A Peculiar Case of Isolated Bilateral Tympanic Plate Fractures.

Tympanic plate fractures are uncommon injuries and carry the risk of external auditory canal stenosis. These injuries are often associated with fractures of adjacent bones like the mandible, maxilla, and temporal bone. Isolated bilateral tympanic bone fractures have rarely been reported. The most frequently advocated treatment for these injuries is surgical to prevent canal stenosis in the future. The effectiveness of non-operative management has been seldom reported. In the current case report, we present an uncommon injury with isolated bilateral tympanic plate fractures secondary to trauma to the mandible with no associated mandible or condylar fractures that were treated non-operatively. The functional outcomes were favorable at one year of follow-up.

Pharmacotherapy and revascularization strategies of peripheral artery disease.

The global epidemiological transition of atherosclerotic vascular diseases is witnessing a rapid redistribution of its burden, shifting from high-income to low- and middle-income countries. With a wide clinical spectrum, spanning from intermittent claudication to more complex critical limb threatening ischemia, nonhealing ulcers, gangrene as well as acute limb ischemia, peripheral artery disease is often faced with the challenges of under-diagnosis and under-treatment despite its high prevalence. The management of peripheral arterial disease in patients with multiple comorbidities presents a formidable challenge and remains a pressing global health concern. In this review, we aim to provide an in-depth overview of the pathophysiology of peripheral artery disease and explore evidence-based management strategies encompassing pharmacological, lifestyle, interventional, and surgical approaches. By addressing these challenges, the review contributes to a better understanding of the evolving landscape of peripheral artery disease, offering insights into effective and holistic management strategies.

Comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'.

A single 300 mg dose of tafenoquine, in combination with chloroquine, is currently approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥16 years. Recently, however, Watson et al. suggested that the approved dose of tafenoquine is insufficient for radical cure, and that a higher 450 mg dose could reduce P. vivax recurrences substantially (Watson et al., 2022). In this response, we challenge Watson et al.'s assertion based on empirical evidence from dose-ranging and pivotal studies (published) as well as real-world evidence from post-approval studies (ongoing, therefore currently unpublished). We assert that, collectively, these data confirm that the benefit-risk profile of a single 300 mg dose of tafenoquine, co-administered with chloroquine, for the radical cure of P. vivax malaria in patients who are not G6PD-deficient, continues to be favourable where chloroquine is indicated for P. vivax malaria. If real-world evidence of sub-optimal efficacy in certain regions is observed or dose-optimisation with other blood-stage therapies is required, then well-designed clinical studies assessing safety and efficacy will be required before higher doses are approved for clinical use.

Single Center Outcomes of Percutaneous Deep Vein Arterialization in Patients with End-Stage Peripheral Artery Disease.

Background: Peripheral artery disease (PAD) can present as chronic limb threatening ischemia (CLTI) with ischemic pain and tissue loss. Progression of distal disease can lead to a "no option" or end-stage disease without traditional open or endovascular revascularization due to lack of pedal targets. Innovations in endovascular technology allow for the use of percutaneous deep vein arterialization (pDVA) to treat patients with CLTI. Purpose: We describe our experience and technique for treating four patients with end-stage PAD with pDVA. Research Design: Four patients with end-stage PAD were followed during and after pDVA creation. Technical success, complications, wound healing, and freedom from major amputation were analyzed. Data Collection and Analysis: Patient data and outcomes were collected via chart review and at time of follow up appointments in vascular surgery clinic. Results: Technical success was 100%, without post-procedural complications, and patients were continued on antiplatelet and anticoagulation. Three patients (75%) had successful wound healing, with 2 patients healing after transmetatarsal amputation (TMA), and 1 healing a distal foot ulceration that did not require surgery. One patient had worsening ischemic breakdown of a TMA, despite re-intervention on the pDVA, which required a below knee amputation (BKA). Freedom from major amputation was 75% overall, with an average follow-up time of 410 days post-procedure (Range: 113-563 days). Conclusions: Percutaneous deep vein arterialization attempts to provide blood flow to the preserved venous bed in patients with end-stage PAD. Exploration and utilization of this technique continues to expand in the modern vascular era. This case series highlights 4 patients with end-stage PVD who underwent pDVA, with 100% procedural success, and 75% limb salvage rate.

Lifestyle Approach and Medical Therapy of Lower Extremity Peripheral Artery Disease.

Lower extremity peripheral artery disease (PAD) is common among patients with several risk factors, such as elderly, smoking, hypertension, and diabetes mellitus. Notably, PAD is associated with a higher risk of cardiovascular complications. Non-invasive interventions are beneficial to improve morbidity and mortality among patients with PAD. Traditional risk factors like smoking, diabetes mellitus, hypertension, and dyslipidemia play a significant role in the development of PAD. Still, additional factors such as mental health, glycemic control, diet, exercise, obesity management, lipid-lowering therapy, and antiplatelet therapy have emerged as important considerations. Managing these factors can help improve outcomes and reduce complications in PAD patients. Antiplatelet therapy with aspirin or clopidogrel is recommended in PAD patients, with clopidogrel showing more significant benefits in symptomatic PAD individuals. Managing several risk factors is crucial for improving outcomes and reducing complications in patients with PAD. Further research is also needed to explore the potential benefits of novel therapies. Ultimately, a comprehensive approach to PAD management is essential for improving morbidity and mortality among patients with this condition.

Pharmacist-led interventions in optimising the use of oral anticoagulants in patients with atrial fibrillation in general practice in England: a retrospective observational study.

BACKGROUND: Oral anticoagulation (OAC) is the mainstay of treatment for the prevention of strokes in patients with atrial fibrillation (AF). Direct oral anticoagulants (DOACs) account for increasing OAC in patients with AF. However, prescribing DOACs for patients with established AF poses various challenges and general practice pharmacists may have an important role in supporting their management. AIM: To investigate the effectiveness of pharmacist-led interventions in general practice in optimising the use of OAC therapies in AF. DESIGN & SETTING: A retrospective observational study in general practices in Bradford. METHOD: The data were collected retrospectively from 1 November 2018-31 December 2019 using electronic health record data. The data were analysed: 1) to identify patients with AF not on OAC; 2) to describe inappropriate DOAC prescriptions; and 3) to calculate HAS-BLED scores. RESULTS: Overall, 76.3% (n = 470) of patients with AF received OAC therapy, and of these, 63.4% received DOACs. Pharmacist-led interventions increased DOAC prescribing by 6.0% (P = 0.03). Inappropriate DOAC use was identified in 24.5% of patients with AF, with underdosed and overdosed identified in 9.7% and 14.8%, respectively. Post-intervention, inappropriate prescribing was reduced to 1.7%. The mean HAS-BLED score decreased from 3.00 to 2.22 (P<0.01). Successful transition from vitamin K antagonist (VKA) therapy to DOACs was achieved in 25.7% of patients. CONCLUSION: Pharmacist-led interventions have successfully improved the use of OAC therapies in patients with AF, and effectively managed the bleeding risks and transition from VKA to DOAC therapy, in line with guidelines.

A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.

Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis ( Mtb ) is a classic tool that helps Mtb evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from Mtb -phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion ( p62 KD ) blocks mitophagy flux without impacting mitochondrial quality. In p62 KD cells, Mtb growth and survival are diminished, mainly through witnessing an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting of Mtb is facilitated by enhanced TOM20 + mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. In p62 KD cells, TOM20 + -MDVs biogenesis is MIRO1/MIRO2-dependent and delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection in p62 KD cells, TOM20 + -MDVs get extensively targeted to Mtb -phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting of Mtb . Triggering MQC collapse in p62 KD cells further diminishes Mtb survival signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.

Acceptance of Endoscopes in Otology - An Indian Perspective and Review of the Literature.

Introduction The role of endoscopes in the ear, nose, and throat (ENT) field has been described since the 1980s; It started with endoscopic nasal surgeries, followed by otological and laryngological procedures, and, since then, it has experienced a rapid evolution. Endoscopes help otologists understand how to approach difficult areas of middle ear, as well as the physiology of middle ear cleft. Objectives Despite the introduction of endoscopes in the field of otology, microscopes are still widely used in clinics and in operation theaters either alone or with endoscopes. The present study, which was conducted amongst otologists in India, is on their experience with and knowledge of the use of the endoscope compared to microscopes. Methods A Google form-based questionnaire comprising 18 questions was developed and sent online to otologist all over the country. The final dataset included responses from 354 active otologists. Results Out of 354 participants, only 3% had more than 5 years of experience in endoscopic ear surgery (EES), and 16.1% had never worked with an endoscope. Endoscopes were used in clinics and in operation theaters by 74.9% of the participants. Conclusion There has been a rise in the acceptance and use of endoscopes among Indian otologists and otology surgeons in last few decades.

Clinical Profile, Intensive Care Needs and Predictors of Outcome Among Children Admitted with Non-COVID Severe Acute Respiratory Illness (SARI) During the Pandemic.

OBJECTIVES: To study the epidemiology of non-coronavirus disease-2019 (non-COVID-19) respiratory viral infections with respect to their clinical profile, intensive care needs and predictors of outcome once the non-pharmacological interventions (NPI) during the coronavirus disease-2019 (COVID-19) pandemic were relaxed. METHODS: Retrospective analysis of children with Severe Acute Respiratory Illness (SARI) who were SARS-CoV-2 negative, admitted to the Pediatric Emergency/Intensive Care Unit (PICU) from July 2021 through October 2021 was conducted. RESULTS: One hundred and thirty nine children with median age of 11 (4-28.5) mo were included. Besides respiratory symptoms in all, diarrhea was reported in 90 (64.7%) children. Nearly half (n = 66; 47%) presented in hypoxemic respiratory failure (SpO2 <88%). Fifty-two (37.4%) children had co-morbidities, commonest being congenital heart disease in 12 (23.1%). Baseline parameters revealed leukopenia (specifically lymphopenia) 39 (28%), elevated aspartate transaminase [Serum glutamic-oxaloacetic transaminase (SGOT)] in 108 (77.6%), elevated N-acetyl-cysteine-activated creatinine kinase (CK-NAC) 23 (79%) and lactate dehydrogenase (LDH) 15 (88%). Intensive care needs included mechanical ventilation 51 (36.6%), vasoactive support 34 (24.5%), and renal replacement therapy 10 (7.1%). Forty-two (30.2%) children developed multi-organ dysfunction syndrome (MODS). One hundred and three (74.1%) children were discharged, 31 (22.3%) died, and 5 (3.6%) left against medical advice. On multivariate regression analysis, elevated liver enzymes (>5 times normal), hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted mortality. CONCLUSIONS: A surge in non-COVID SARI was observed once lockdown measures were relaxed. Nearly 1/3rd progressed to multi-organ failure and died. Elevated liver enzymes, hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted death.

Sensorineural Hearing Loss in Unilateral Mucosal Type of Chronic Otitis Media.

Sensorineural hearing loss is relatively well established in the squamosal chronic otitis media. However, its association with mucosal COM is still debated. The present study aimed at evaluating the prevalence of sensorineural hearing loss in unilateral mucosal COM. The study was conducted at a tertiary care hospital in New Delhi, and 60 patients with unilateral mucosal chronic otitis media were recruited. Pure tone thresholds were ascertained for air and bone conduction in an acoustically treated room and matched against certain patient and disease characteristics. In this study, the combined prevalence of SNHL/Mixed Hearing loss in mucosal COM was found to be 8.3%. A statistically significant association between SNHL/Mixed HL was seen in the 40-50-year age group (p-0.004). Prevalence with a disease duration of more than 10 years was 33% (p-0.019). All the patients who presented with SNHL/Mixed HL had an actively discharging ear. 80% of the patients who presented with SNHL/Mixed HL had large perforations. SNHL/Mixed HL prevalence of 28.6% was found in smokers, compared to 5.7% in non-smokers (p-0.039). The risk of developing SNHL/Mixed HL increased with increasing patients' age, disease duration, and size of the perforation and smokers.

IVUS Improves Outcomes With SUPERA Stents for the Treatment of Superficial Femoral-Popliteal Artery Disease.

BACKGROUND: Nitinol interwoven bare metal stents represent an advancement in stent technology; however, nominal deployment remains an area of focus. Intravascular ultrasound (IVUS) has been shown to improve outcomes in both the coronary and peripheral vasculature by providing the operator with greater vessel detail; however, the use of adjunctive IVUS with nitinol bare metal stents has not been widely studied. This studies aims to determine the effect of IVUS when used adjunctively with nitinol interwoven bare metal stents in the management of femoropopliteal lesions. DESIGN: Retrospective study. METHODS: This study included a cohort of 200 consecutive patients with peripheral artery disease. All patients were treated with ≥1 Supera bare metal stent, and 91 received adjunctive IVUS imaging prior to stent deployment. Deployment conditions of nominal, compressed, and elongated were measured, and the primary clinical outcomes included target lesion reintervention, amputation, and mortality. This study also showed that 8.3 number needed to treat (NNT) patients must be treated with IVUS to avoid an additional revascularization event. RESULTS: The patients who received IVUS had a significantly greater number of nominally deployed stents (p<0.001). Patients who had IVUS imaging also had significantly lower reintervention rates compared with those who did not receive IVUS imaging (p=0.047). CONCLUSION: The IVUS and angiography decreases clinically-driven target lesion reintervention and increases nominal deployment compared with angiography alone in femoropopliteal lesions treated with interwoven bare metal nitinol stents. CLINICAL IMPACT: Endovascular surgones may conisder the adjuctive use of IVUS when using the Supera stent for the treatment of infra inguinal superficial femoral artery lesions. The adjunct use of IVUS may lead to improved sizing, vessel prep, deployment, and ultiamtely reduction in CD-TLR.

Mitigating a Bioactivation Liability with an Azetidine-Based Inhibitor of Diacylglycerol Acyltransferase 2 (DGAT2) En Route to the Discovery of the Clinical Candidate Ervogastat.

We recently disclosed SAR studies on systemically acting, amide-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) that addressed metabolic liabilities with the liver-targeted DGAT2 inhibitor PF-06427878. Despite strategic placement of a nitrogen atom in the dialkoxyaromatic ring in PF-06427878 to evade oxidative O-dearylation, metabolic intrinsic clearance remained high due to extensive piperidine ring oxidation as exemplified with compound 1. Piperidine ring modifications through alternate N-linked heterocyclic ring/spacer combination led to azetidine 2 that demonstrated lower intrinsic clearance. However, 2 underwent a facile cytochrome P450 (CYP)-mediated α-carbon oxidation followed by azetidine ring scission, resulting in the formation of ketone (M2) and aldehyde (M6) as stable metabolites in NADPH-supplemented human liver microsomes. Inclusion of GSH or semicarbazide in microsomal incubations led to the formation of Cys-Gly-thiazolidine (M3), Cys-thiazolidine (M5), and semicarbazone (M7) conjugates, which were derived from reaction of the nucleophilic trapping agents with aldehyde M6. Metabolites M2 and M5 were biosynthesized from NADPH- and l-cysteine-fortified human liver microsomal incubations with 2, and proposed metabolite structures were verified using one- and two-dimensional NMR spectroscopy. Replacement of the azetidine substituent with a pyridine ring furnished 8, which mitigated the formation of the electrophilic aldehyde metabolite, and was a more potent DGAT2 inhibitor than 2. Further structural refinements in 8, specifically introducing amide bond substituents with greater metabolic stability, led to the discovery of PF-06865571 (ervogastat) that is currently in phase 2 clinical trials for the treatment of nonalcoholic steatohepatitis.

A phase 1 study to investigate the absorption, distribution, metabolism and excretion of brepocitinib in healthy males using a 14 C-microdose approach.

AIMS: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa ) using a 14 C microtracer approach. METHODS: This was a phase 1 open-label, nonrandomized, fixed sequence, two-period, single-dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14 C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 µg dose of 14 C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed. RESULTS: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported. CONCLUSION: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug-related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039.

The impact of COVID-19 on electronic repeat dispensing (eRD) in general practice.

BACKGROUND: Electronic repeat dispensing (eRD) has been part of the community pharmacy contact since 2005 and a requirement in the General Medical Services contract since 2019. NHS England highlights benefits of eRD as increased efficiency in general practice of 2.7 million hours annually if 80% of all repeat prescriptions are issued as eRD. Despite clear benefits to patients, community pharmacies and general practices, the uptake of eRD remains low and variable across general practices in West Yorkshire, UK. OBJECTIVES: To investigate the impact of COVID-19 on eRD in general practice and understand the key enablers to its uptake. METHODS: A 19-item questionnaire was developed and piloted during cognitive interviews. A cross-sectional survey was conducted via emails to general practices in West Yorkshire, UK, between July 2020 and November 2020. RESULTS: Sixty-seven complete responses were received (23 pharmacists, 21 practice managers, 11 general practitioners, seven pharmacy technicians, four advanced practitioners, one prescription clerk). 59% of respondents were aware of eRD uptake in their surgery (mean value 4.56% ± 0.229%). Higher uptake of eRD was demonstrated where the general practice integrated eRD into routine workflows during the repeat prescription reauthorisation process (P < 0.001) and where an eRD service lead is nominated (P = 0.04). CONCLUSION: Utilising eRD in the respective practices should be considered due to potential efficiency gains and the increase in average eRD utilisation observed in the study participating general practices was from 7.2% average uptake in March 2020 to 10.4% November 2020, as the response to COVID-19. The stated benefits of eRD by NHS England of 2.7 million hours per annum predates the roll out of electronic transmission of prescriptions suggesting further research is needed to quantify the efficiency gains in present NHS general practice environments.

Psychedelic Treatments for Substance Use Disorder and Substance Misuse: A Mixed Methods Systematic Review.

Renewed interest in psychedelic substances in the 21st century has seen the exploration of psychedelic treatments for various psychiatric disorders including substance use disorder (SUD). This review aimed to assess the effectiveness of psychedelic treatments for people with SUD and those falling below diagnostic thresholds (i.e. substance misuse). We systematically searched 11 databases, trial registries, and psychedelic organization websites for empirical studies examining adults undergoing psychedelic treatment for SUD or substance misuse, published in the English language, between 2000 and 2021. Seven studies investigating treatment using psilocybin, ibogaine, and ayahuasca, alone or adjunct with psychotherapy reported across 10 papers were included. Measures of abstinence, substance use, psychological and psychosocial outcomes, craving, and withdrawal reported positive results, however, this data was scarce among studies examining a wide range of addictions including opioid, nicotine, alcohol, cocaine and unspecified substance. The qualitative synthesis from three studies described subjective experience of psychedelic-assisted treatments enhanced self-awareness, insight, and confidence. At present, there is no sufficient research evidence to suggest effectiveness of any of the psychedelics on any specific substance use disorder or substance misuse. Further research using rigorous effectiveness evaluation methods with larger sample sizes and longer-term follow-up is required.

Janus ß-PdXY (X/Y = S, Se, Te) materials with high anisotropic thermoelectric performance.

Two-dimensional (2D) materials have garnered considerable attention as emerging thermoelectric (TE) materials owing to their unique density of states (DOS) near the Fermi level. We investigate the TE performance of Janus ß-PdXY (X/Y = S, Se, Te) monolayer materials as a function of carrier concentration and temperature in the mid-range from 300 to 800 K by combining density functional theory (DFT) and semi-classical Boltzmann transport theory. The phonon dispersion spectra and AIMD simulations confirm their thermal and dynamic stability. The transport calculation results reveal the highly anisotropic TE performance of both n and p-type Janus ß-PdXY monolayers. Meanwhile, the coexistence of low phonon group velocity and a converged scattering rate leads to a lower lattice thermal conductivity (Kl) of 0.80 W mK-1, 0.94 W mK-1, and 0.77 W mK-1 along the y-direction for these Janus materials, while the high TE power factor is attributed to the high Seebeck coefficient (S) and electrical conductivity, which are due to the degenerate top valence bands of these Janus monolayers. The combination of lower Kl and a high-power factor at 300 K (800 K) leads to an optimal figure of merit (ZT) of 0.68 (2.21), 0.86 (4.09) and 0.68 (3.63) for p-type Janus PdSSe, PdSeTe and PdSTe monolayers, respectively. To evaluate rational electron transport properties, the effects of acoustic phonon scattering (τac), impurity scattering (τimp), and polarized phonon scattering (τpolar) are included in the temperature-dependent electron relaxation time. These findings indicated that the Janus ß-PdXY monolayers are promising candidates for TE conversion devices.

Perception of college-going girls towards corneal donation in North India: A latent class analysis study.

Purpose: To assess the perception of college-going girls toward corneal donation in Northern India. Methods: An online survey with a pre-structured, pre-validated questionnaire was conducted on 1721 college-going girls in Northern India. The knowledge and attitude scores were regressed, and latent class analysis was carried out. Results: The average of scores for all participants was computed individually for the knowledge questions and the attitude questions, and based on this score, total participants were divided into two groups: Better corneal donation behaviors (BCDB) and poor corneal donation behaviors. The binomial logistic regression model of knowledge domain for predicting BCDB, age of the participant, their awareness about corneal donation, and willingness to discuss eye donation among family members were found significant. Similarly, for the attitude domain, awareness about corneal donation, knowledge about hours within which ideal eye donation needs to be undertaken, and knowledge about eye donation during coronavirus disease 2019 (COVID-19) pandemic were found to be significant. Latent class analysis identified one subset of participants having poorer knowledge and attitude scores and that they were more from a rural background, were having more than first order as birth order, were belonging to SC/ST classes, had illiterate or secondary education of father and mother, and were living in rented houses. Conclusion: The findings of the study significantly contribute to devising a mechanism to improve knowledge and influencing the attitude about eye donation among the youth, especially young women, who can act as counselors and motivators for the masses as well as their own families, in the generations to come.