Postoperative recovery of colorectal patients enhanced with dexmedetomidine (PReCEDex): a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Intraoperative administration of dexmedetomidine has shown promise in improving postoperative gastrointestinal function. In the context of colorectal surgery, the results remain inconsistent. This review aims to provide a synthesis of studies assessing the effect of dexmedetomidine on postoperative gastrointestinal function in colorectal surgery patients. METHODS: CENTRAL, Emcare, Embase, and MEDLINE were searched up to September 2023. Randomized controlled trials involving adult patients (≥ 18 years) undergoing elective colorectal surgery, comparing dexmedetomidine administration to a control group, and reporting on postoperative gastrointestinal function were included. Non-comparative and emergent procedures were excluded. Primary outcome was time to first flatus or bowel movement, and secondary outcomes included length of stay and time to solid oral intake. Risk of bias was assessed using the Cochrane risk of bias tool for randomized studies. RESULTS: After screening 1194 citations, eight studies were included. Studies comprised of 570 patients in the dexmedetomidine group (mean age: 65.8 years, 43% female, mean BMI: 22.7 kg/m2) and 556 patients in control group (mean age 70.6 years, 40% female, mean BMI 22.5 kg/m2). Dexmedetomidine administration resulted in a shorter time to flatus (MD -4.55 h, 95% CI: 20.14-8.95, p < 0.005, very low certainty of evidence), a shorter time to first bowel movement (MD -11.9 h, 95% CI: 18.74-5.05, p < 0.005, very low certainty of evidence), a shorter time to solid oral intake (MD -4.34 h, 95% CI: 17.43-11.24, p < 0.005, moderate certainty of evidence), and a shorter length of stay (MD -.06 days, 95% CI: 1.99-0.12, p < 0.05, very low certainty of evidence). CONCLUSION: In adult patients undergoing elective colorectal surgery, intraoperative use of dexmedetomidine results in clinically meaningful improvements in postoperative gastrointestinal function and consequently, shorter length of stay. Therefore, dexmedetomidine may serve as a valuable adjunct in enhancing postoperative recovery of patients following elective colorectal surgery, thereby reducing healthcare utilization, and improving patient outcomes.

Detectability of semen remained in a condom under various conditions.

Some research has identified the prevalence and motivation of using condoms by assailants during sexual assault cases proving the necessity of analyzing condom trace evidence. The majority of the papers published have discussed forensic analysis of lubricants from condoms retrieved at sexual assault scenes but those discussing the identification of semen from condoms are rare. Therefore, the present study aims to provide insight into the detectability of the semen that remained in a condom, to examine the effect of exposure time, environmental conditions, and condom type, and ultimately to determine the capability of the AP test and Microscopic examination for identification of this sample type. In the study, samples were collected from three male donors after being instructed on the proper way of collecting the semen sample. The received samples from the donors were checked first by microscopic examination to observe the sperm to confirm that the sample being handled was semen. After confirmation, samples were transferred to 4 prepared condoms (brands: dkt xxx and Manforce) and kept in conditions i.e. two condoms in a refrigerator maintained from 2 to 10°C and other ones at ambient temperature (weather status: summer season of average 39°C). The samples were analyzed into two batches, the first analysis batch was conducted after the samples were exposed to the conditions within 11-60 days. After analysis from the first batch, the samples were continuously kept in the same condition for the consecutive second batch conducted when the samples reached 40-90 days. This study has determined that semen remaining in a condom can be detected and each test studied is appropriate according to the exposure stage, i.e., time and conditions of exposure. It has been found that nonmotile spermatozoa can be observed when semen remains in the condom for a few days. However, if the sample reaches approximately 25 days at room temperature above 25°C or 54 days below 10°C, the semen may dry out limiting the effectiveness of microscopic examination. Despite this, even semen that remained in a condom for up to 90 days can be identified by Acid Phosphatase. Results on condom type used reveal that condom constituents can crossreact with semen but none of them can limit the semen identification with Acid Phosphatase.

N-Glycosylation-induced pathologic protein conformations as a tool to guide the selection of biologically active small molecules.

Post-translational modifications such as protein N-glycosylation, significantly influence cellular processes. Dysregulated N-glycosylation, exemplified in Grp94, a member of the Hsp90 family, leads to structural changes and the formation of epichaperomes, contributing to pathologies. Targeting N-glycosylation-induced conformations offers opportunities for developing selective chemical tools and drugs for these pathologic forms of chaperones. We here demonstrate how a specific Grp94 conformation induced by N-glycosylation, identified previously via molecular dynamics simulations, rationalizes the distinct behavior of similar ligands. Integrating dynamic ligand unbinding information with SAR development, we differentiate ligands productively engaging the pathologic Grp94 conformers from those that are not. Additionally, analyzing binding site stereoelectronic properties and QSAR models using cytotoxicity data unveils relationships between chemical, conformational properties, and biological activities. These findings facilitate the design of ligands targeting specific Grp94 conformations induced by abnormal glycosylation, selectively disrupting pathogenic protein networks while sparing normal mechanisms.

Synthesis and Characterization of Click Chemical Probes for Single-Cell Resolution Detection of Epichaperomes in Neurodegenerative Disorders.

Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.

Utility of Chemical Shift Imaging and Diffusion-weighted Images/Apparent Diffusion Coefficient Maps as a Tool for Evaluation of Solid Renal Tumors.

OBJECTIVES: To study the utility of chemical shift imaging (CSI) and diffusion-weighted images (DWI)/apparent diffusion coefficient (ADC) maps for the evaluation of solid renal tumors. METHODS: Magnetic resonance imaging (MRI) has an equivalent application as computerized tomography (CT) in the characterization of renal masses. It offers a radiation-free imaging technique and has a better soft tissue contrast than CT. Also, MRI is favored in patients with chronic kidney disease. MRI is useful when findings on CT are equivocal. The role of DWI in characterizing solid renal lesions as malignant is encouraging, and DWI can be particularly useful when gadolinium is contraindicated. CSI is useful in differentiating angiomyolipoma (AML) from clear cell (cc) renal cell carcinoma (RCC). We did a cross-sectional study on 24 patients with solid renal masses. MRI of the upper abdomen (from the dome of the diaphragm to the iliac crest) will be done on an MRI machine in our department (1.5T, ACHIEVA, Phillips medical system) using the torso coil. RESULT: There was no significant association seen in terms of ADC values and histological subtypes (χ2 = 11.222, p = 0.082). In our study, 50% (one out of two) of AML showed a signal drop, whereas 40% of cases (6 out of 15) of ccRCC and 66% (two out of three) of papillary RCC showed a signal drop. CONCLUSION: In this article, we concluded CSI, although a useful tool to look for microscopic fat, can't be used as a reliable marker to rule in cc-carcinoma as both AML and papillary cell carcinoma have microscopic fat. Further, no histological classification can be done on the basis of DWI/ADC images.

Phosphorylation-Driven Epichaperome Assembly: A Critical Regulator of Cellular Adaptability and Proliferation.

The intricate protein-chaperone network is vital for cellular function. Recent discoveries have unveiled the existence of specialized chaperone complexes called epichaperomes, protein assemblies orchestrating the reconfiguration of protein-protein interaction networks, enhancing cellular adaptability and proliferation. This study delves into the structural and regulatory aspects of epichaperomes, with a particular emphasis on the significance of post-translational modifications in shaping their formation and function. A central finding of this investigation is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 situated within an intrinsically disordered region, as critical determinants in epichaperome assembly. Our data demonstrate that the phosphorylation of these serine residues enhances HSP90's interaction with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Furthermore, this study establishes a direct link between epichaperome function and cellular physiology, especially in contexts where robust proliferation and adaptive behavior are essential, such as cancer and stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone complexes in diseases characterized by epichaperome dysregulation, bridging the gap between fundamental research and precision medicine.

Frailty in inflammatory bowel disease: analysis of the National Inpatient Sample 2015-2019.

AIM: Preoperative frailty has been associated with adverse postoperative outcomes in various populations, but of its use in patients with inflammatory bowel disease (IBD) remains sparse. The present study aimed to characterize the impact of frailty, as measured by the modified frailty index (mFI), on postoperative clinical and resource utilization outcomes in patients with IBD. METHODS: This retrospective population-based cohort study assessed patients from the National Inpatient Sample database from 1 September 2015 to 31 December 2019. Corresponding International Classification of Diseases 10th Revision Clinical Modification codes were used to identify adult patients (>18 years of age) with IBD, undergoing either small bowel resection, colectomy or proctectomy. Patient demographics and institutional data were collected for each patient to calculate the 11-point mFI. Patients were categorized as either frail or robust using a cut-off of 0.27. Primary outcomes were postoperative in-hospital morbidity and mortality, whilst secondary outcomes included system-specific morbidity, length of stay, in-hospital healthcare costs and discharge disposition. Logistic and linear regression models were used for primary and secondary outcomes. RESULTS: Overall, 7144 patients with IBD undergoing small bowel resection, colectomy or proctectomy were identified, 337 of whom were classified as frail (i.e., mFI < 0.27). Frail patients were more likely to be women, older, have lower income and a greater number of comorbidities. After adjusting for relevant covariates, frail patients were at greater odds of in-hospital mortality (adjusted odds ratio [aOR] 5.42, 95% CI 2.31-12.77, P < 0.001), overall morbidity (aOR 1.72, 95% CI 1.30-2.28, P < 0.001), increased length of stay (adjusted mean difference 1.3 days, 95% CI 0.09-2.50, P = 0.035) and less likely to be discharged to home (aOR 0.59, 95% CI 0.45-0.77, P < 0.001) compared to their robust counterparts. CONCLUSIONS: Frail IBD patients are at greater risk of postoperative mortality and morbidity, and reduced likelihood of discharge to home, following surgery. This has implications for clinicians designing care pathways for IBD patients following surgery.

Progress in microwave absorbing materials: A critical review.

Microwave-absorbing materials play a significant role in various applications that involve the attenuation of electromagnetic radiation. This critical review article provides an overview of the progress made in the development and understanding of microwave-absorbing materials. The interaction between electromagnetic radiation and absorbing materials is explained, with a focus on phenomena such as multiple reflections, scattering, and polarizations. Additionally, types of losses that affect the performance of microwave absorbers are also discussed, including dielectric loss, conduction loss, relaxation loss, magnetic loss, and morphological loss. Each of these losses has different implications for the effectiveness of microwave absorbers. Further, a detailed review is presented on various types of microwave absorbing materials, including carbonaceous materials, conducting polymers, magnetic materials, metals and their composites, 2D materials (such as MXenes and 2D-transition metal dichalcogenides), biomass-derived materials, carbides, sulphides, phosphides, high entropy (HE) materials and metamaterials. The characteristics, advantages, and limitations of each material are examined. Overall, this review article highlights the progress achieved in the field of microwave-absorbing materials. It underlines the importance of optimizing different types of losses to enhance the performance of microwave absorbers. The review also recognizes the potential of emerging materials, such as 2D materials and high entropy materials, in further advancing microwave-absorbing properties.

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease.

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes-namely, protein assemblies-under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation's influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.

Prucalopride and Bowel Function Post Gastrointestinal Surgery: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Prolonged postoperative ileus (PPOI) contributes to morbidity and prolonged hospitalization. Prucalopride, a selective 5-hydroxytryptamine receptor agonist, may enhance bowel motility. This review assesses whether the perioperative use of prucalopride compared to placebo is associated with accelerated return of bowel function post gastrointestinal (GI) surgery. METHODS: OVID, CENTRAL, and EMBASE were searched as of January 2024 to identify randomized controlled trials (RCTs) comparing prucalopride and placebo for prevention of PPOI in adult patients undergoing GI surgery. The primary outcomes were time to stool, time to flatus, and time to oral tolerance. The secondary outcomes were incidence of PPOI, length of stay (LOS), postoperative complications, adverse events, and overall costs. The Cochrane risk of bias tool for randomized trials and the Grading of Recommendations, Assessment, Development, and Evaluations framework were used. An inverse variance random effects model was used. RESULTS: From 174 citations, 3 RCTs with 139 patients in each treatment group were included. Patients underwent a variety of GI surgeries. Patients treated with prucalopride had a decreased time to stool (mean difference 36.82 hours, 95% CI 59.4 to 14.24 hours lower, I2 = 62%, low certainty evidence). Other outcomes were not statistically significantly different (very low certainty evidence). Postoperative complications and adverse events could not be meta-analyzed due to heterogeneity; yet individual studies suggested no significant differences (very low certainty evidence). DISCUSSION: Current RCT evidence suggests that prucalopride may enhance postoperative return of bowel function. Larger RCTs assessing patient important outcomes and associated costs are needed before routine use of this agent.

Tobacco use in currently married pregnant & lactating women in India; key findings from the National Family Health Survey-5.

Background: Tobacco use among pregnant and lactating women carries dangerous repercussions for women and their children. Limited information is available at the national level on the prevalence and determinants of tobacco use in this vulnerable sub-population of women. This study aims to estimate the prevalence of tobacco use among currently married pregnant and lactating women and its association with demographic, behavioural and regional determinants in India. Methods: A cross-sectional study was conducted during which secondary data from the fifth National Family Health Survey, 2019-2020, was analysed. The prevalence and associated 95% confidence intervals (CI) for different forms of tobacco use were documented among currently married pregnant and lactating women. Adjusted Odds Ratio and 95% CI were calculated using multivariate logistic regression to identify the independent factors associated with different forms of tobacco use among respondents after applying sampling weights. Findings: In India, the prevalence of tobacco use among currently married pregnant and lactating women was 2.5% and 3.2%, respectively, with over 85% of tobacco-using currently married pregnant (85.6%) and lactating (85.6%) women using smokeless tobacco (SLT) only. Age group 30-34 years, working women and the richest wealth quintile were found to be independent predictors of smoked tobacco use among currently married pregnant women. In contrast, among the currently married lactating women, the middle wealth quintile and South Indian region were found to be independent predictors of smoked tobacco use. Interpretation: Smokeless tobacco was found to be the most prevalent type of tobacco consumed by pregnant and lactating women in India. There is an urgent need to curb tobacco use in this vulnerable sub-population of women in the country by sensitising them to the harmful consequences of tobacco use by integrating tobacco awareness and cessation services during routine ante-natal examinations. Funding: No funding was received for this study.

Postoperative Gastrointestinal Dysfunction After Neuromuscular Blockade Reversal With Sugammadex Versus Cholinesterase Inhibitors in Patients Undergoing Gastrointestinal Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Postoperative gastrointestinal dysfunction (POGD) commonly occurs following gastrointestinal (GI) surgery and is associated with specific anesthetic agents. Cholinesterase inhibitors employed for reversing neuromuscular blockade have been implicated in development of POGD. Sugammadex, a novel reversal agent, is linked with reduced POGD. However, there is a lack of comprehensive comparative review between these agents regarding their impact on POGD following GI surgery. This study aims to systematically review the effects of sugammadex on POGD compared to cholinesterase inhibitors following GI surgery. METHODS: MEDLINE, EMBASE, and CENTRAL were searched as of July 2022 to identify articles comparing sugammadex with cholinesterase inhibitors in patients undergoing gastrointestinal surgery, specifically in relation to POGD. Secondary endpoints included length of hospital stay, readmission rates, pulmonary complications, and postoperative morbidity. RESULTS: From 198 citations, 2 randomized controlled trials (RCTs) and 3 retrospective cohorts with 717 patients receiving sugammadex and 812 patients receiving cholinesterase inhibitors were included. Significantly lower rates of prolonged postoperative ileus (OR .44, 95% CI .25-.77, P < .05, I2 = 56%, low certainty evidence) was observed with sugammadex. No significant difference in any other outcome was observed. Narrative review of readmission data demonstrated no significant difference. CONCLUSION: The use of sugammadex following gastrointestinal surgery is associated with significantly lower rates of prolonged postoperative ileus compared to cholinesterase inhibitors. However, these do not translate into a significant reduction in length of stay, morbidity, or postoperative nausea and vomiting. Results are limited by the numer of studies included and missing data, more robust RCTs are needed before recommendations can be made.

The role of warmed-humidified carbon dioxide insufflation in colorectal surgery: A systematic review and meta-analysis.

BACKGROUND: Maintenance of normothermia is a crucial part of enhanced recovery after colorectal surgery. Dry-cold carbon dioxide (CO2 ) traditionally used for insufflation in laparoscopic surgery and negative pressure operating theatres has been associated with intraoperative hypothermia. Studies suggest that use of warmed-humidified CO2 may promote normothermia. However, due to a scarcity of high-quality studies demonstrating a proven benefit on intraoperative core body temperature, its use in colorectal surgery remains limited. Therefore, the aim of this review was to evaluate the effects of warmed-humidified CO2 compared to traditional dry-cold CO2 , or ambient air in operating theatres, during colorectal surgery. METHODS: A search of Medline, EMBASE, and CENTRAL was performed. Randomised controlled trials (RCTs) that compared patients receiving warmed-humidified CO2 with either dry-cold CO2 insufflation in laparoscopic procedures or no insufflation during open surgery were included. The primary outcome was change in intraoperative core body temperature. Secondary outcomes included length of stay, operating time, return of gastrointestinal function, wound infection, and postoperative pain. A pairwise meta-analysis was performed using inverse variance random effects. RESULTS: Among the six RCTs included, 208 patients received warmed-humidified CO2 (42.3% female, mean age: 65.8 years) and 210 patients received either dry-cold CO2 in laparoscopic procedures or no gas insufflation during open procedures (46.2% female, mean age: 66.1 years). No significant difference was found for change in intraoperative core body temperature (MD = 0.01, 95% CI: -0.1, 0.11, p = 0.90, very low certainty). Patients in the warmed-humidified CO2 group had significantly higher pain scores on postoperative day 1 (MD = 1.61, 95% CI: 0.91, 2.31, p < 0.05, very low certainty). No significant differences were found in any of the other secondary outcomes studied. CONCLUSION: Patients undergoing colorectal surgery receiving warmed-humidified CO2 do not experience any clinically meaningful difference in core body temperature change compared to their counterparts receiving dry-cold CO2 insufflation or no insufflation. However, patients may report greater pain scores on postoperative day 1 with warmed-humidified CO2 . There is likely no clinically important difference between warmed-humidified CO2 and dry-cold CO2 for patients undergoing colorectal surgery. Patient, clinician, and institution factors should be considered when deciding between these two insufflation modalities.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Fragility of Statistically Significant Outcomes in Colonic Diverticular Disease Randomized Trials: A Systematic Review.

BACKGROUND: The p value has been criticized as an oversimplified determination of whether a treatment effect exists. One alternative is the fragility index. It is a representation of the minimum number of nonevents that would need to be converted to events to increase the p value above 0.05. OBJECTIVE: To determine the fragility index of randomized controlled trials assessing the efficacy of interventions for patients with diverticular disease since 2010 to assess the robustness of current evidence. DESIGN: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to August 2022. SETTINGS: Articles were eligible for inclusion if they were randomized trials conducted between 2010 and 2022 with parallel, superiority designs evaluating interventions in patients with diverticular disease. Only randomized trials with dichotomous primary outcomes with an associated p value of <0.05 were considered for inclusion. PARTICIPANTS: Any surgical or medical intervention for patients with diverticular disease. MAIN OUTCOME MEASURES: The fragility index was determined by adding events and subtracting nonevents from the groups with the smaller number of events. Events were added until the p value exceeded 0.05. The smallest number of events required was considered the fragility index. RESULTS: After screening 1271 citations, 15 randomized trials met the inclusion criteria. Nine of the studies evaluated surgical interventions and 6 evaluated medical interventions. The mean number of patients randomly assigned and lost to follow-up per randomized controlled trial was 92 (SD 35.3) and 9 (SD 11.4), respectively. The median fragility index was 1 (range, 0-5). The fragility indices for the included studies did not correlate significantly with any study characteristics. LIMITATIONS: Small sample, heterogeneity, and lack of inclusion of studies with continuous outcomes. CONCLUSIONS: The randomized trials evaluating surgical and medical interventions for diverticular disease are not robust. Changing a single-outcome event in most studies was sufficient to make a statistically significant study finding not significant. See Video Abstract . FRAGILIDAD DE LOS RESULTADOS ESTADSTICAMENTE SIGNIFICATIVOS EN ENSAYOS ALEATORIOS DE ENFERMEDAD DIVERTICULAR DEL COLON UNA REVISIN SISTEMTICA: ANTECEDENTES:El valor p ha sido criticado por una determinación demasiado simplificada de si existe un efecto del tratamiento. Una alternativa es el Índice de Fragilidad. Es una representación del número mínimo de no eventos que deberían convertirse en eventos para aumentar el valor p por encima de 0,05.OBJETIVO:Determinar el IF de ensayos controlados aleatorios que evalúan la eficacia de las intervenciones para pacientes con enfermedad diverticular desde 2010 para evaluar la solidez de la evidencia actual.FUENTES DE DATOS:Se realizaron búsquedas en MEDLINE, Embase y CENTRAL desde el inicio hasta agosto de 2022.SELECCIÓN DE ESTUDIOS:Los artículos eran elegibles para su inclusión si eran ensayos aleatorizados realizados entre 2010 y 2022 con diseños paralelos de superioridad que evaluaran intervenciones en pacientes con enfermedad diverticular. Sólo se consideraron para su inclusión los ensayos aleatorizados con resultados primarios dicotómicos con un valor de p asociado menor que 0,05.INTERVENCIÓNES:Cualquier intervención quirúrgica o médica para pacientes con enfermedad diverticular.PRINCIPALES MEDIDAS DE VALORACIÓN:El índice de fragilidad se determinó sumando eventos y restando no eventos de los grupos con el menor número de eventos. Se agregaron eventos hasta que el valor p superó 0,05. El menor número de eventos requeridos se consideró índice de fragilidad.RESULTADOS:Después de examinar 1271 citas, 15 ensayos aleatorios cumplieron los criterios de inclusión. Nueve de los estudios evaluaron intervenciones quirúrgicas y seis evaluaron intervenciones médicas. El número medio de pacientes aleatorizados y perdidos durante el seguimiento por ECA fue 92 (DE 35,3) y 9 (DE 11,4), respectivamente. La mediana del índice de fragilidad fue 1 (rango: 0-5). Los índices de fragilidad de los estudios incluidos no se correlacionaron significativamente con ninguna característica del estudio.LIMITACIONES:Muestra pequeña, heterogeneidad y falta de inclusión de estudios con resultados continuos.CONCLUSIONES:Los ensayos aleatorios que evalúan las intervenciones quirúrgicas y médicas para la enfermedad diverticular no son sólidos. Cambiar un solo evento de resultado en la mayoría de los estudios fue suficiente para que un hallazgo estadísticamente significativo del estudio no fuera significativo. (Traducción- Dr. Ingrid Melo ).

Development of sweep frequency ultrasonic interferometer for high precision velocity measurement in liquids.

An ultrasonic interferometer with variable separation between the transducer and reflector is widely used for the measurement of ultrasonic propagation velocity in liquids. The inherent limitation of such an interferometer is due to the mechanical movement of its reflector for ultrasonic wavelength measurement in a liquid medium. It is observed that the ultrasonic velocity measurement precision is adversely affected at higher frequencies compared to lower ones. For instance, in our experimentation, a standard deviation of ±21.5 m/s (±1.43%) was obtained for velocity measurement at 1.84 MHz with the consideration of two consecutive maxima, which increases drastically to ±76.8 m/s (±5.12%) at 9.4 MHz. These measurements can significantly be improved by considering many maxima and averaging for wavelength estimation. However, it still requires design attention and improvement, particularly for higher frequencies. In this article, a sweep-frequency based ultrasonic interferometer design with a fixed separation for liquid characterization is proposed and described. This technique overcomes the limitations of mechanical movement systems and also provides a better and uniform precision for lower as well as higher frequencies. The functionality of the developed sweep frequency method was tested in water, carbon tetrachloride, ethylene glycol, and glycerol, which shows good agreement with literature values. The velocity measurement in double distilled water by the developed technique at 1 Hz sweep resolution has shown an improved standard deviation of ±0.74 m/s (±0.05%) at 9.4 MHz.

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein-protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib's residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug-target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.

Uncovering a mammalian neural-specific poly(A) binding protein with unique properties.

The mRNA 3' poly(A) tail plays a critical role in regulating both mRNA translation and turnover. It is bound by the cytoplasmic poly(A) binding protein (PABPC), an evolutionarily conserved protein that can interact with translation factors and mRNA decay machineries to regulate gene expression. Mammalian PABPC1, the prototypical PABPC, is expressed in most tissues and interacts with eukaryotic translation initiation factor 4G (eIF4G) to stimulate translation in specific contexts. In this study, we uncovered a new mammalian PABPC, which we named neural PABP (neuPABP), as it is predominantly expressed in the brain. neuPABP maintains a unique architecture as compared with other PABPCs, containing only two RNA recognition motifs (RRMs) and maintaining a unique N-terminal domain of unknown function. neuPABP expression is activated in neurons as they mature during synaptogenesis, where neuPABP localizes to the soma and postsynaptic densities. neuPABP interacts with the noncoding RNA BC1, as well as mRNAs coding for ribosomal and mitochondrial proteins. However, in contrast to PABPC1, neuPABP does not associate with actively translating mRNAs in the brain. In keeping with this, we show that neuPABP has evolved such that it does not bind eIF4G and as a result fails to support protein synthesis in vitro. Taken together, these results indicate that mammals have expanded their PABPC repertoire in the brain and propose that neuPABP may support the translational repression of select mRNAs.

Use of Native-PAGE for the Identification of Epichaperomes in Cell Lines.

Epichaperomes are disease-associated pathologic scaffolds, composed of tightly bound chaperones, co-chaperones, and other factors. They mediate anomalous protein-protein interactions inside cells, which aberrantly affects the function of protein networks, and in turn, cellular phenotypes. Epichaperome study necessitates the implementation of methods that retain these protein complexes in their native cellular states for analysis. Here we describe a protocol for detection and composition analysis of epichaperomes in cell homogenates through native polyacrylamide gel electrophoresis.

An Evaluation of Malaria Surveillance System in Punjab, India, 2020.

Background: India accounted for 6% of global burden of malaria with 95% population residing in malaria endemic areas. However, Punjab is in the malaria elimination phase with annual parasite incidence (API) <1/1000 population. Objectives: We evaluated malaria surveillance system in Punjab using CDC's updated guidelines for evaluating public health surveillance systems to provide recommendations for strengthening the existing system and to overcome the challenges in the path of malaria free Punjab. Methods: We chose two districts of Punjab, Amritsar (lowest API) and Mansa (highest API), interviewed stakeholders, and performed a retrospective desk review. We evaluated the overall usefulness of the system and assessed seven attributes at state, district, health facility, and village level during July-August 2020. Results: In Punjab, there was progressive decline in the malaria cases from 2,955 cases in 2009 to 1,140 in 2019 and no malaria deaths since 2011. Regarding various attributes, overall score for flexibility was good (85.9%); average for simplicity (77%), acceptability (74%), data quality (74%), and timeliness (70%); and poor for representativeness (59%) and stability (57%). Conclusions: Malaria surveillance system was useful in analyzing the trends of morbidity and mortality and for generating data to drive policy decisions. To improve stability, representativeness, and acceptability, surveillance staff should not be engaged in supplemental work, and reports from private sector must be ensured. Supportive supervision and regular trainings should be carried out regarding reporting formats, guidelines, and timely epidemiological investigations to improve timeliness, data quality, and simplicity.