Current intensity‐ and polarity‐specific online and aftereffects of transcranial direct current stimulation: An fMRI study

Transcranial direct current stimulation (tDCS) induces polarity‐ and dose‐dependent neuroplastic aftereffects on cortical excitability and cortical activity, as demonstrated by transcranial magnetic stimulation (TMS) and functional imaging (fMRI) studies. However, lacking systematic comparative studies between stimulation‐induced changes in cortical excitability obtained from TMS, and cortical neurovascular activity obtained from fMRI, prevent the extrapolation of respective physiological and mechanistic bases. We investigated polarity‐ and intensity‐dependent effects of tDCS on cerebral blood flow (CBF) using resting‐state arterial spin labeling (ASL‐MRI), and compared the respective changes to TMS‐induced cortical excitability (amplitudes of motor evoked potentials, MEP) in separate sessions within the same subjects (n = 29). Fifteen minutes of sham, 0.5, 1.0, 1.5, and 2.0‐mA anodal or cathodal tDCS was applied over the left primary motor cortex (M1) in a randomized repeated‐measure design. Time‐course changes were measured before, during and intermittently up to 120‐min after stimulation. ROI analyses indicated linear intensity‐ and polarity‐dependent tDCS after‐effects: all anodal‐M1 intensities increased CBF under the M1 electrode, with 2.0‐mA increasing CBF the greatest (15.3%) compared to sham, while all cathodal‐M1 intensities decreased left M1 CBF from baseline, with 2.0‐mA decreasing the greatest (?9.3%) from sham after 120‐min. The spatial distribution of perfusion changes correlated with the predicted electric field, as simulated with finite element modeling. Moreover, tDCS‐induced excitability changes correlated more strongly with perfusion changes in the left sensorimotor region compared to the targeted hand‐knob region. Our findings reveal lasting tDCS‐induced alterations in cerebral perfusion, which are dose‐dependent with tDCS parameters, but only partially account for excitability changes.     

A comprehensive review on Brigatinib – A wonder drug for targeted cancer therapy in non-small cell lung cancer

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90?mg of brigatinib for 7?days and then 180?mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.     

Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients’ abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P?=?.01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE⁺) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n?=?21). For patients who underwent HSCT with GdE⁺ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n?=?27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE⁺ status is a strong predictor of disease progression in untreated patients.? This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.     

A Longitudinal Survey for Genome-based Identification of SARS-CoV-2 in Sewage Water in Selected Lockdown Areas of Lahore City,Pakistan: A Potential Approach for Future Smart Lockdown Strategy

In 2019, the newly emerged SARS-CoV-2 virus caused pneumonia-like illness. The disease rapidly spread globally, leading to a worldwide outbreak referred to as the COVID-19 pandemic. The affected patients show symptoms of fever, dry cough, respiratory distress, myalgia, and gastrointestinal disturbance. As of April 5, 2021, 132,083,022 people worldwide were affected by COVID-19, while 2,868,454 people died due to the disease[1]. SARS-CoV-2-positive patients may remain asymptomatic or start showing symptoms in 2?14 days after exposure to the virus[2]. The viral infection can be diagnosed from nasopharyngeal, throat, alveolar lavage, lacrimal, blood, and stool samples. The patient starts shedding the virus in stool regardless of being symptomatic or asymptomatic, which makes sewage-based detection of the virus to be more beneficial in the early infection stage.     

Treatment of renal stones with flexible ureteroscopy in preschool age children

The aim of the study is to evaluate the efficacy and safety of retrograde intrarenal surgery (RIRS) to treat renal stones in preschool age (<7 years) children. From September 2005 to May 2013, a total of 65 children (31 boys and 34 girls) with 72 renal stones were treated using RIRS. Patients were considered stone-free when the absence of residual fragments was observed on imaging studies. In the presence of residual calculi >4 mm, a second-stage RIRS was performed. The pre-operative, operative and post-operative data of the patients were retrospectively analyzed. A total of 65 patients with a mean age of 4.31 ± 1.99 years (6 months–7 years) were included in the present study. The mean stone size was 14.66 ± 6.12 mm (7–30 mm). The mean operative time was 46.47 ± 18.27 min. In 5 (7.69 %) patients, the initial procedure failed to reach the renal collecting system and ended with the insertion of a pigtail stent. The stone-free rates were 83.07 and 92.3 % after the first and second procedures, respectively. Complications were observed in 18 (27.7 %) patients and classified according to the Clavien system. Post-operative hematuria (Clavien I) occurred in 6 (9.2 %) patients, post-operative urinary tract infection with fever (Clavien II) was observed in 10 (15.4 %) patients, and ureteral wall injury (Clavien III) was noted in 2 (3 %) patients. RIRS is an effective and safe procedure that can be used to manage renal stones in preschool age children.