Off-Label Use of Peripheral Paclitaxel Drug-Coated Balloons in Management of Recurrent Coronary In-Stent Restenosis.

Background: While not available for clinical use in the United States, dedicated drug-coated balloons (DCB) are currently under investigation for the management of coronary in-stent restenosis (ISR). Peripheral drug-coated balloons (P-DCB) have been used off-label for coronary ISR. Further data regarding this practice are needed. We aimed to describe outcomes in patients who underwent off-label P-DCB angioplasty for coronary ISR. Methods: We analyzed data on P-DCB angioplasty for coronary ISR at a single high-volume center between April 1, 2015, and December 30, 2017. Demographic and procedural details were collected, with systematic follow-up as clinically indicated. Results: Data from 31 patients treated with P-DCB angioplasty (mean age 68.0 ± 10.7 years) with coronary ISR (17 recurrent and 14 first time) were analyzed. Most patients presented with high-grade angina (81%) or myocardial infarction (13%). Treated ISR lesions were in native coronary arteries (68%), saphenous vein grafts (SVG, 23%), and the left internal mammary artery (10%). Diffuse intrastent ISR was common (69%) with a mean lesion length of 21.7 ± 12.4 mm. No postprocedural myocardial infarction occurred and 1 nonprocedural mortality occurred during index admission. At follow-up (median: 283, interquartile range [IQR]: 354 days), repeat angiography was performed in 19 patients (median: 212, IQR: 188 days), and 11 patients had target lesion recurrent ISR (Kaplan-Meier event-free survival estimate: 44.7%, 95% CI, 26.1%-76.5%). Conclusions: In the absence of availability of dedicated coronary DCB, treatment of coronary ISR using P-DCB angioplasty was feasible, although follow-up demonstrated continued risk for recurrent ISR in this high-risk population.

Diffusion-weighted Imaging: New Paradigm in Diagnosis of Early Acute Pancreatitis.

BACKGROUND: Diffusion-weighted imaging (DWI) has come up as a newer diagnostic modality for the diagnosis of early functional changes in various organs including the pancreas. DWI has shown the ability of early and accurate diagnosis of inflammatory pathologies, before the appearance of morphological changes on imaging. OBJECTIVES: The objectives of this study were to study the diagnostic accuracy of DWI in the diagnosis of early acute interstitial pancreatitis. MATERIALS AND METHODS: The present retrospective observational study was conducted at the department of radiodiagnosis of a tertiary teaching hospital for 1 year. Fifty patients who underwent magnetic resonance imaging of the pancreas with clinical or laboratory diagnosis of early pancreatitis were included in the study. The diagnostic accuracy of DWI was analyzed on the basis of quantitative (apparent diffusion coefficient [ADC] values) evaluation in the diagnosis of early acute pancreatitis. Threshold values for ADC were derived for differentiation of inflamed versus normal pancreas. Sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) were obtained by drawing the receiver operating characteristic (ROC) curve. RESULTS: The mean ADC values in the patient group (0.882 × 10-3 mm2/s ± 0.102) were significantly lower than the control group (1.178 × 10-3 mm2/s ± 0.232) with P < 0.001. The ROC curve deciphered a cutoff value of 0.937 × 10-3 mm2/s with a sensitivity of 84%, specificity of 86%, PPV of 85.71%, and NPV of 84.31% for diagnosis of acute pancreatitis using quantitative ADC values. CONCLUSION: DWI can thus be a succinct modality for early diagnosis of pancreatitis with excellent diagnostic accuracy and superlative advantage of lack of contrast and radiation in comparison to computed tomography scan.

Résumé Contexte:L'imagerie pondérée en diffusion (DWI) est apparue comme une nouvelle modalité de diagnostic pour le diagnostic des changements fonctionnels précoces.dans divers organes, dont le pancréas. DWI a montré la capacité de diagnostic précoce et précis des pathologies inflammatoires , avant apparition de modifications morphologiques à l'imagerieObjectifs:Les objectifs de cette étude étaient d'étudier la précision diagnostique du CFA chez le diagnostic de pancréatite interstitielle aiguë précoceMatériels et méthodes:La présente étude observationnelle rétrospective a été menée à le service de radiodiagnostic d'un CHU pendant 1 an. Cinquante patients ayant bénéficié d'une imagerie par résonance magnétique du les pancréas présentant un diagnostic clinique ou de laboratoire de pancréatite précoce ont été inclus dans l'étude. La précision diagnostique du DWI a été analysée sur la base d'une évaluation quantitative (valeurs du coefficient de diffusion apparent [ADC]) dans le diagnostic de la pancréatite aiguë précoce. Seuil les valeurs de l'ADC ont été dérivées pour différencier le pancréas enflammé du pancréas normal. Sensibilité, spécificité, valeur prédictive positive (VPP),et des valeurs prédictives négatives (NPV) ont été obtenues en traçant la courbe des caractéristiques de fonctionnement du récepteur (ROC)Résultats:L'ADC moyenles valeurs du groupe de patients (0.882 × 10−3 mm2/s ± 0.102) étaient significativement inférieures à celles du groupe témoin (1.178 × 10−3 mm2/s ± 0.232) avec P < 0.001. La courbe ROC a décrypté une valeur seuil de 0.937 × 10−3 mm2/s avec une sensibilité de 84 %, une spécificité de 86 %, une VPP de 85.71 %, et VPN de 84.31 % pour le diagnostic de pancréatite aiguë à l'aide des valeurs quantitatives de l'ADCConclusion:La DWI peut donc être une modalité succincte pour le diagnostic précoce de la pancréatite avec une excellente précision diagnostique et l'avantage exceptionnel de l'absence de contraste et de rayonnement par rapport à la tomodensitométrie.

How Can We Treat If We Do Not Measure: A Systematic Review of Neurogenic Bowel Objective Measures.

Background: Guidelines fail to recommend objective measures to assist with treatment of neurogenic bowel dysfunction (NBD) in spinal cord injury (SCI). Objectives: The main objective was to review the literature to identify the objective measures used in all NBD populations and to present their results and any correlations performed to validated subjective measures. Methods: A systematic review of the literature was performed in accordance with PRISMA (2020) guidelines, including all records from January 2012 to May 2023 with MeSH terms like "neurogenic bowel" indexed in the following databases: PubMed, EMBASE, CINAHL, Cochrane Central Trials Register, and ClinicalTrials.gov. Abstracts were excluded if they did not include objective measures or if they only mentioned the esophagus, stomach, and/or small bowel. Records were screened independently by at least two collaborators, and differences were resolved by unanimous agreement. Results: There were 1290 records identified pertaining to NBD. After duplicates were removed, the remaining records were screened for a total of 49 records. Forty-one records (82%) included subjective measures. Two-thirds of the articles involved the population with SCI/disease (n = 552) and one-third were non-SCI NBD (n = 476). Objective measures were categorized as (1) transit time, (2) anorectal physiology testing, and (3) miscellaneous. Of the 38 articles presenting results, only 16 (42%) performed correlations of objective measures to subjective measures. Conclusion: There is an abundance of literature supporting the use of objective outcome measures for NBD in SCI. Strong correlations of subjective measures to objective outcome measures were generally lacking, supporting the need to use both measures to help with NBD management.

The Clinical and Economic Burden of Antibiotic Use in Pediatric Patients With Varicella Infection: A Retrospective Cohort Analysis of Real-World Data in England.

BACKGROUND: Varicella is a highly infectious disease, particularly affecting children, that can lead to complications requiring antibiotics or hospitalization. Antibiotic use for varicella management is poorly documented. This study assessed antibiotic use for varicella and its complications in a pediatric population in England. METHODS: Data were drawn from medical records in the Clinical Practice Research Datalink and Hospital Episode Statistics data sets. The study included patients <18 years old with varicella diagnosed during 2014-2018 and 3-month follow-up available. We determined varicella-related complications, medication use, healthcare resource utilization, and costs from diagnosis until 3 months after diagnosis. RESULTS: We identified 114 578 children with a primary varicella diagnosis. Of these, 7.7% (n = 8814) had a varicella-related complication, the most common being ear, nose, and throat related (37.1% [n = 3271]). In all, 25.9% (n = 29 706 of 114 578) were prescribed antibiotics. A higher proportion of patients with complications than without complications were prescribed antibiotics (64.3% [n = 5668 of 8814] vs 22.7% [n = 24 038 of 105 764]). Mean annualized varicella-related costs were £2 231 481 for the study cohort. Overall, antibiotic prescriptions cost approximately £262 007. CONCLUSIONS: This study highlights high antibiotic use and healthcare resource utilization associated with varicella management, particularly in patients with complications. A national varicella vaccination program in England may reduce varicella burden and related complications, medication use, and costs.

First Experience With Augmented Reality Guidance for Cerebral Embolic Protection During TAVR.

Background: Augmented reality (AR) guidance holds potential to improve transcatheter interventions by enabling visualization of and interaction with patient-specific 3-dimensional virtual content. Positioning of cerebral embolic protection devices (CEP) during transcatheter aortic valve replacement (TAVR) increases patient exposure to radiation and iodinated contrast, and increases procedure time. AR may enhance procedural guidance and facilitate a safer intervention. Objectives: The purpose of this study was to develop and test a novel AR guidance system with a custom user interface that displays virtual, patient-specific 3-dimensional anatomic models, and assess its intraprocedural impact during CEP placement in TAVR. Methods: Patients undergoing CEP during TAVR were prospectively enrolled and assigned to either AR guidance or control groups. Primary endpoints were contrast volume used prior to filter placement, times to filter placement, and fluoroscopy time. Postprocedure questionnaires were administered to assess intraprocedural physician experience with AR guidance. Results: A total of 24 patients presenting for TAVR were enrolled in the study (12 with AR guidance and 12 controls). AR guidance eliminated the need for aortic arch angiograms prior to device placement thus reducing contrast volume (0 mL vs 15 mL, P < 0.0001). There was no significant difference in the time required for filter placement or fluoroscopy time. Postprocedure questionnaires indicated that AR guidance increased confidence in wiring of the aortic arch and facilitated easier device placement. Conclusions: We developed a novel AR guidance system that eliminated the need for additional intraprocedural angiograms prior to device placement without any significant difference in time to intervention and offered a subjective improvement in performance of the intervention.

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: NCT03992846. TRIAL REGISTRATION DATE: 20 June 2019. DATE OF FIRST PATIENT'S ENROLLMENT: 13 June 2019.

Diagnostic Yield of CSF Testing in Infants for Disorders of Biogenic Amine Neurotransmitter Metabolism.

BACKGROUND AND OBJECTIVES: Biochemical testing of CSF for neurotransmitter metabolites and their cofactors is often used in the diagnostic evaluation of infants with neurologic disorders but requires an invasive, labor-intensive procedure with many potential sources of error. Our aim was to determine the diagnostic yield of CSF testing for biogenic amines (serotonin, norepinephrine, epinephrine, and dopamine) and their cofactors in identifying inborn errors of neurotransmitter metabolism among infants. METHODS: We evaluated all infants aged 1 year or younger who underwent CSF biogenic amine neurotransmitter (CSFNT) testing at Children's Hospital of Philadelphia (CHOP) and Boston Children's Hospital (BCH) between 2008 and 2017 in this cross-sectional study. The primary outcome was the proportion of individuals who received a diagnostic result from CSFNT testing. Secondary assessments included the proportion of infants who obtained a diagnostic result from other types of diagnostic testing. RESULTS: The cohort included 323 individuals (191 from CHOP and 232 from BCH). The median age at presentation was 110 days (range 36-193). The most common presenting features were seizures (71%), hypotonia (47%), and developmental delay (43%). The diagnostic yield of CSFNT testing was zero. When CSF pyridoxal-5-phosphate level was assayed with CSFNT testing, 1 patient had a diagnostic result. An etiologic diagnosis was identified in 163 patients (50%) of the cohort, with genetic testing having the highest yield (120 individuals, 37%). DISCUSSION: Our findings support the case for deimplementation of CSFNT testing as a standard diagnostic test of etiology in infants aged 1 year or younger presenting with neurologic disorders.

Clinical and Economic Burden of Antibiotic Use Among Pediatric Patients With Varicella Infection in the Outpatient Setting: A Retrospective Cohort Analysis of Real-world Data in France.

BACKGROUND: Varicella infects 90% of children before age 9. Though varicella is self-limiting, its complications may require antibiotics, though how antibiotics are utilized for varicella in France is not well known. This study assessed antibiotic use and costs associated with varicella and its complications in pediatric patients managed in the outpatient setting in France. METHODS: A retrospective cohort study using the Cegedim Strategic Data-Longitudinal Patient Database, an electronic medical record database from general practitioners and office-based specialists in France, was conducted. Children <18 years old diagnosed with varicella between January 2014 and December 2018 with 3-month follow-up available were included. We used descriptive analysis to assess varicella-related complications, medication use, healthcare resource utilization and costs. RESULTS: Overall, 48,027 patients were diagnosed with varicella; 15.3% (n = 7369) had ≥1 varicella-related complication. Antibiotics were prescribed in up to 25.1% (n = 12,045/48,027) of cases with greater use in patients with complications (68.1%, n = 5018/7369) compared with those without (17.3%, n = 7027/40,658). Mean medication and outpatient varicella-related costs were €32.82 per patient with medications costing a mean of €5.84 per patient; antibiotics contributed ~23% to total costs annually. CONCLUSION: This study showed high antibiotic use for the management of varicella and its complications. A universal varicella vaccination program could be considered to alleviate complications and associated costs in France.

A review of the pharmacology, clinical outcomes, and real-world effectiveness, safety, and non-contraceptive effects of NOMAC/E2.

Selecting an appropriate oral contraceptive can be challenging for healthcare professionals due to the abundance of marketed contraceptive options with different clinical and real-world effectiveness and safety profiles. Nomegestrol acetate + 17ß-estradiol (NOMAC/E2) is a combined oral contraceptive (COC) that inhibits ovulation by suppressing ovarian function by a 17-hydroxy-progesterone derivative and an estrogen identical to that endogenously produced by the ovaries. This narrative review examines clinical and real-world studies of NOMAC/E2 based on a background literature search using PubMed and Google Scholar. The review outlines the pharmacology of NOMAC/E2, including its progestational activity, pharmacokinetics, and effects on carbohydrate metabolism, lipid metabolism, and coagulation parameters, and summarizes key clinical efficacy and safety data that led to the approval of NOMAC/E2 in Europe, Brazil, and Australia. To help elucidate how NOMAC/E2 clinical trial data translate into a real-world setting, this review describes the effectiveness and safety of NOMAC/E2 in prospective studies that include over 90,000 users (half of whom received NOMAC/E2), outlining its effects on risk of thrombosis, menstrual bleeding patterns, weight, mood, acne, bone health, and patient quality of life. Non-contraceptive benefits of NOMAC/E2 for women with endometriosis, dysmenorrhea, or pre-menstrual dysphoric disorder are also discussed. These data demonstrate that NOMAC/E2 has a long half-life and rapid absorption, is effective at preventing unwanted pregnancies, and exhibits a favorable safety profile in both clinical trials and real-world settings. Importantly, NOMAC/E2 is not associated with increased risk of venous thromboembolism, a major safety concern of healthcare professionals for women receiving hormonal contraceptives. This review highlights NOMAC/E2 as a differentiated option among COCs and could help inform oral contraceptive choice to ultimately improve patient management and outcomes in real-world settings.

Transcriptomic Profiling of OSCC Patients in an Indian Subset.

BACKGROUND: Tumor-specific biomarkers are needed for accomplishing antidote in early detection, as well as prognosis and designing therapeutic strategies. Comprehensive transcriptome profiling offers critical insights into the disease and reveal new avenue for drug discovery. METHODS: Total 5 cancerous and histopathological normal tissue pairs of 5 OSCC patients included in the petite study. Transcriptome sequencing was performed using Roche's 454 sequencing platform followed by CLC Genomics Workbench was used to examine gene expression in OC development. RESULTS: A total 2082 genes were differentially expressed across all the five tumor-control pairs collected from the OC patients during the surgery. From these 1092 upregulated and 273 downregulated genes, whereas 717 genes were found to be non-significant. The genes with pvalue <0.05 and log2foldchange > 1 or log2foldchange < -1 were considered for further enrichment analysis. Topfunn was used for gene enrichment analysis to identify gene enrichment pathway analysis found some cancer related pathways such as TNF signaling, p53 signaling pathway, cGMP-PKG signaling pathway, Apelin signaling pathway and IL-17 signaling pathway were strikingly involved in proliferation and apoptosis of tumor cells. The PPI network construction was performed and identified 8 best protein interactions. CONCLUSION: The current study reports molecular biomarkers including INHBA, FJX1, OLR1, CDK2, IGHM, CXCL11, SH2D5 and FABP5 associated with cancer that can led to identify potential therapeutic targets for the better prognosis of the cancer patients. The signature candidate can be translated to clinical practice to increase early diagnostic accuracy.

In-hospital outcomes of transcatheter aortic valve replacement in patients with chronic and end-stage renal disease: a nationwide database study.

BACKGROUND: Chronic kidney disease (CKD) and end-stage renal disease (ESRD) have been associated with worse outcomes after transcatheter aortic valve replacement (TAVR). With TAVR indications extending to a wider range of patient populations, it is important to understand the current implications of chronic renal insufficiency on clinical outcomes. We aim to determine the impact of CKD and ESRD on in-hospital outcomes after TAVR. METHODS: We queried the National Inpatient Sample for TAVR performed between 2016 and 2020 using International Classification of Diseases-10th Revision codes. We compared in-hospital mortality and clinical outcomes between three groups: normal renal function, CKD and ESRD. The association between CKD/ESRD and outcomes was tested with multivariable logistic regression analyses, using normal renal function as baseline. RESULTS: In the five-year study period, 279,195 patients underwent TAVR (mean age 78.9 ± 8.5 years, 44.4% female). Of all patients, 67.1% had normal renal function, 29.2% had CKD, and 3.7% had ESRD. There were significant differences in age, sex, and prevalence of comorbidities across groups. In-hospital mortality was 1.3%. Compared to patients with normal renal function, patients with renal insufficiency had higher in-hospital mortality, with the highest risk found in patients with ESRD (adjusted odds ratio: 1.4 [95% confidence interval: 1.2-1.7] for CKD; adjusted odds ratio: 2.4 [95% confidence interval: 1.8-3.3] for ESRD). Patients with CKD or ESRD had a higher risk of cardiogenic shock, need for mechanical circulatory support, and vascular access complications, compared to those with normal renal function. In addition, patients with ESRD had a higher risk of cardiac arrest and periprocedural acute myocardial infarction. The incidence of conversion to open heart surgery was 0.3% and did not differ between groups. Post-procedural infectious and respiratory complications were more common among patients with CKD or ESRD. CONCLUSION: Patients with CKD and ESRD are at higher risk of in-hospital mortality, cardiovascular, and non-cardiovascular complications after TAVR. The risk of complications is highest in patients with ESRD and does not result in more frequent conversion to open heart surgery. These results emphasize the importance of individualized patient selection for TAVR and procedural planning among patients with chronic renal insufficiency.

Rheumatic Heart Disease in the Developing World.

Despite recent public policy initiatives, rheumatic heart disease (RHD) remains a major source of morbidity worldwide. Rheumatic heart disease occurs as a sequela of Streptococcus pyogenes (group A streptococcal [GAS]) infection in patients with genetic susceptibility. Strategies for prevention of RHD or progression of RHD include prevention of GAS infection with community initiatives, effective treatment of GAS infection, and secondary prophylaxis with intramuscular penicillin. The cardiac surgical community has attempted to improve the availability of surgery in RHD-endemic areas with some success, and operative techniques and outcomes of valve repair continue to improve, potentially offering patients a safer, more durable operation. Innovation offers hope for a more scalable solution with improved biomaterials and transcatheter delivery technology; however, cost remains a barrier.

The Clinical and Economic Burden of Antibiotic Use in Pediatric Patients with Varicella Infection: a Retrospective Cohort Analysis of Real-World Data in England.

BACKGROUND: Varicella is a highly infectious disease, particularly affecting children, that can lead to complications requiring antibiotics or hospitalization. Antibiotic use for varicella management is poorly documented. This study assessed antibiotic use for varicella and its complications in a pediatric population in England. METHODS: Data were drawn from medical records in the Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Patients <18 years old diagnosed with varicella during 2014-2018 with 3-month follow-up available were included. We described varicella-related complications, medication use, healthcare resource utilization, and costs from diagnosis until 3-month post-diagnosis. RESULTS: We identified 114,578 children with a primary varicella diagnosis. 7.7% (n = 8,814) had a varicella-related complication, the most common being ear, nose, and throat related (37.1%, n = 3,271). In all, 25.9% (n = 29,706/114,578) were prescribed antibiotics. A higher proportion of patients with complications than those without complications were prescribed antibiotics (64.3%, n = 5,668/8,814 vs. 22.7%, n = 24,038/105,764). Mean annualized varicella-related costs were £2,231,481 for the study cohort. Overall, antibiotic prescriptions cost ∼£262,007. CONCLUSIONS: This study highlights high antibiotic use and healthcare resource utilization associated with varicella management, particularly in patients with complications. A national varicella vaccination program in England may reduce varicella burden and related complications, medication use, and costs.

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.

N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

Characterization of a fungal α-galactosidase and its synergistic effect with ß-mannanase for hydrolysis of galactomannan.

An acid stable α-galactosidase was produced and purified from mannolytic fungal strain, Penicillium aculeatum APS1. Enzyme was produced using wheat bran and copra cake moistened with corn steep liquor by solid state fermentation. APS1αgal having molecular weight of 65.4 kDa was purified to electrophoretic homogeneity by three phase partitioning and gel permeation chromatography with high enzyme recovery. APS1αgal was found to be maximally active at 55 °C and pH 4.5, having high stability at acidic pH. Thermal stability and thermal inactivation kinetics of APS1αgal were also studied. APS1αgal was found to effectively hydrolyse oligosaccharides as well as polysaccharides having α-1,6 linked galactose. Abolishment of enzyme activity in N-brommosuccinimide revealed an important role of tryptophan residue in catalysis. APS1αgal had shown outstanding tolerance to NaCl and proteases. MALDI-TOF MS/MS analysis indicated that enzyme is probably a member of family GH27. Synergistic interaction between APS1αgal and ß-mannanase for hydrolysis of galactomannan was very clear and maximum 2.0° of synergy was found under simultaneous mode of action. This study reports a new source of α-galactosidase with biochemical properties suitable for applications in food and feed industries.

Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2.

Histamine receptor 2 (HRH2) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HRH2. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HRH2-based sensor in yeast to evaluate the role of key residues in the HRH2 active site on histamine and 8HQ-based blocker binding. We find that the HRH2 mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HRH2:D186A and HRH2:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HRH2 blockers that interact with both ends of the HRH2 binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HRH2:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HRH2 therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.

Diagnosis of Coexisting Valvular Heart Diseases Using Image-to-Sequence Translation of Contact Microphone Recordings.

OBJECTIVE: Development of a contact microphone-driven screening framework for the diagnosis of coexisting valvular heart diseases (VHDs). METHODS: A sensitive accelerometer contact microphone (ACM) is employed to capture heart-induced acoustic components on the chest wall. Inspired by the human auditory system, ACM recordings are initially transformed into Mel-frequency cepstral coefficients (MFCCs) and their first and second derivatives, resulting in 3-channel images. An image-to-sequence translation network based on the convolution-meets-transformer (CMT) architecture is then applied to each image to find local and global dependencies in images, and predict a 5-digit binary sequence, where each digit corresponds to the presence of a specific type of VHD. The performance of the proposed framework is evaluated on 58 VHD patients and 52 healthy individuals using a 10-fold leave-subject-out cross-validation (10-LSOCV) approach. RESULTS: Statistical analyses suggest an average sensitivity, specificity, accuracy, positive predictive value, and F1 score of 93.28%, 98.07%, 96.87%, 92.97%, and 92.4% respectively, for the detection of coexisting VHDs. Furthermore, areas under the curve (AUC) of 0.99 and 0.98 are respectively reported for the validation and test sets. CONCLUSION: The high performances achieved prove that local and global features of ACM recordings effectively characterize heart murmurs associated with valvular abnormalities. SIGNIFICANCE: Limited access of primary care physicians to echocardiography machines has resulted in a low sensitivity of 44% when using a stethoscope for the identification of heart murmurs. The proposed framework provides accurate decision-making on the presence of VHDs, thus reducing the number of undetected VHD patients in primary care settings.

Thermotolerant and protease-resistant GH5 family ß-mannanase with CBM1 from Penicillium aculeatum APS1: purification and characterization.

In past several years, mannanases has attracted many researchers owing to its extensive industrial applications. The search for novel mannanases with high stability still continues. Present investigation was focused on purification of extracellular ß-mannanase from Penicillium aculeatum APS1 and its characterization. APS1 mannanase was purified to homogeneity by chromatography techniques. Protein identification by MALDI-TOF MS/MS revealed that the enzyme belongs to GH family 5 and subfamily 7, and possesses CBM1. The molecular weight was found to be 40.6 kDa. The optimum temperature and pH of APS1 mannanase were 70 °C and 5.5, respectively. APS1 mannanase was found to be highly stable at 50 °C and tolerant at 55-60 °C. The enzyme was very sensitive to Mn+2, Hg+2 and Co+2 metal ions and stimulated by Zn+2. Inhibition of activity by N-bromosuccinimide suggested key role of tryptophan residues for catalytic activity. The purified enzyme was efficient in hydrolysis of locust bean gum, guar gum and konjac gum and kinetic studies revealed highest affinity towards locust bean gum (LBG). APS1 mannanase was found to be protease resistant. Looking at the properties, APS1 mannanase can be a valuable candidate for applications in bioconversion of mannan-rich substrates into value-added products and also in food and feed processing.

Therapeutic inertia related to the injectable glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes in UK primary care.

AIMS: To determine the extent of therapeutic inertia related to the weekly injectable glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes (T2D) in the United Kingdom. MATERIALS AND METHODS: Adults with T2D who received their first primary care prescription of dulaglutide or semaglutide between January and July 2019 were identified from the UK Clinical Practice Research Datalink GOLD primary care database. Doses prescribed, glycated haemoglobin (HbA1c), body mass index (BMI) and concomitant T2D medications were assessed at first prescription and at 3, 6 and 9 months. RESULTS: Of the patients prescribed dulaglutide (N = 748; mean [SD] age 59.0 [11.2] years) and semaglutide (N = 437; mean [SD] age 58.4 [10.6] years), 93.0% and 89.0%, respectively, had an HbA1c level ≥7.5% (≥58.46 mmol/mol), and 56.4% and 54.9%, respectively, had an HbA1c level ≥9.0% (≥74.86 mmol/mol), at first prescription. At 6 to 9 months, 75.0% of those on dulaglutide 0.75 mg and 57.6% of those on semaglutide 0.25 mg or 0.5 mg had an HbA1c level ≥7.5% (≥58.46 mmol/mol). At 9 months, 21.9% of the dulaglutide cohort were on the suboptimal dose of 0.75 mg, and 46.1% of the semaglutide cohort were on the suboptimal doses of 0.25 mg or 0.5 mg. CONCLUSIONS: Multiple examples of therapeutic inertia were identified, including first prescription at HbA1c levels considerably above target and failure to escalate to optimal doses even with evidence of suboptimal metabolic control. A substantial proportion of patients therefore did not achieve optimal HbA1c targets.

Neurologic complications of infective endocarditis in children.

OBJECTIVES: To define the frequency and characteristics of acute neurologic complications in children hospitalised with infective endocarditis and to identify risk factors for neurologic complications. STUDY DESIGN: Retrospective cohort study of children aged 0-18 years hospitalised at a tertiary children's hospital from 1 January, 2008 to 31 December, 2017 with infective endocarditis. RESULTS: Sixty-eight children met Duke criteria for infective endocarditis (43 definite and 25 possible). Twenty-three (34%) had identified neurologic complications, including intracranial haemorrhage (25%, 17/68) and ischaemic stroke (25%, 17/68). Neurologic symptoms began a median of 4.5 days after infective endocarditis symptom onset (interquartile range 1, 25 days), though five children were asymptomatic and diagnosed on screening neuroimaging only. Overall, only 56% (38/68) underwent neuroimaging during acute hospitalisation, so additional asymptomatic neurologic complications may have been missed. Children with identified neurologic complications compared to those without were older (48 versus 22% ≥ 13 years old, p = 0.031), more often had definite rather than possible infective endocarditis (96 versus 47%, p < 0.001), mobile vegetations >10mm (30 versus 11%, p = 0.048), and vegetations with the potential for systemic embolisation (65 versus 29%, p = 0.004). Six children died (9%), all of whom had neurologic complications. CONCLUSIONS: Neurologic complications of infective endocarditis were common (34%) and associated with mortality. The true frequency of neurologic complications was likely higher because asymptomatic cases may have been missed without screening neuroimaging. Moving forward, we advocate that all children with infective endocarditis have neurologic consultation, examination, and screening neuroimaging. Additional prospective studies are needed to determine whether early identification of neurologic abnormalities may direct management and ultimately reduce neurologic morbidity and overall mortality.