.6% of participants reported problems in mobility, 28.3% in self-care, 62.1% in usual activities, 62.7% in pain/discomfort, and 42.4% in anxiety/depression. Mean (SD) total sum score was 7.9 (2.0), index score was 0.69 (0.21), and VAS score was 63.7 (18.4). In adjusted analyses, mobility, self-care, usual activities, and the total sum score were significantly associated with 30-day readmission and readmission/death. Differences in C-statistic for LACE readmission prediction models with and without EQ-5D-3L were small. AIC analysis suggests that readmission prediction models containing EQ-5D-3L dimensions or scores were more often preferred to those with the LACE index only. IDI analysis indicates that the discrimination slope of readmission prediction models is significantly improved with the addition of mobility, self-care, or the total sum score of the EQ-5D-3L. CONCLUSION: The EQ-5D-3L, especially the mobility and self-care dimensions as well as the total sum score, improves 30-day readmission prediction of the LACE index and is associated with 30-day readmissions or readmissions/death.

Presumed Natural History of Combined Hamartoma of the Retina and Retinal Pigment Epithelium.

PURPOSE: To correlate structural changes of combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) with patient age. DESIGN: Retrospective study. PARTICIPANTS: Fifty eyes of 49 patients (age range, 1-74 years) with CHRRPE studied at 9 tertiary vitreoretinal institutions. METHODS: We analyzed the clinical findings with respect to lesion topography and pigmentation as well as investigated the OCT findings regarding the thickness, vitreoretinal interface, outer plexiform layer distortion, ellipsoid zone disruption, and retinal pigment epithelium-Bruch's membrane complex involvement of CHRRPE. MAIN OUTCOME MEASURES: Clinical and imaging findings of CHRRPE at different ages. RESULTS: Analysis of 50 CHRRPE patients revealed that younger patients were more likely to demonstrate partial thickness involvement of the retina (P = 0.009) with predominantly inner retinal layer involvement (P = 0.04). The inverse was true for older patients with CHRRPE. In addition, older patients more commonly showed pigmentary changes. Eyes with CHRRPE were more likely to show an increase in central macular thickness independently of tumor location. CONCLUSIONS: Based on these findings, we believe that CHRRPE typically begins in the inner retina and continues toward the outer retina over time, with increase in central macular thickness, despite the location of the tumor.