A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting ß2-agonist reliever or ICS/formoterol reliever only in mild asthma.

INTRODUCTION/BACKGROUND: Mild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting ß2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. AIMS/OBJECTIVES: To assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. RESULTS: The SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. CONCLUSIONS: This is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting ß2-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy.

INTRODUCTION: Asthma treatments based solely on diagnostic label do not benefit patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting ß2-agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted. METHODS: Searches of databases including MEDLINE and Embase identified randomised controlled trials (RCTs) of patients with asthma, aged ≥12 years, published 1998-2022, containing ≥1 regular ICS dosing or ICS/formoterol-containing treatment arm, and reporting patient traits and outcomes of interest. Relevant data was extracted and underwent a feasibility assessment to determine suitability for meta-analysis. RESULTS: The SLR identified 39 RCTs of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV1, smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were deemed feasible for inclusion in meta-analyses due to sufficient comparable reporting. Subgroups of clinical outcomes stratified by levels of patient traits were reported in 16 RCTs. CONCLUSION: A systematic review of studies of regular ICS dosing with SABA or ICS/formoterol-containing treatment strategies in asthma identified consistent reporting of five traits and outcomes, allowing exploration of associations with treatment response. Conversely, many other traits and outcomes, although being potentially relevant, were inconsistently reported and limited subgroup reporting meant analyses of treatment response for subgroups of traits was not possible. We recommend more consistent measurement and reporting of clinically relevant patient traits and outcomes in respiratory RCTs.

Meta-analysis and cost-effectiveness analysis of intranasal corticosteroid treatment in allergic rhinitis with ocular symptoms.

BACKGROUND: Intranasal corticosteroid (INCS) has a beneficial effect on ocular symptoms in allergic rhinitis (AR). To our knowledge, the cost-effectiveness of available INCS for AR with ocular symptoms is yet to be demonstrated. OBJECTIVE: To evaluate the cost-effectiveness of INCSs including Budesonide (BANS), Mometasone furoate (MFNS), Triamcinolone (TANS), and Fluticasone furoate (FFNS) on ocular symptoms associated with AR in the Thai context. METHODS: The percentage of effectiveness in improving total ocular symptoms score (TOSS) was derived from the result of a meta-analysis that estimated the SMD of each INCS treatment compared to placebo as clinical input parameters. A cost-effectiveness analysis based on a decision-tree model to assess one-year costs and outcomes from a Thai societal perspective. The outcomes were to compare incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analyses (PSA) were also conducted to capture parameter uncertainties. RESULTS: 13 eligible RCTs with a total of 3,722 patients with SAR were included in the analysis. The percentage of effectiveness of FFNS, MFNS, TANS, and BANS was 59.89%, 45.60%, 24.89%, and 16.00%, respectively. The ICER of FFNS, MFNS, and TANS is THB-6,539.92, 4,593.83, and 1,401.24 compared to BANS. CECA result showed the probability of using FFNS is considered cost-effective in 87.50% of cases from zero value followed by MFNS (0.80%), TANS (5.40%), and BANS (6.30%). With a threshold greater than THB20,000, FFNS is considered a cost-effective strategy. CONCLUSIONS: FFNS is a cost-effective option compared to alternative INCSs in Thailand for treating AR with ocular symptoms.

Serum Expression Level of MicroRNA-122 and its Significance in different Stages of Hepatitis B Virus Infection.

This study aims to determine the serum expression level of miRNA-122 and its significance in the different stages of Hepatitis B virus infection. The study subjects were recruited and grouped for Hepatitis B associated with Chronic Hepatitis B infection, hepatic sclerosis, hepatocellular carcinoma, and healthy controls were also considered. Venous blood was collected from the participants including the controls and routine blood tests and quantification of miRNA-122 were done and analyzed in each case of hepatitis B infection and compared with that of healthy controls. The miRNA-122 was determined, which came to be highest in patients with Chronic Hepatitis B while patients with hepatic sclerosis and patients with hepatocellular carcinoma showed a subsequent number of copies. The number of copies of miRNA-122 in the CHB, hepatic sclerosis, and HCC group was significantly higher than in the healthy control. The quantification of miRNA-122 and subsequently plotting the ROC curve has shown that miRNA-122 can be considered as a biomarker of hepatitis B for screening and diagnosis purposes.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS/long-acting ß2-agonist plus short-acting ß2 agonist reliever or maintenance and reliever therapy for asthma.

INTRODUCTION: Current treatment for moderate-severe asthma with inhaled corticosteroid (ICS)-based therapy can follow two strategies: a single inhaler maintenance and reliever therapy (MART) regimen, or regular dosing with ICS/long-acting ß2-agonist used as maintenance therapy plus a separate short acting ß2-agonist reliever inhaler. It would be clinically useful to understand the potential of patient traits to influence regular dosing or MART treatment outcomes. OBJECTIVES: A systematic literature review (SLR) and meta-analysis was conducted to identify specific patient traits that may predict improved clinical outcomes with regular dosing or MART. RESULTS: The SLR identified 28 studies in patients with moderate-severe asthma assessing regular dosing or MART treatments and reporting the traits and outcomes of interest. Network meta-regressions found no significant difference in the relative efficacy of regular dosing as compared with MART on any of the clinical outcomes (exacerbation rate, time to first exacerbation, FEV1, reliever use and adherence) for any of the patient traits (baseline lung function, baseline ACQ, age, BMI, and smoking history) evaluated. However, some trends towards traits influencing treatment efficacy were identified. Inconsistent reporting of traits and outcomes was observed between trials. CONCLUSIONS: The analysed patient traits evaluated in this study were associated with similar efficacy for the analysed outcomes to either regular dosing or MART; however, trends from the data observed encourage future analyses for possible identification of additional traits, or a combination of traits, that may be of interest. More comparable reporting of clinically important traits and outcomes would improve future analyses.

A Comparative Analysis of Outcomes of Conventional Cold Dissection Versus Laser Tonsillectomy in Pediatric Cases in a Tertiary Care Hospital in Haryana.

Tonsillectomy is one of the commonest ENT procedures done in paediatric population, the technique of which has evolved over years to decrease the morbidity associated with the surgery. This prospective randomized comparative study is done to evaluate the efficacy of two different techniques of this surgery, conventional cold dissection and laser tonsillectomy based on operative time, blood loss, post-operative pain and occurrence of secondary complications. The study was done in 68 patients of paediatric age group, 34 in each group underwent cold dissection and laser tonsillectomy. Operative time and bleeding were significantly low for laser group. Pain score was comparable in early post-operatives days, but was high towards the end of first week. Our study reported only one incidence of complication in the form of a secondary bleeding.

A Prospective Observational Study to Determine Rate of Thromboprophylaxis in Oncology Patients Undergoing Abdominal or Pelvic Surgery.

Venous thromboembolism (VTE) is common in patients with cancer and is a leading cause of death. In addition to the hypercoagulable state associated with malignancy, cancer-related surgery and subsequent immobilization further increase the risk of VTE. Guidelines suggest extended prophylaxis up to 4 weeks with low-molecular-weight heparin (LMWH) in such patients. This study is conducted to determine the proportion of patients receiving thromboprophylaxis among those undergoing surgery for malignant abdominal or pelvic tumor. This prospective, multicenter, observational study included 300 patients (217 [72.3%] were women). Mean age and duration of cancer were 53.2 and 1.2 years, respectively. A total of 162 (54%) patients received thromboprophylaxis of which only pharmacological in 78 [48.1%], only mechanical in 27 [16.7%], and both pharmacological and mechanical in 57 [35.2%] patients. LMWH (128, 79.0%) and graduated compression stockings (74, 45.7%) were the commonly used modalities. VTE prophylaxis was given in only half of the patients. Physician education to increase adherence to international guidelines is very important. Trial Registration No. CTRI/2013/05/003617. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13193-021-01281-0.

Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1.

Mitochondrial quality control is mediated by the PTEN-induced kinase 1 (PINK1), a cytoprotective protein that is dysregulated in inflammatory lung injury and neurodegenerative diseases. Here, we show that a ubiquitin E3 ligase receptor component, FBXO7, targets PINK1 for its cellular disposal. FBXO7, by mediating PINK1 ubiquitylation and degradation, was sufficient to induce mitochondrial injury and inflammation in experimental pneumonia. A computational simulation-based screen led to the identification of a small molecule, BC1464, which abrogated FBXO7 and PINK1 association, leading to increased cellular PINK1 concentrations and activities, and limiting mitochondrial damage. BC1464 exerted antiinflammatory activity in human tissue explants and murine lung inflammation models. Furthermore, BC1464 conferred neuroprotection in primary cortical neurons, human neuroblastoma cells, and patient-derived cells in several culture models of Parkinson's disease. The data highlight a unique opportunity to use small molecule antagonists that disrupt PINK1 interaction with the ubiquitin apparatus to enhance mitochondrial quality, limit inflammatory injury, and maintain neuronal viability.

To Evaluate the Pre and Post Shunt Sensorineural Hearing Loss in Hydrocephalus Patients.

Hydrocephalus means watery head and defined as disturbance of formation, flow, or absorption of cerebrospinal fluid. The clinical presentation of hydrocephalus includes hearing loss especially sensorineural hearing loss (SNHL). Ventriculoperitoneal (VP) shunting is the most commonly performed procedure in these patients. Pure tone audiogram, impedence and BAEPs, were done for preoperative hearing assessment in 20 hydrocephalus patients. Out of 20 patients, 12 cases (60%) had SNHL while, rest 8 (40%) patients had mixed hearing loss. Post VP shunting hearing improvement was observed in 14 patients (70%) whereas it worsened in 30% of patients. The result is even better if shunt is placed at early age.

Oxidative stress and biomarker of TNF-α, MDA and FRAP in hypertension.

Concurrent with the misbalance of oxidizing agents and antioxidants, high blood pressure is a major physical burden condition in the current scenario. Tumor necrosis factor-α (TNF-α) plays a vital role in the pathogenesis of hypertension. Tumor necrosis factor-α, inhibitor improves clinical symptoms however their outcome on high blood pressure has not been investigated. We investigated the inflammatory marker TNF-α, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) in hypertensive patients. We measured randomly blood pressure using an ambulatory observe in hypertensive patients, measured systolic BP X 140 mmHg and/or diastolic BP X 90 mmHg were considered hypertensive. Total 60 cases were considered in the study that involves 30 hypertensive patients and 30 normal control. Measurements of serum concentrations of TNF-α, MDA, FRAP in hypertension patients was done in both the groups. Serum TNF-α was found to be remarkably increased in study subjects as compared to normal group (r=0.32, p<0.0001*). Serum MDA was also raised in hypertensive as compared to control (r=0.99**, p<0.0001*). While Serum FRAP was found to be decreased in hypertensive group in comparison to healthy control (r=0.23, p<0.0001*). It is concluded that high blood pressure leads to generation of oxidative stress with remarkable elevation of TNF-α and malondialdehyde levels. While reduced FRAP indicates its probable role in lipid peroxidation and in the pathogenesis of hypertension.

Treatment of Tympanic Membrane Retraction Pockets by Excision and Cartilage Tympanoplasty: A Prospective Study.

To assess the role of cartilage tympanoplasty in management of retraction pockets of the pars flaccida. This was a prospective study at a tertiary care centre. Twenty patients having grade III or grade IV retraction pockets were included in the study. Retraction pockets were treated by excision and cartilage tympanoplasty. Findings noted on follow-up were recorded and analysed. Graft was taken up in 18 (90%) cases with residual perforation in 2 (10%) cases. Recurrence of retraction pockets was observed in 6 (30%) cases. Hearing was improved up to 15 dB in 16 (80%) cases. It is concluded that grade III and IV retraction pockets can be well managed by excision and cartilage tympanoplasty.

Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants.

Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening. As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations. In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake. We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX. Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes. Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway. Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening. Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective. These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant LRRK2 pathogenesis.SIGNIFICANCE STATEMENT Cognitive dysfunction and dementia are common features of Parkinson's disease (PD), causing significant disability. Mutations in LRRK2 represent the most common known genetic cause of PD. We found that PD-linked LRRK2 mutations increased dendritic and mitochondrial calcium uptake in cortical neurons and familial PD patient fibroblasts, accompanied by increased expression of the mitochondrial calcium transporter MCU. Blocking the ERK1/2-dependent upregulation of MCU conferred protection against mutant LRRK2-elicited dendrite shortening, as did inhibiting MCU-mediated calcium import. Conversely, stimulating the export of calcium from mitochondria was also neuroprotective. These results implicate increased susceptibility to mitochondrial calcium overload in LRRK2-driven neurodegeneration, and suggest possible interventions that may slow the progression of cognitive dysfunction in PD.

KCOT Occurring in Bilateral Maxillary Sinus in Non-Syndromic Patient.

Odontogenic Keratocyst (OKC) also termed as Keratocystic Odontogenic Tumour (KCOT) (WHO 2005) is a pathology with unique behavior because of which it is under much scrutiny and continued study. The pathology usually presents itself commonly in mandible and less commonly in maxilla. The occurrence of KCOT in maxillary sinus is reported as rare and multiple occurrences are mostly associated along with the presence of Nevoid Basal Cell Carcinoma (NBCC) syndrome. Here, we present a rare case of bilateral Maxillary OKC involving maxillary sinuses, without the presence of NBCC syndrome. An interesting feature of this case is the presence of left upper third molar in ectopic position in maxillary sinus and a vertically impacted right third molar suggesting an origin from the dental lamina.

Role of PTFE Patch Saphenoplasty in Reducing Neovascularization and Recurrence in Varicose Veins.

Varicose veins have a high recurrence rate following surgery. Besides poor surgical technique, majority of these recurrences are attributable to neovascularization after both primary and repeat surgery. Authors have studied the effectiveness of a polytetrafluoroethylene (PTFE) patch interposition between the ligated vein stump and the overlying soft tissue at saphenofemoral junction in decreasing recurrence of varicose veins after initial surgery. Study was conducted on 50 patients of varicose veins with saphenofemoral junction incompetence. Patients were randomly divided into two groups, group A and group B alternately. In group A, standard surgical procedure was done followed by PTFE patch application. In group B, same surgical procedure was applied as in group A, with the exception of PTFE patch application. Patients in both groups were given similar postoperative care. A full venous duplex ultrasound assessment was performed in all the patients postoperatively. Neovascularization was observed in five patients (20 %) of group B, while it was not seen in any of the patients in group A at 1-year follow-up. This difference in neovascularization across the two groups was found to be statistically significant with a p value of 0.0251. Hence, authors concluded that patch saphenoplasty helps in reducing recurrence in varicose veins by decreasing neovascularization at saphenofemoral junction.

An expected consequence approach to route choice in the maritime transportation of crude oil.

Maritime transportation is the major conduit of international trade, and the primary link for global crude oil movement. Given the volume of oil transported on international maritime links, it is not surprising that oil spills of both minor and major types result, although most of the risk-related work has been confined to the local settings. We propose an expected consequence approach for assessing oil-spill risk from intercontinental transportation of crude oil that not only adheres to the safety guidelines specified by the International Maritime Organization but also outlines a novel technique that makes use of coarse global data to estimate accident probabilities. The proposed estimation technique, together with four of the most popular cost-of-spill models from the literature, were applied to study and analyze a realistic size problem instance. Numerical analyses showed that: a shorter route may not necessarily be less risky; an understanding of the inherent oil-spill risk of different routes could potentially facilitate tanker routing decisions; and the associated negotiations over insurance premium between the transport company and the not-for-profit prevention and indemnity clubs. Finally, we note that only the linear model should be used with one of the three nonlinear cost-of-spill models for evaluating tanker routes.

Sirtuin-4 modulates sensitivity to induction of the mitochondrial permeability transition pore.

The sustained opening of the mitochondrial permeability transition pore (PTP) is a decisive event in the onset of irreversible cell injury. The PTP is modulated by numerous exogenous and endogenous effectors, including mitochondrial membrane potential, ions and metabolites. Mitochondrial sirtuins have recently emerged as pivotal mediators of mitochondrial metabolism. In the present study, we demonstrate that sirt-4 modulates sensitivity to PTP onset induced by calcium and the oxidative cross linking reagent phenylarsine oxide, and PTP dependent cytotoxicity brought about by TNF or doxorubicin. Moreover, the ability of sirt-4 to modulate onset of the PTP is dependent on the expression of glutamate dehydrogenase-1.

Sirtuin-3 modulates Bak- and Bax-dependent apoptosis.

Sirtuin-3 exhibits properties of a tumor suppressor partly emanating from its ability to control the state of mitochondrial metabolism, with depletion of sirt-3 increasing tumor cell survival. In the present study we demonstrate that depletion of sirtuin-3 brings about an anti-apoptotic phenotype via stimulating cyclophilin-D activity, which promotes the binding of hexokinase II to the mitochondria, thereby preventing Bak/Bax dependent mitochondrial injury and cell death. By contrast, increased expression of sirtuin-3 decreases cyclophilin-D activity, resulting in detachment of hexokinase II from the mitochondria and potentiation of Bak- and Bax-induced mitochondrial injury and loss of cell viability.

A young non-immunocompromised woman with diffuse alveolar opacities.

Diffuse alveolar opacities (DAO) due to pulmonary tuberculosis are usually described in immunocompromised patients. In adult patients residing in high endemic areas such as India, alveolar opacities are not reported frequently in non-immunocompromised pulmonary tuberculosis patients. We describe a twenty-five-year-old woman who presented with bilateral diffuse alveolar opacities and initial diagnostic work up was directed to non-tuberculosis etiologies. Her sputum was not suggestive of tuberculous or any other infective etiology. However, histopathological examination of specimen from fine needle aspiration cytology through percutaneous route suggested chronic granulomatous disease with detection of mycobacterium. Polymerase chain reaction test in BAL and FNAC specimen confirmed tubercular etiology. Though not frequent, pulmonary tuberculous etiology is worth considering in the differential diagnosis of DAO as not only tuberculosis is fully treatable but also early detection shall help to avoid unnecessary invasive tests and cut down transmission to contacts.

Transarticular shear fractures of the distal humerus.

BACKGROUND: Capitellar fractures result from shearing and wedging forces transmitted to the elbow that create complex injury patterns that are difficult to stabilize. The fracture often extends into the trochlea and is associated with posterior comminution of the humerus and soft tissue injury. Diverse fixation techniques are required to restore the anatomy perfectly to ensure elbow function is regained. MATERIALS AND METHODS: This study presents the results of treatment of 26 patients followed up prospectively and treated within a week of injury. Clinical and radiographic evaluations were done annually by an independent reviewer, and the Mayo Elbow Performance Index (MEPI) was calculated. RESULTS: Results were excellent in 9 patients, good in 9, and fair in 8 when assessed at an average of 46 months (range, 19-94 months) postoperatively using the MEPI, which averaged 81.3 (range 65-100). The poorer results occurred in patients with severe injuries associated with posterior comminution of the humerus and who required more extensive reconstructive procedures. All pain scores improved significantly and activities of daily living were restored in all groups, All returned to employment within 6 months, but 6 (3 type 2 and 3 type 3) had altered their roles from manual to administrative work. CONCLUSION: This series reflects the challenges in reconstructing precisely this cartilage-covered sphere, especially when there are multiple fragments. Modern techniques of fracture stabilization that concentrate on restoring a circular structure may require a different approach and engineering solutions. LEVEL OF EVIDENCE: Level 4; Case series, treatment study.