A Comprehensive Analysis of Conventional Acupuncture and Pharmacological Approaches for Cardiac Arrhythmias: An Umbrella Review.

With a global incidence of approximately 3.4% and an annual mortality rate of 3.7 million, cardiac arrhythmias (CAs) are a pressing global health issue. Their increasing prevalence, especially among older people, is intensifying the challenge for health care systems worldwide. This study aims to compare the safety and effectiveness of acupuncture and pharmacological treatments for CAs, addressing critical gaps in understanding optimal therapeutic approaches. A search of PubMed, EMBASE, and the Cochrane database of systematic reviews was performed to identify data compiled through September 2023 for this umbrella review. Randomized controlled trials (RCTs) as the foundation for meta-analyses and peer-reviewed systematic reviews were the primary focus of the literature search. The Grading of Recommendations Assessment, Development, and Evaluation method was used to assess the overall certainty of the evidence, whereas AMSTAR 2 and the Cochrane Collaboration tool were used to evaluate the quality of the included reviews. Following a comprehensive review, three systematic analyses of 27 RCTs were integrated. Acupuncture led to a slightly greater reduction in the recurrence rate of paroxysmal supraventricular tachycardia (SVT) compared to standard pharmaceutical therapy (risk ratio [RR], 1.06; 95% confidence interval [CI], 0.88-1.27; I2 = 56%; P = .55), although the difference was not statistically significant. In contrast, acupuncture significantly outperformed pharmacological treatment in the context of ventricular premature beats (VPBs) (RR, 1.16; 95 CI, 1.08-1.25; I2 = 0%; P < .0001). The reduction in paroxysmal atrial fibrillation (AF)/atrial flutter was increased with acupuncture, albeit without statistical significance (RR, 1.12; 95% CI, 0.88-1.42; I2 = 0%; P = .36). Acupuncture also led to a greater reduction in heart rate (HR) compared to pharmaceutical treatment despite notable heterogeneity and a lack of statistical significance (mean difference, -1.55; 95% CI, -41.37 to 38.28; I2 = 99%; P = .94). Adverse events were effectively managed, affirming the favorable safety profile of acupuncture. Our study suggests that acupuncture leads to a greater reduction in the recurrence rates of VPBs, AF, and atrial flutter but not significantly so in paroxysmal SVT or post-treatment HR. While promising for specific arrhythmias, the varying effectiveness of acupuncture underscores the need for further research and clinical assessment to determine its precise role and suitability in managing particular cardiac conditions.

Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth.

Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

Molecular docking analysis of Omt-A protein model from Aspergillus flavus with synthetic compounds.

Aflatoxin is a potent mycotoxin of Aspergillus flavus that has been classified as a Group I carcinogen. O-methyltransferase A (Omt-A) is a critical enzyme in the formation of aflatoxin. It catalyzes the methylation of norsalic acid to form the highly toxic intermediate averantin. The ligand-protein interaction of Omt-A was performed with piperlonguminin and blasticidins. The maximum affinity of -10.6 was found for the 5ICC_A piperlonguminine at site1 (X,Y,Z: -15.282, 21.785, 5.672). Compounds such as Blasticidin S, Neoeriocitrin, Blasticidin S - hydrochloric acid, 6,6''-Bigenkwanin, Pipernomaline, and Eriodictyol were found to have binding features to protein residues, as shown by computational interaction at the molecular level.

A Review of miRNA Regulation in Japanese Encephalitis (JEV) Virus Infection.

Japanese encephalitis (JE) is a mosquito-borne disease that causes neuronal damage and inflammation of microglia, and in severe cases, it can be fatal. JE infection can resist cellular immune responses and survive in host cells. Japanese encephalitis virus (JEV) infects macrophages and peripheral blood lymphocytes. In addition to regulating biological signaling pathways, microRNAs in cells also influence virus-host interactions. Under certain circumstances, viruses can change microRNA production. These changes affect the replication and spread of the virus. Host miRNAs can contain viral pathogenicity by downregulating the antiviral immune response pathways. Simultaneous profiling of miRNA and messenger RNA (mRNA) could help us detect pathogenic factors, and dual RNA detection is possible. This work highlights important miRNAs involved in human JE infection. In this study, we have shown the important miRNAs that play significant roles in JEV infection. We found that during JEV infection, miRNA-155, miR-29b, miRNA-15b, miR-146a, miRNA-125b-5p, miRNA-30la, miR-19b-3p, and miR-124, cause upregulation of human genes whereas miRNA-432, miRNA-370, microRNA-33a-5p, and miRNA-466d-3p are responsible for downregulation of human genes respectively. Further, these miRNAs are also responsible for the inflammatory effects. Although several other miRNAs critical to the JEV life cycle are yet unknown, there is currently no evidence for the role of miRNAs in persistence.

Mapping Processes in the Emergency Department Using the Functional Resonance Analysis Method.

Emergency departments (EDs) are dynamic, complex, and demanding environments. Introducing changes that lead to improvements in EDs can be challenging owing to the high staff turnover and mix, high patient volume with different needs, and being the front door to the hospital for the sickest patients. Quality improvement is a methodology applied routinely in EDs to instigate change to improve several outcomes such as waiting times, time to definitive treatment, and patient safety. Introducing the changes needed to transform the system in this way is seldom straightforward with the risk of "not seeing the forest for the trees" when attempting to change the system. In this article, we demonstrate how the functional resonance analysis method can be used to capture the experiences and perceptions of frontline staff to identify the key functions in the system (the trees), to understand the interactions and dependencies between them to make up the ED ecosystem ("the forest") and to support quality improvement planning, identifying priorities and patient safety risks.

Effects of Lean Interventions Supported by Digital Technologies on Healthcare Services: A Systematic Review.

Despite the increasing utilization of lean practices and digital technologies (DTs) related to Industry 4.0, the impact of such dual interventions on healthcare services remains unclear. This study aims to assess the effects of those interventions and provide a comprehensive understanding of their dynamics in healthcare settings. The methodology comprised a systematic review following the PRISMA guidelines, searching for lean interventions supported by DTs. Previous studies reporting outcomes related to patient health, patient flow, quality of care, and efficiency were included. Results show that most of the improvement interventions relied on lean methodology followed by lean combined with Six Sigma. The main supporting technologies were simulation and automation, while emergency departments and laboratories were the main settings. Most interventions focus on patient flow outcomes, reporting positive effects on outcomes related to access to service and utilization of services, including reductions in turnaround time, length of stay, waiting time, and turnover time. Notably, we found scarce outcomes regarding patient health, staff wellbeing, resource use, and savings. This paper, the first to investigate the dual intervention of DTs with lean or lean-Six Sigma in healthcare, summarizes the technical and organizational challenges associated with similar interventions, encourages further research, and promotes practical applications.

Professional Competence and Its Effect on the Implementation of Healthcare 4.0 Technologies: Scoping Review and Future Research Directions.

BACKGROUND: The implementation of Healthcare 4.0 technologies faces a number of barriers that have been increasingly discussed in the literature. One of the barriers presented is the lack of professionals trained in the required competencies. Such competencies can be technical, methodological, social, and personal, contributing to healthcare professionals managing and adapting to technological changes. This study aims to analyse the previous research related to the competence requirements when adopting Healthcare 4.0 technologies. METHODS: To achieve our goal, we followed the standard procedure for scoping reviews. We performed a search in the most important databases and retrieved 4976 (2011-present) publications from all the databases. After removing duplicates and performing further screening processes, we ended up with 121 articles, from which 51 were selected following an in-depth analysis to compose the final publication portfolio. RESULTS: Our results show that the competence requirements for adopting Healthcare 4.0 are widely discussed in non-clinical implementations of Industry 4.0 (I4.0) applications. Based on the citation frequency and overall relevance score, the competence requirement for adopting applications of the Internet of Things (IoT) along with technical competence is a prominent contributor to the literature. CONCLUSIONS: Healthcare organisations are in a technological transition stage and widely incorporate various technologies. Organisations seem to prioritise technologies for 'sensing' and 'communication' applications. The requirements for competence to handle the technologies used for 'processing' and 'actuation' are not prevalent in the literature portfolio.

False Positivity of rK39 Test in Five Chronic Myeloid Leukemia Cases from Bihar, India: A Possible Challenge to Leishmaniasis Diagnosis.

A rapid and noninvasive rK39 rapid diagnostic test (RDT) is the best and most reliable tool for visceral leishmaniasis (VL) screening in the field. However, splenic and bone marrow aspiration remain two gold standard methods for microscopic identification of Leishmania donovani (LD) bodies and confirmatory diagnosis of VL. Five patients with signs and symptoms of fever, loss of appetite, loss of weight, hepatomegaly, and massive splenomegaly were found to be false positive with the rK39 RDT. These patients were suspected to have chronic myeloid leukemia (CML) because their blood pictures showed a total white blood cell count of > 100,000/mm3 and abnormal cells such as stab, segmented promyelocytes, myelocytes, metamyelocytes, and blast cells. Splenic aspirate and bone marrow were negative for Leishmania donovani bodies. The bone marrow showed myeloid series of cells, that is, myelocytes, metamyelocytes, stab and segmented cells, blast cells, and markedly increased myeloid:erythroid ratio. Later, the CML diagnosis was confirmed in all cases by breakpoint cluster region-tyrosine protein kinase (BCR-ABL) gene positive test results. In this study, the rK39 RDT's false positivity was observed in CML cases. It could have important implications for the differential diagnosis of VL with CML. The rK39 positive test result in CML cases was a serendipitous occurrence; this should be validated further to determine the utility of the rK39 test in the differential diagnosis of VL with CML.

Advanced case of PKDL due to delayed treatment: A rare case report.

Post-kala-azar dermal leishmaniasis (PKDL) is clinical outcome of visceral leishmaniasis (VL) and is thought to be the potential reservoir of parasite. Miltefosine (MF) is the only oral drug existing for treatment of post-kala-azar dermal leishmaniasis (PKDL). Increased miltefosine tolerance in clinical isolates of Leishmania donovani has been reported and is one of the major concerns in the treatment of PKDL. Here, we report a highly ulcerated PKDL case that was successfully cured after miltefosine treatment.

Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells.

This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer cells compared to normal human fibroblasts. Compared to artemisinin, AG-1 is more toxic to human breast, prostate, head-neck, pancreas and skin cancer cells; 50% inhibition (IC50) 123 µM in AG-1 vs. 290 µM in artemisinin-treated breast cancer cells. AG-1 treatment decreased (~ 5 folds) cyclin D1 protein expression that correlated with an increase in the percentage of cells in the G1-phase, suggesting a G1 delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and H2AX protein levels. Results from electron paramagnetic resonance spectroscopy showed Fe-catalyzed formation of AG-1 carbon-centered radicals in a cell-free system. Flow cytometry analysis of H2DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with N-acetyl-l-cysteine and antioxidant enzymes (superoxide dismutase and catalase) significantly suppressed AG-1-induced toxicity, suggesting that superoxide and hydrogen peroxide contribute to AG-1-induced toxicity in human cancer cells. AG-1 represents a novel class of anti-cancer drug that is more potent than its parent compound, artemisinin.

Molecular docking studies of chloroquine and its derivatives against P23pro-zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies.

The arthropod-transmitted chikungunya virus has emerged as an epidemic menace that causes debilitating polyarthritis. With this life-threatening impact on humans, the possible treatment requires to cure the viral infectivity. But, devoid of any vaccine against the chikungunya virus (CHIKV), there is a need to develop a novel chemotherapeutic strategy to treat this noxious infection. CHIKV carries highly compact P23pro-zbd structure that possesses potential RNA-binding surface domains which extremely influences the use of RNA template during genome replication at the time of infection and pathogenesis. Therefore, computational approaches were used to explore the novel small molecule inhibitors targeting P23pro-zbd domain. The tertiary structure was modeled and optimized using in silico approaches. The results obtained from PROCHECK (93.1% residues in favored regions), ERRAT (87.480 overall model quality) and ProSA (Z-score: -11.72) revealed the reliability of the proposed model. Interestingly, a previously reported inhibitor, chloroquine possesses good binding affinities with the target domain. In-depth analysis revealed that chloroquine derivatives such as didesethyl chloroquine hydroxyacetamide, cletoquine, hydroxychloroquine exhibited a better binding affinity. Notably, MD simulation analysis exhibited that Thr1312, Ala1355, Ala1356, Asn1357, Asp1364, Val1366, Cys1367, Ala1401, Gly1403, Ser1443, Tyr1444, Gly1445, Asn1459, and Thr1463 residues are the key amino acid responsible for stable ligand-protein interaction. The results obtained from this study provide new insights and advances the understanding to develop a new approach to consider effective and novel drug against chikungunya. However, a detailed in vivo study is required to explore its drug likeliness against this life-threatening disease.

Noninvasive Sweat-Based Diagnosis of Visceral Leishmaniasis and Post Kala-Azar Dermal Leishmaniasis.

The diagnosis of visceral leishmaniasis (VL) is one of the foremost barriers in the control of this disease, as demonstration of the parasite by splenic/bone marrow aspiration is relatively difficult and requires expertise and laboratory support. The aim of the present study was to find a noninvasive diagnostic approach using the existing recombinant kinesine-39 (rK-39) immunochromatographic nitrocellulose strips test (ICT) with a human sweat specimen for the diagnosis of VL. The investigation was carried out on specimens (blood, sweat, and urine) collected from 58 confirmed VL, 50 confirmed post kala-azar dermal leishmaniasis (PKDL), 36 healthy control, and 35 patients from other diseases. The data obtained from this study reveal that 96.6% clinically confirmed active VL participants were found to be positive when tested against a sweat specimen. Interestingly, the scenario was similar when tested against a blood specimen (96.6% positive by rK-39). Moreover, a test of both sweats and blood specimens from 50 PKDL participants resulted in 100% positivity, whereas no healthy control participants were found to be rK-39 positive. The sensitivity of the rK-39 ICT in sweat specimen was 94.7%, whereas the specificity was 100% in healthy controls from endemic, nonendemic, and other infectious diseases, respectively. No difference was observed in sweat specimen of VL and PKDL cases which signifies its reliability. However, further evaluation of this method on a larger scale could enhance the reliability of the proposed model so that it could be used efficiently in VL management and eradication.

Severe Manifestations of Chikungunya Fever in Children, India, 2016.

Chikungunya is a relatively benign disease, and a paucity of literature on severe manifestations in children exits. We describe a cohort of pediatric chikungunya fever patients in New Delhi, India, who had severe sepsis and septic shock, which can develop during the acute phase of illness.

Fluid Overload and Renal Angina Index at Admission Are Associated With Worse Outcomes in Critically Ill Children.

Objectives: We investigated the association of fluid overload and oxygenation in critically sick children, and their correlation with various outcomes (duration of ventilation, ICU stay, and mortality). We also assessed whether renal angina index (RAI) at admission can predict mortality or acute kidney injury (AKI) on day 3 after admission. Design and setting: Prospective study, pediatric intensive care in a tertiary hospital. Duration: June 2013-June 2014. Patients: Patients were included if they needed invasive mechanical ventilation for >24 h and had an indwelling arterial catheter. Patients with congenital heart disease or those who received renal replacement therapy (RRT) were excluded. Methods: Oxygenation index, fluid overload percent (daily, cumulative), RAI at admission and pediatric logistic organ dysfunction (PELOD) score were obtained in all critically ill children. KDIGO classification was used to define AKI, using both creatinine and urine output criteria. Admission data for determination of RAI included the use of vasopressors, invasive mechanical ventilation, percent fluid overload, and change in kidney function (estimated creatinine clearance). Univariable and multivariable approaches were used to assess the relations between fluid overload, oxygenation index and clinical outcomes. An RAI cutoff >8 was used to predict AKI on day 3 of admission and mortality. Results: One hundred and two patients were recruited. Fluid overload predicted oxygenation index in all patients, independent of age, gender and PELOD score (p < 0.05). Fluid overload was associated with longer duration of ventilation (p < 0.05), controlled for age, gender, and PELOD score. Day-3 AKI rates were higher in patients with a RAI of 8 or more, and higher areas under the RAI curve had better prediction rates for Day-3 AKI. An RAI <8 had high negative predictive values (80-95%) for Day-3 AKI. RAI was better than traditional markers of pediatric severity of illness (PELOD) score for prediction of AKI on day 3. Conclusions: This study emphasizes that positive fluid balance adversely affects intensive care in critically ill children. Further, the RAI prediction model may help optimize treatment and improve clinical prediction of AKI.

Severe Sepsis and Septic Shock Associated with Chikungunya Fever in an Adolescent.

Chikungunya is usually a benign disease, and little is known on the occurrence of severe clinical complications. We describe a 12-year-old boy with rapid onset septic shock and multi-organ failure associated with chikungunya fever. Severe sepsis and septic shock can be associated with chikungunya.

Homology Modeling of Leishmania donovani Enolase and its Molecular Interaction with Novel Inhibitors.

INTRODUCTION: The treatment of Indian tropical disease such as kala-azar is likely to be troublesome to the clinicians as AmpB- and miltefosine-resistant Leishmania donovani has been reported. The rationale behind designed a novel inhibitors of model of L. donovani enolase and performing a binding study with its inhibitors to gain details of the interaction between protein residues and ligand molecules. METHODS AND MATERIALS: The L. donovani enolase model consists of two typical domains. The N-terminal one contains three-stranded antiparallel ß-sheets, followed by six α-helices. The C-terminal domain composes of eleven-stranded mixed α/ß-barrel with connectivity. The first α-helix within the C-terminal domain, H7, and the second ß-strand, S7, of the barrel domain was arranged in an antiparallel fashion compared to all other α-helices and ß-strands. The root-mean-square deviation between predicted model and template is 0.4 Å. The overall conformation of L. donovani enolase model is similar to those of Trypanosoma cruzi enolase and Streptococcus pneumoniae enolase crystal structures. RESULT: The key amino acid residues within the docking complex model involved in the interaction between model enolase structure and ligand molecule are Lys70, Asn165, Ala168, Asp17, and Asn213. CONCLUSION: Our theoretical prediction may lead to the establishment of prophylactic and therapeutic approaches for the treatment of kala-azar. This biomedical informatics analysis will help us to combat future kala-azar.

Inertial Microfluidic Cell Stretcher (iMCS): Fully Automated, High-Throughput, and Near Real-Time Cell Mechanotyping.

Mechanical biomarkers associated with cytoskeletal structures have been reported as powerful label-free cell state identifiers. In order to measure cell mechanical properties, traditional biophysical (e.g., atomic force microscopy, micropipette aspiration, optical stretchers) and microfluidic approaches were mainly employed; however, they critically suffer from low-throughput, low-sensitivity, and/or time-consuming and labor-intensive processes, not allowing techniques to be practically used for cell biology research applications. Here, a novel inertial microfluidic cell stretcher (iMCS) capable of characterizing large populations of single-cell deformability near real-time is presented. The platform inertially controls cell positions in microchannels and deforms cells upon collision at a T-junction with large strain. The cell elongation motions are recorded, and thousands of cell deformability information is visualized near real-time similar to traditional flow cytometry. With a full automation, the entire cell mechanotyping process runs without any human intervention, realizing a user friendly and robust operation. Through iMCS, distinct cell stiffness changes in breast cancer progression and epithelial mesenchymal transition are reported, and the use of the platform for rapid cancer drug discovery is shown as well. The platform returns large populations of single-cell quantitative mechanical properties (e.g., shear modulus) on-the-fly with high statistical significances, enabling actual usages in clinical and biophysical studies.

Severe Hypertriglyceridemia Causing Pancreatitis in a Child with New-onset Type-I Diabetes Mellitus Presenting with Diabetic Ketoacidosis.

The triad of pancreatitis, hypertriglyceridemia, and diabetic ketoacidosis and its treatment has not been extensively discussed in the pediatric literature. We report a 4-year-old child with severe hypertriglyceridemia, pancreatitis, and diabetic ketoacidosis. Hypertriglyceridemia and pancreatitis with diabetic ketoacidosis can be successfully managed with insulin and hydration therapy in children. Early recognition of this triad is important as insulin requirements, recovery duration, and prognosis can be altered.

Altered Glycolysis and Mitochondrial Respiration in a Zebrafish Model of Dravet Syndrome.

Altered metabolism is an important feature of many epileptic syndromes but has not been reported in Dravet syndrome (DS), a catastrophic childhood epilepsy associated with mutations in a voltage-activated sodium channel, Nav1.1 (SCN1A). To address this, we developed novel methodology to assess real-time changes in bioenergetics in zebrafish larvae between 4 and 6 d postfertilization (dpf). Baseline and 4-aminopyridine (4-AP) stimulated glycolytic flux and mitochondrial respiration were simultaneously assessed using a Seahorse Biosciences extracellular flux analyzer. Scn1Lab mutant zebrafish showed a decrease in baseline glycolytic rate and oxygen consumption rate (OCR) compared to controls. A ketogenic diet formulation rescued mutant zebrafish metabolism to control levels. Increasing neuronal excitability with 4-AP resulted in an immediate increase in glycolytic rates in wild-type zebrafish, whereas mitochondrial OCR increased slightly and quickly recovered to baseline values. In contrast, scn1Lab mutant zebrafish showed a significantly slower and exaggerated increase of both glycolytic rates and OCR after 4-AP. The underlying mechanism of decreased baseline OCR in scn1Lab mutants was not because of altered mitochondrial DNA content or dysfunction of enzymes in the electron transport chain or tricarboxylic acid cycle. Examination of glucose metabolism using a PCR array identified five glycolytic genes that were downregulated in scn1Lab mutant zebrafish. Our findings in scn1Lab mutant zebrafish suggest that glucose and mitochondrial hypometabolism contribute to the pathophysiology of DS.