Vagus nerve stimulation for cardiovascular diseases: Is there light at the end of the tunnel?

Autonomic dysfunction and chronic inflammation contribute to the pathogenesis and progression of several cardiovascular diseases (CVD), such as heart failure with preserved ejection fraction, atherosclerotic CVD, pulmonary arterial hypertension, and atrial fibrillation. The vagus nerve provides parasympathetic innervation to the heart, vessels, and lungs, and is also implicated in the neural control of inflammation through a neuroimmune pathway involving the spleen. Stimulation of the vagus nerve (VNS) can in principle restore autonomic balance and suppress inflammation, with potential therapeutic benefits in these diseases. Although VNS ameliorated CVD in several animal models, early human studies have demonstrated variable efficacy. The purpose of this review is to discuss the rationale behind the use of VNS in the treatment of CVD, to critically review animal and human studies of VNS in CVD, and to propose possible means to overcome the challenges in the clinical translation of VNS in CVD.

A deviant anterior portal vein in the hepatoduodenal ligament with aberrant origin of hepatic arteries directly from the celiac trunk: A case report of two patients underwent pylorus preserving pancreatoduodenectomy (PPPD).

INTRODUCTION: The portal vein (PV) originates behind the neck of the pancreas, where it is formed classically by the union of the superior mesenteric vein (SMV) and the splenic vein (SV) [1]. It courses upwards towards the liver in the free margin of the lesser omentum, the hepatoduodenal ligament, along with other structures of the portal triad, i.e. proper hepatic artery (PHA) and common bile duct (CBD) anterior to it [1]. The PV is found posterior to the PHA and CBD. The abdominal aorta perfuses abdominal viscera via three ventral branches celiac trunk (CA), superior mesenteric artery (SMA), and inferior mesenteric artery (IMA). The celiac trunk supplies the derivates of the foregut and is divided into the left gastric artery (LGA), splenic artery (SA), and common hepatic artery (CHA). The CHA, after its origin, is divided into the gastroduodenal artery (GDA) and PHA. After giving off the right gastric artery (RGA), the PHA bifurcates into the right and left hepatic arteries (RHA, LHA) [2]. IMPORTANCE: This case report aims to share the rare variations in the anatomy of hepatoduodenal ligament structures to increase awareness and understanding among fellow surgeons which may reduce complications. CASE PRESENTATION: We are reporting 2 cases in which during pancreaticoduodenectomy Portal vein was present anteriorly in the portal triad and the common hepatic artery was absent; instead, both the right and left hepatic arteries originated directly from the CA posterior to PV. This retro-portal origin of hepatic arteries directly from CA is not reported in Michel's classification of hepatic artery variations [3]. CLINICAL DISCUSSION: The confluence of SMV and SV posterior to the neck of the pancreas forms the PV. The portal vein runs upwards in the free edge of the lesser omentum. Anteriorly it is related to the CBD laterally and CHA anteromedially. Posteriorly it is related to the inferior vena cava (IVC), and PV is separated from IVC by epiploic foramen [4]. The overall reported incidence in the variation of the portal vein anatomy is 25%. Among all the variations seen, the anterior PV with posteriorly bifurcating hepatic artery is present in only 10 % of the cases [5]. There is an increased risk of hepatic artery anatomical variation in the presence of portal vein variants. Michel's classification [6] classified variations in the hepatic artery anatomy. In our cases, the hepatic artery anatomy was standard and was classified as Type 1. The bile duct was normal anatomic (lateral to the PV). Hence our cases are unique in describing isolated variant locations and courses. Detailed information about the anatomy of the portal triad and all possible variants can help reduce the incidence of iatrogenic complications during surgeries like liver transplants and pancreatoduodenectomies. Before the advancement of modern imaging techniques, the variations in the anatomy of the portal triad were clinically irrelevant and considered less significant. However, recent literature supports that variant anatomy of the hepatic portal triad can prolong the time of surgery and increase the risk of iatrogenic complications. The clinical relevance of variable hepatic artery anatomy has immense importance in hepatobiliary surgeries, including liver transplants where the viability of the graft depends on adequate arterial perfusion. In addition to that, in pancreatoduodenectomies, aberrant arterial anatomy with a reteroportal course is associated with an increased number of reconstructions [7] and bilio-enteric anastomosis disruptions since the CBD derives its blood supply from the hepatic arteries. Therefore, the imaging must be carefully interpreted with radiologists' help before surgical planning. As surgeons preoperative imaging is usually seen for the abnormal origin of hepatic arteries and vascular involvement in case of malignancies. "Eyes don't see what mind doesn't know", the anterior portal vein is a rare entity and should be considered while reviewing preoperative imaging for operative planning. In our cases, EUS and CT scans, both were done but we determined resectability on scans and abnormal origin (replaced or accessory arteries) only. Above mentioned findings were noted during surgery but now in every preoperative scan, we try to determine the presence of all possible variations including the reported ones. CONCLUSION: Detailed knowledge about the anatomy of the portal triad and all possible variants can help reduce the incidence of iatrogenic complications during surgeries like liver transplants and pancreatoduodenectomies. It also reduces the time of surgery. A careful review of all possible variations in preoperative scans with appropriate knowledge all anatomical variations helps avoid unpleasant events and hence, reduce morbidity and mortality.

The efficacy of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

Aim: The efficacy of antifibrinolytics in subarachnoid hemorrhage remains unclear due to conflicting evidence from studies. Materials & methods: Online databases were queried to include randomized controlled trials and propensity matched observational studies. We used Review Manager for the statistical analysis, presenting results as odds ratios with 95% CI. Results: The 12 shortlisted studies included 3359 patients, of which 1550 (46%) were in the intervention (tranexamic acid) group and 1809 (54%) in the control group. Antifibrinolytic therapy significantly reduced the risk of rebleeding (OR: 0.55; 95% CI: 0.40-0.75; p = 0.0002) with no significant decrease in poor clinical outcome (OR: 1.02; 95% CI: 0.86-1.20; p = 0.85) and all-cause mortality (OR: 0.92; CI: 0.72-1.17; p = 0.50). Conclusion: In patients with subarachnoid hemorrhage, antifibrinolytics reduce the risk of rebleeding without significantly affecting mortality or clinical outcomes.

Acoustic monitoring of an aircraft auxiliary power unit.

In this paper, the development and implementation of a novel approach for fault detection of an aircraft auxiliary power unit (APU) has been demonstrated. The developed approach aims to target the proactive identification of faults, in order to streamline the required maintenance and maximize the aircraft's operational availability. The existing techniques rely heavily on the installation of multiple types of intrusive sensors throughout the APU and therefore present a limited potential for deployment on an actual aircraft due to space constraints, accessibility issues as well as associated development and certification requirements. To overcome these challenges, an innovative approach based on non-intrusive sensors i.e., microphones in conjunction with appropriate feature extraction, classification, and regression techniques, has been successfully demonstrated for online fault detection of an APU. The overall approach has been implemented and validated based on the experimental test data acquired from Cranfield University's Boeing 737-400 aircraft, including the quantification of sensor location sensitivities on the efficacy of the acquired models. The findings of the overall analysis suggest that the acoustic-based models can accurately enable near real-time detection of faulty conditions i.e., Inlet Guide Vane malfunction, reduced mass flows through the Load Compressor and Bleed Valve malfunction, using only two microphones installed in the periphery of the APU. This study constitutes an enabling technology for robust, cost-effective, and efficient in-situ monitoring of an aircraft APU and potentially other associated thermal systems i.e., environmental control system, fuel system, and engines.

Functional Outcome Of Bristow-Latarjet Procedure In Post-Traumatic Recurrent Anterior Shoulder Instability.

BACKGROUND: Due to its lack of bony support, the shoulder joint has the broadest range of motion out of all the joints in the body. Instead, one of the joints that dislocate most frequently is the shoulder joint. Multiple pathologic abnormalities, including the traumatic separation of the anterior-inferior capsule-labral complex from the glenoid rim, are caused by repeated anterior glenohumeral dislocation. The objective of the study is to ascertain the Bristow-LATARJET procedure's efficacy in situations of recurrent post-traumatic anterior shoulder instability. METHODS: From 31 January 2020 to 31 July 2020, a descriptive case series was undertaken in the orthopaedic surgery department of the Lahore General Hospital. For this study, 71 patients who met the inclusion and exclusion criteria were recruited, and all interventions were conducted while the patients were lying in a beach chair while under general anaesthesia. The Delto-pectoral incision surgical technique was applied. For 12 weeks, all patients underwent clinical follow-up, and the results were documented. RESULTS: There were 50(70.4%) males and 21(29.6%) females in this study & the mean age of the patients were 34.64±10.73. There were 37(52.1%) patients among them the outcome of treatment (Rowe Scale at 12th week) was excellent, among 21(29.6%) it was good, among 8(11.3%) it was fair and among 5 (7.0%) it was poor. There was a significant association between the outcome of treatment (Rowe scale at 12th week) and age groups (p-value: 0.000). CONCLUSIONS: The Bristow-LATARJET procedure is deemed to be a very productive, safe, and problem-free procedure for curing post-traumatic reoccurring traumatic anterior shoulder instability.

A Case of Intracranial Vertebral Artery Stenosis Treated with Percutaneous Transluminal Angioplasty and Stenting Guided by Brain Oximetry.

Surgical treatment should be considered for patients with severe vertebrobasilar artery (VBA) stenosis or progressive symptoms, but there is currently no clear treatment algorithm. We report a case of symptomatic intracranial vertebral artery stenosis with repeated cerebral infarction treated by percutaneous transluminal angioplasty (PTA) and stenting and monitoring of oxygen saturation by a brain oximeter. The patient was a 76-year-old man referred to our hospital due to infarction in the right cerebellum. Angiography showed 60% stenosis in the right vertebral artery and 90% stenosis in the left vertebral artery with progressive stenosis in the left. The patient was treated with intravenous and oral triple antiplatelet therapy but had dizziness again with new cerebral infarctions in the left cerebellum and right pontine. We shaved the patient's hair up to the superior nuchal line and placed left and right oximeter probes on each cerebellar hemisphere (2 cm lateral and 2 cm caudal from the external occipital protuberance). Under evaluation of blood flow in the posterior circulation with INVOS Cerebral/Somatic Oximeter, PTA and stent placement were performed for left vertebral artery stenosis. Postoperatively, the dizziness disappeared, and the patient was discharged on his own with good outcome. He has not had a recurrent stroke in over 6 years. Although medical treatment is generally considered the first choice for VBA stenosis, recurrent cerebral infarction occurs at a high rate in symptomatic lesions, and the prognosis is poor. In addition, the perioperative complication rate is not low, and there is no established method for evaluating perfusion of posterior circulation. The brain oximeter is already known to be useful in carotid artery (CA) revascularisation. In this report, we were able to perform a minimally invasive evaluation of blood flow in the posterior circulation using the brain oximeter which might be useful for surgical revascularisation not only in CA but also in VBA.

Thiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates.

Peptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as precursors of aza-amino acids, that, upon activation, can be integrated in a peptide sequence to generate azapeptides using conventional peptide synthetic methods. This methodology facilitates peptide editing-replacing targeted amino acid(s) with aza-amino acid(s) within a peptide-to form azapeptides with preferred therapeutic characteristics (extending half-life/bioavailability, while at the same time typically preserving structural features and biological activities). We demonstrate the convenience of this azapeptide synthesis platform in two well-studied peptides with short half-lives: FSSE/P5779, a tetrapeptide inhibitor of HMGB1/MD-2/TLR4 complex formation, and bradykinin, a nine-residue vasoactive peptide. This bench-stable thiocarbazate platform offers a robust and universal approach to optimize peptide-based therapeutics.

Translation and validation of stroke impact scale-16 in Urdu for Pakistan.

Objective: To translate and validate the Urdu version of stroke impact scale-16 for Pakistani society. METHODS: The prospective cohort study was conducted from February 2018 to February 2020 after approval from the ethics review board of The University of Lahore, Lahore, Pakistan, and copmprised patients with mild to moderate stroke who were recruited from five public and two private hospitals of the Punjab province. Established guidelines were followed to translate the Stroke Impact Scale-16. The patients were concurrently evaluated on Barthel Index, Stroke Rehabilitation Assessment of Movement, Modified Rivermead Mobility Index, Modified Rankin Scale, Short Form 36 Health Survey Questionnaire and the Hospital Anxiety and Depression Scale to assess the validity of Stroke Impact Scale-16, and spearmen correlation coefficient was used to determine the correlation among the scales. Analysis of variance was employed to determine the discriminant validity. Intraclass correlation coefficient, weighted kappa, Cronbach's alpha and item-total correlation were calculated to establish the stability and consistency of Stroke Impact Scale-16. Data was analysed using SPSS 25. RESULTS: Of the 90 patients, 50(55.5%) were females and 40(45.5%) were males. The subjects were aged 50-80 years. The correlation of Stroke Impact Scale-16 was strong with the established tools and ranged from 0.78 to 0.91. The discriminant validity was also significant (p<.001) across all Modified Rankin Scale levels. The Intraclass correlation coefficient was 0.94 and Cronbach's alpha was 0.91 for test-retest reliability and internal consistency, respectively. All corrected item-total correlation values exceeded the priori minimum standard (>0.40) and ranged from 0.51 to 0.68. The weighted kappa for item reliability also achieved priori criteria (>0.40) and ranged from 0.53 to 0.88. Conclusion: With slight modifications, the Urdu version of Stroke Impact Scale-16 was found to have satisfactory psychometric properties and can be used in clinical and research settings for stroke survivors in Pakistan.

kHz-frequency electrical stimulation selectively activates small, unmyelinated vagus afferents.

BACKGROUND: Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic activation of C-afferents could be used to mechanistically study and treat diseases of peripheral organs in which vagal reflexes are involved, but it has not been achieved. METHODS: We stimulated the vagus in rats and mice using trains of kHz-frequency stimuli. Stimulation effects were assessed using neuronal c-Fos expression, physiological and nerve fiber responses, optogenetic and computational methods. RESULTS: Intermittent kHz stimulation for 30 min activates specific motor and, preferentially, sensory vagus neurons in the brainstem. At sufficiently high frequencies (>5 kHz) and at intensities within a specific range (7-10 times activation threshold, T, in rats; 15-25 × T in mice), C-afferents are activated, whereas larger, A- and B-fibers, are blocked. This was determined by measuring fiber-specific acute physiological responses to kHz stimulus trains, and by assessing fiber excitability around kHz stimulus trains through compound action potentials evoked by probing pulses. Aspects of selective activation of C-afferents are explained in computational models of nerve fibers by how fiber size and myelin shape the response of sodium channels to kHz-frequency stimuli. CONCLUSION: kHz stimulation is a neuromodulation strategy to robustly and selectively activate vagal C-afferents implicated in physiological homeostasis and disease, over larger vagal fibers.

Threshold adjusted vagus nerve stimulation after asphyxial cardiac arrest results in neuroprotection and improved survival.

BACKGROUND: Vagus nerve stimulation (VNS) has shown therapeutic potential in a variety of different diseases with many ongoing clinical trials. The role of VNS in reducing ischemic injury in the brain requires further evaluation. Cardiac arrest (CA) causes global ischemia and leads to the injury of vital organs, especially the brain. In this study, we investigated the protective effects of customized threshold-adjusted VNS (tVNS) in a rat model of CA and resuscitation. METHODS: Sprague-Dawley rats underwent 12 min asphyxia-CA followed by resuscitation. Rats were assigned to either post-resuscitation tVNS for 2 h or no-tVNS (control). tVNS was applied by electrode placement in the left cervical vagus nerve. To optimize a threshold, we used animal's heart rate and determined a 15-20% drop from baseline levels as the effective and physiological threshold for each animal. The primary endpoint was 72 h survival; secondary endpoints included neurological functional recovery, reduction in brain cellular injury (histopathology), cardiac and renal injury parameters (troponin I and creatinine levels, respectively). RESULTS: In comparison to the control group, tVNS significantly improved 72 h survival and brain functional recovery after 12 minutes of CA. The tVNS group demonstrated significantly reduced numbers of damaged neurons in the CA1 hippocampal region of the brain as compared to the control group. Similarly, the tVNS group showed decreased trend in plasma troponin I and creatinine levels as compared to the control group. CONCLUSIONS: Our findings suggest that using tVNS for 2 h after 12 minutes of CA attenuates ischemia neuronal cell death, heart and kidney damage, and improves 72 h survival with improved neurological recovery.

Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model.

Interfaces between the nervous and immune systems have been shown essential for the coordination and regulation of immune responses. Non-invasive ultrasound stimulation targeted to the spleen has recently been shown capable of activating one such interface, the splenic cholinergic anti-inflammatory pathway (CAP). Over the past decade, CAP and other neuroimmune pathways have been activated using implanted nerve stimulators and tested to prevent cytokine release and inflammation. However, CAP studies have typically been performed in models of severe, systemic (e.g., endotoxemia) or chronic inflammation (e.g., collagen-induced arthritis or DSS-induced colitis). Herein, we examined the effects of activation of the splenic CAP with ultrasound in a model of local bacterial infection by lung instillation of 105 CFU of Streptococcus pneumoniae. We demonstrate a time-dependent effect of CAP activation on the cytokine response assay during infection progression. CAP activation-induced cytokine suppression is absent at intermediate times post-infection (16 hours following inoculation), but present during the early (4 hours) and later phases (48 hours). These results indicate that cytokine inhibition associated with splenic CAP activation is not observed at all timepoints following bacterial infection and highlights the importance of further studying neuroimmune interfaces within the context of different immune system and inflammatory states.

Exploring the Nexus Between E-Business Processes and Organizational Performance: Can Technological Opportunism Play Any Role?

The digitization of business processes has gained much scholarly and practical attention in the recent past. To understand their effectiveness, particularly in connection to organizational performance, the current study developed and tested a comprehensive framework. Through obtaining data from 350 manufacturing businesses, the study investigated using Smart PLS3 and found a significant influence of online procurement, channel management, and service delivery capabilities on organizational performance. Furthermore, the study also found the significant direct and moderating potential of technological opportunism to harness organizational performance. The study concludes that e-business processes serve as crucial resources and capabilities for businesses to achieve their goals and objectives. The study offers contributory implications for theory and practice indicating for strategic investment of e-business processes for businesses aiming to boost their performance.

Strategic Attributes and Organizational Performance: Toward an Understanding of the Mechanism Applied to the Banking Sector.

The study examines and theorizes the importance of strategic attribute constructs (strategic orientation, organizational culture, and organizational internal market orientation) as applied to Pakistan's banking sector by identifying their roles in enhancing organizational performance and the mediating effect of organizational commitment. The current study adopted quantitative research designs and methods to determine structural relationships between the proposed constructs. A total of 10 hypotheses were tested underpinned by the Resource-Based View of the Firm and Social Exchange theories. The strategic attributes studied were significantly and positively related to, and enhance, organizational performance if the banks: (1) focus on strategic positioning, (2) fostering a strong organizational culture, (3) strategize internal marketing practices, and (4) boost organizational commitment. The findings supported the mediating role of organizational commitment between strategic attributes and organizational performance. This study contributes to existing literature and supports prior research while filling in gaps in the literature concerning developing countries.

Strategies for precision vagus neuromodulation.

The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies.

Biosynthetic pathways of triterpenoids and strategies to improve their Biosynthetic Efficiency.

"Triterpenoids" can be considered natural products derived from the cyclization of squalene, yielding 3-deoxytriterpenes (hydrocarbons) or 3-hydroxytriterpenes. Triterpenoids are metabolites of these two classes of triterpenes, produced by the functionalization of their carbon skeleton. They can be categorized into different groups based on their structural formula/design. Triterpenoids are an important group of compounds that are widely used in the fields of pharmacology, food, and industrial biotechnology. However, inadequate synthetic methods and insufficient knowledge of the biosynthesis of triterpenoids, such as their structure, enzymatic activity, and the methods used to produce pure and active triterpenoids, are key problems that limit the production of these active metabolites. Here, we summarize the derivatives, pharmaceutical properties, and biosynthetic pathways of triterpenoids and review the enzymes involved in their biosynthetic pathway. Furthermore, we concluded the screening methods, identified the genes involved in the pathways, and highlighted the appropriate strategies used to enhance their biosynthetic production to facilitate the commercial process of triterpenoids through the synthetic biology method.

Entropy Generation during Head-On Interaction of Premixed Flames with Inert Walls within Turbulent Boundary Layers.

The statistical behaviours of different entropy generation mechanisms in the head-on interaction of turbulent premixed flames with a chemically inert wall within turbulent boundary layers have been analysed using Direct Numerical Simulation data. The entropy generation characteristics in the case of head-on premixed flame interaction with an isothermal wall is compared to that for an adiabatic wall. It has been found that entropy generation due to chemical reaction, thermal diffusion and molecular mixing remain comparable when the flame is away from the wall for both wall boundary conditions. However, the wall boundary condition affects the entropy generation during flame-wall interaction. In the case of isothermal wall, the entropy generation due to chemical reaction vanishes because of flame quenching and the entropy generation due to thermal diffusion becomes the leading entropy generator at the wall. By contrast, the entropy generation due to thermal diffusion and molecular mixing decrease at the adiabatic wall because of the vanishing wall-normal components of the gradients of temperature and species mass/mole fractions. These differences have significant effects on the overall entropy generation rate during flame-wall interaction, which suggest that combustor wall cooling needs to be optimized from the point of view of structural integrity and thermodynamic irreversibility.

Follicular Lymphoma of Breast: A Case Report from Pakistan.

Introduction: Breast lymphoma (BL) is a rare breast tumour and accounts for <1% of all breast malignancies. It is further categorised into primary BL and secondary BL. This manuscript presents a case report of a patient diagnosed with secondary BL. Case Description: A 51-year-old female presented in the one-stop breast clinic with 6-month history of having a static and painless left breast lump. Mass was firm, non-tender and 2 cm in size. It was not adherent to skin or muscle and it was present in the upper outer quadrant of the left breast. Mammo-sonography revealed a circumscribed mass of 17 mm in the outer quadrant of the left breast. There were enlarged ipsilateral lymph nodes. Core biopsy suggested atypical lymphoid infiltrates. She underwent wide local excision of breast and axillary nodal mass. The definitive histological diagnosis revealed non-Hodgkin's follicular lymphoma grade 2/3. Staging computed tomography scan features were suggestive of cervical lymphadenopathy. Hence, staging workup proved this to be a case of secondary BL. Practical Implication: The early diagnosis of BL is highly relevant. Its diagnosis is challenging due to non-specific clinical presentation and imaging features. Commonly FL is diagnosed on excisional biopsy or after wide local breast mass excision. Primary and secondary lymphomas, though rare, should be considered in the differential diagnosis of breast malignancies.

Outcomes of Philadelphia Positive Acute Lymphoblastic Leukemia in Adolescent and Young Adults.

Background Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) accounts for 25% of acute lymphoblastic leukemia cases in the adolescent and young adult (AYA) age subgroup. It is associated with poor outcomes and is considered a standard indication for allogeneic stem cell transplant (Allo-SCT). Improved outcomes have been reported with addition of tyrosine kinase inhibitors (TKIs) to chemotherapy in children and the role of Allo-SCT is now being debated in the first remission. Complete response (CR) at three months is associated with improved survival even without Allo-SCT in first CR. In this study, we have analyzed disease-free survival (DFS), overall survival (OS), and factors affecting survival outcomes of Ph+ ALL in the AYA subgroup, in resource-limited settings treated with chemotherapy and TKIs. Materials and methods This is a retrospective, multicenter cohort study of Ph+ ALL AYA patients, aged 18-40 years, and registered between January 2015 and December 2020. Primary objectives are to calculate disease-free survival (DFS) and overall survival (OS). Secondary objectives are to identify prognostic factors affecting response rates and outcomes. List of cases was obtained from hospital information system (HIS) and data were collected from patient case notes and electronic medical records. Data analysis was done utilizing the SPSS statistical program (Armonk, NY: IBM Corp.). Results Forty-nine patients were identified with Ph+ ALL with a median age of 23 years (range: 18-40 years) and a male-to-female ratio of 2.5:1. None of the patients had central nervous system (CNS) disease. White cell count was >30,000 per mm3 in 26% of patients, while 13% had additional cytogenetic abnormalities. Thirty-three percent patients received adult (hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone {CVAD}) protocols while 67% received pediatric-inspired (Berlin-Frankfurt-Munster {BFM} 2000 or UK-ALL 2003/2011) protocols. TKI therapy was received by 66% of patients during treatment (early: 37%; late: 29%) and 34% did not receive TKIs due to financial constraints. CR after induction was achieved in 69% cases. Induction mortality was 16%. The median DFS for the entire cohort was 27 months (0.93-53.06) and the median OS was 29 months (8.89-49.10). The median OS in Allo-SCT group was not reached vs 8.0±8.8 months (p=0.05) with chemotherapy only. The OS was significantly better in patients with no additional cytogenetic abnormalities, pediatric-inspired chemotherapy protocols, early use of TKIs in induction phase, Allo-SCT, and post-Allo-SCT use of TKIs. Conclusion Addition of TKIs to pediatric-inspired chemotherapy protocols in Ph+ ALL AYA patients and Allo-SCT results in better overall survival. TKI availability remains a significant issue in low-income countries due to significant financial burden on the patients. Allo-SCT continues to be an attractive option, particularly in low-income countries providing an option for cure in Ph+ ALL.

Effects of intensive multiplanar trunk training coupled with dual-task exercises on balance, mobility, and fall risk in patients with stroke: a randomized controlled trial.

OBJECTIVE: We determined whether an exercise regime comprising high-intensity training, multiplanar trunk movements, and dual-task practice could improve trunk control, balance, functional mobility, and reduce fall risk in patients with hemiplegic stroke. METHODS: In this randomized controlled trial, 74 patients (mean age 61.71 years) were randomly assigned to the experimental and comparison groups. Primary outcome was trunk impairment scale (TIS) scores. Secondary outcomes were scores on the Berg balance scale, 10-meter walk test, Timed-up-and-go test, timed-Up-Go-cognitive, and Stroke Impact Scale-16 to measure between-group changes from baseline. We used linear mixed modeling to identify changes over time within and between groups on each scale and whether changes persisted at 6- and 12-month follow-ups. RESULTS: We observed significantly increased mean TIS scores from baseline to 3 months post-treatment (7.74); the increased scores were maintained at 6- and 12-month follow-ups (8.60 and 8.43, respectively). In the experimental group, all secondary outcomes showed significant and clinically meaningful results. Fall risk between groups was significantly reduced at 6 and 12 months. CONCLUSIONS: Intensive multiplanar trunk movements coupled with dual-task practice promoted trunk control, balance, and functional recovery in patients with stroke, reduced fall risk, and improved independent mobility.Trial registration: #IRCT20200127046275N1.