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Objective: The incidence of stroke is greater in patients with end-stage renal disease (ESRD) as compared to the general population. It is thought that there may be a few extra risk factors in ESRD patients suffering from stroke as compared to ESRD patients without stroke. This study aims to better understand the risk factors for stroke that are unique to patients with ESRD. Methods: In order to find out the different causative factors influencing the production of ischemic stroke (IS) in patients with ESRD, we carried out this retrospective study at the DHQ hospital in Faisalabad. In this study total of sixty patients were recruited and further divided into two groups. The first group consisted of 30 patients with ESRD with a history of ischemic stroke, while 30 patients with stroke-free dialysis were selected as the age and gender control group. Patients with and without ischemic stroke were compared in terms of demographic characteristics, stroke risk factors, and lab results. Results: Patients with acute ischemic stroke had an average age of 56.70 ± 8.87 years with 52% male whereas the non-ischemic stroke group had an average age of 58.9 ± 9.20 years. Small vascular obstruction was found to be the most common subtype of IS (42%), followed by atherosclerosis of large vessels (28%). Compared with patients who did not have a stroke, patients who had a stroke had significantly higher rates of hypertension (HTN), higher systolic (SBP) and diastolic blood pressure (DBP) at admission. The group with a stroke had significantly lower total cholesterol and LDL cholesterol. Lower levels of low-density lipoprotein (LDL) and higher systolic blood pressure were found to be the independent risk factor for an ischemic stroke in a multivariate analysis (OR=1.025, 95% CI p=0.045 and OR=1.458, 95% CI, P=0.03 respectively). Conclusion: According to the findings of our study, ESRD patients with hypertension and diabetes have a higher chance of ischemic stroke and the lower LDL levels and higher systolic blood pressure were the independent predictors of ischemic stroke. Keywords: Hemodialysis, Ischemic stroke, risk factors, Hypertension, end stage renal disease

PURPOSE Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis. PATIENTS AND METHODS Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. RESULTS Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), including 20.0% complete responses (n=18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5-not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n=164), the most common treatment-emergent adverse events (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE. CONCLUSION Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.

Purpose:Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.Experimental Design:To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].Results:We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.Conclusions:For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501

Supplemental Figure 2: Progression free survival of patients without prior BTKi exposure who had progressed on venetoclax and were then treated with BTKi.

Supplemental Figure 1: Overall survival of entire cohort from initiation of venetoclax.

Clinical outcomes in chronic lymphocytic leukemia (CLL) have improved with targeted therapy, including Bruton tyrosine kinase inhibitors such as acalabrutinib. A semi-Markov model with three health states (progression-free, progressed disease, and death) estimated cost per quality-adjusted life-year (QALY) gained for acalabrutinib ± obinutuzumab vs chlorambucil + obinutuzumab in treatment-naive CLL (based on ELEVATE-TN). The model used direct costs and resource utilization from the US Medicare perspective and utility values sourced from literature. Sensitivity analyses tested the robustness of the model. Over a 30-year lifetime horizon, the model base case analysis suggested that acalabrutinib monotherapy had an incremental cost of $206,329 and 2.52 QALYs gained versus chlorambucil + obinutuzumab, resulting in an incremental cost-effectiveness ratio (ICER) of $81,960/QALY. Acalabrutinib + obinutuzumab had an incremental cost of $423,747 and 2.79 QALYs gained (ICER: $152,153/QALY). Probabilistic sensitivity analysis showed the probability of acalabrutinib monotherapy being cost-effective as 59% to 73% at a $100,000-to-150,000/QALY willingness-to-pay threshold; the probability of acalabrutinib + obinutuzumab being cost-effective ranged from 34% to 51%. Although the analysis is limited by uncertainty in postprogression survival outcomes, acalabrutinib monotherapy is likely cost-effective vs chlorambucil + obinutuzumab in treatment-naive CLL in the US Medicare setting.

Objective: To compare the mean magnesium level among diabetic and non-diabetic patients presenting with myocardial infarction in a tertiary care hospital. Study Design: Descriptive study Place and Duration: Conducted at Emergency department, Punjab Institute of Cardiology, Lahore during the period from 5th June 2018 to 4th December 2018. Methodology: The non-probability purposive sampling technique was used in this study. Informed consent was obtained from all patients and study protocol was explained. Under aseptic conditions, venous blood samples were obtained from cases at the time of presentation in emergency department. Samples were sent to laboratory of hospital to assess magnesium level. Serum magnesium level was measured by using standard chemical analyzer. Reports were read to note serum magnesium level (as per operational definition). Data was collected by the researcher himself. Both groups were compared using independent sample t test to compare mean serum magnesium level in both groups. A p value

Background: Cervicogenic headache is a type of headache characterized by chronic hemi cranial pain referred to the head from either the cervical spine or soft tissues within the neck. The main symptoms of cervicogenic headaches include pain originating in the neck that can travel to the head or face, headaches that get worse with neck movement, and limited ability to move the neck. Aims and Objectives: This study focused to find out the prevalence of cervicogenic headache among young adults using computers with more than 3 hours of screen time. Material and Methodology: This was a cross-sectional study in which 189 freelancers and entrepreneurs were selected through convenient sampling from private computer institutes of Faisalabad after meeting inclusion exclusion criteria. After sample selection, data was collected through a questionnaire based on Cervicogenic Headache International Study Group (CGHISG) diagnostic criteria. Result: The results of this study showed that cervicogenic headache was prevalent among digital freelancers and entrepreneurs. Data was analyzed by SPSS version 16. Cervicogenic Headache was labeled in 122 (64.5%) people using computer at work or at home for more than 3 hours screen time daily. there was the significant association between cervicogenic headache and working ergonomics of digital freelancers and entrepreneurs with P value less than 0.05. Conclusion: Long working hours in front of a screen could expose freelancers and entrepreneurs to headache and neck pain. There is a considerable prevalence of cervicogenic headache among digital freelancers and entrepreneurs. The greatest cause of cervicogenic headache is a bad posture. Keywords: Cervicogenic headache, Posture, Secondary headaches. Neck pain

Objective: To determine the emerging antibiotic resistance pattern of adult patients of MDR UTI cases caused by E.Coli. Study Design: Retrospective Data. Setting: Departments of Medicine and Obstetrics & Gynecology, Madinah Teaching Hospital / University Medical and Dental College, Faisalabad. Period: August 2016 to Sep 2018. Material & Methods: This retrospective study included 187 patients meeting the operational definition of multi-drug resistance cases of urinary tract infection caused by E. coli. All cases either male or female of age above 15 years with positive reports of urine culture and sensitivity for E.coli were included in the study. Along with the demographic variables urine WBC’s, results of urine culture and sensitivity were noted. Antibiotic sensitivity pattern of all the E.coli resistant UTI cases was analyzed. After identification of the microbe, antimicrobial sensitivity was accessed using Kirby–Bauer disc diffusion method on the Mueller–Hinton agar. The antimicrobial susceptibility test was performed against E. coli strains by using the following antibiotics: Piperacilin, Amoxicilin-Calvulanic, Pipmedic Acid, Cefipime, Ceftrixone, Cefuroxime, Cefoperazone-sulbactam, Ceftazidime, Cephradine, Ciprofloxacin, Ofloxacin, Levofloxacin, ofloxacin, Nitrofurantoin, Amikacin, Tombramycin, Gentamicin, Linezolid, Doxycycline, Sulphamethoxazole, Imipenem, Meropenem, Aztreonam in order to obtain an antibiogram. Results: In our data, 66.8% (n=125) were MDR UTI, and more than half of these cases were 63.2% (n=79) were females. Among the total 187 cases, 97.3% patients were resistant to most of the beta-lactam antibiotics, 95.7% were resistant to most of the quinolones and 68.4% were resistant to most of the aminoglycosides. Conclusion: This increasing antibiotic resistance is very alarming and steps should be taken to reduce the misuse of antibiotics. Studies should be done to control the risk factors leading to E. coli UTI. By following proper pharmacological guidelines, principles to use antibiotics and manage outpatient cases of UTIs, the incidence of MDR UTI can be controlled.

With the advent of targeted therapies for chronic lymphocytic leukemia (CLL), treatment choice has expanded and patients are living longer. Careful consideration is needed regarding treatment duration and sequence, how best to meet patients' needs, balancing toxicities while improving long-term survival and maximizing depth of response. This review addresses these considerations and discusses current targeted treatment dilemmas. Targeted therapies have dramatically transformed the CLL treatment landscape. Two treatment paradigms have emerged using B-cell lymphoma 2 inhibitors (BCL2i) and Bruton's tyrosine kinase (BTK): (i) fixed duration and (ii) continuous treatment. The BCL2i venetoclax can attain deep remissions with a fixed-duration approach, resulting in high rates of undetectable minimal residual disease (uMRD) in treatment-naïve and relapsed/refractory (R/R) patients with CLL. BTKis such as ibrutinib and acalabrutinib achieve high objective response rates and long-term disease control, although they rarely attain complete response or uMRD status as monotherapy. Numerous studies are evaluating the clinical utility of BTKi and BCL2i as combination therapies, where deep remissions have been found to occur. MRD status may also be a useful marker for deciding when to stop continuous therapy, and randomized trials on MRD-guided treatment strategies are currently ongoing. The current treatment choice between continuous or fixed-duration therapy should be based on comorbidities, risks, preferences, and treatment goals, whilst areas of emerging clinical interest include the potential utility of BTKi-BCL2i combination therapies, as well as an MRD-guided treatment strategies in the future.

Superalloys are vastly used in the aerospace industry due to their alluring properties such as maintaining their strength at high-temperature applications. Nevertheless, manufacturing these raw materials to the desired geometrical shapes is one of the main challenges of the subtractive manufacturing industry and they are categorized as hard-to-machine materials. Several approaches such as high-speed machining (HSM), cryogenic cooling, minimum quantity lubrication (MQL), and heat-assisted machining (HAM) are introduced to tackle this matter. HAM is a technique that introduces external heat sources to the workpiece (pre-heating or real-time heating methods) to increase the ductility of the superalloy and therefore reduce the yield and shear strength of the workpiece. By this means, the machining parameters demonstrate an improvement compared to conventional machining. This review article focuses on the research approaches conducted to evaluate the effect of the various heat source applications (gas flame, induction, laser, and plasma) on the material properties and the machinability of the superalloys. Additionally, the heating methodology and heat assistance impact on cutting parameters (forces, tool life, surface integrity, and chip morphology) are outlined. Finally, a comparison of the heat source efficiency and the economics of the various heat applications is performed.

Objective: The objective of the study was to: determine the diagnostic accuracy of AST to platelet ratio index in detecting significant fibrosis in chronic hepatitis C patients by using histopathology as gold standard. Study Design: Cross Sectional study. Settings: Department of Medicine, DHQ Hospital, Faisalabad. Period: 1st Oct 2017 to March 2018. Results: In this study, out of 158 cases, 48.73%(n=77) were between 25-40 years while 51.27%(n=81) were between 41-60 years, mean+SD was calculated as 40.94+9.10 years, 55.06%(n=87) were male and 44.94%(n=71) were females, mean AST and platelet count was calculated as 1.68+0.54 and 191.0+43.75, frequency of significant fibroids in chronic hepatitis C patients by using histopathology as gold standard reveals as 53.16%(n=84) while 46.84%(n=74) had no findings of this morbidity. The diagnostic accuracy of AST to platelet ratio index in detecting significant fibrosis in chronic hepatitis C patients by using histopathology as gold standard was recorded which shows 51.27%(n=81) as true positive, 2.53%(n=4) false positive, 1.89%(n=3) false negative and 44.31%(n=70) were recorded as true negative, sensitivity, specificity, positive predictive value, negative predictive value and accuracy rate was computed as 96.43%, 94.59%, 95.29%, 95.89% and 95.57% respectively. Conclusion: The results of the study reveal that diagnostic accuracy of AST to platelet ratio for detection of significant fibrosis in chronic Hepatitis C patients was satisfactory and it may be used for the avoidance of invasive liver biopsy to initiate the antiviral therapy in these patients.

The GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In chronic lymphocytic leukaemia (CLL) (GALACTIC) was a seamless phase II/III trial designed to test whether consolidation with obinutuzumab is safe and eradicates minimal residual disease (MRD) and, subsequently, whether this leads to prolonged progression-free survival (PFS) in patients with CLL who have recently responded to chemo-immunotherapy. Patients with a response 3-24 months after chemotherapy were assessed for MRD. MRD-positive patients were randomised to receive consolidation therapy with obinutuzumab or no consolidation. The trial closed after the phase II part due to slow recruitment. In all, 48 patients enrolled of whom 19 were MRD negative and were monitored. Of the 29 MRD-positive patients, 14 were randomised to receive consolidation and 15 to no consolidation. At 6 months after randomisation, 10 and 13 consolidated patients achieved MRD negativity by flow cytometry (sensitivity 10

Background: Richter transformation (RT) is an aggressive diffuse large B-cell lymphoma that can occur in 10% of patients with chronic lymphocytic leukemia (CLL). RT has no approved therapies, poor prognosis, and an estimated median overall survival (OS) of 3-11 months. Pirtobrutinib is a well-tolerated highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) with favorable oral pharmacology and promising efficacy in patients with poor-prognosis B-cell malignancies following prior covalent BTKi therapy. We now report on RT patients from BRUIN. Methods: Patients previously treated for B-cell malignancies were eligible for pirtobrutinib monotherapy in dose escalation/expansion within the phase 1/2 BRUIN study. Key endpoints: investigator-assessed overall response rate (ORR) and duration of response (DoR) per Lugano 2014 criteria, and safety. The response-evaluable cohort consisted of patients with RT who completed either first response assessment or discontinued therapy. The safety cohort consisted of patients who received ≥1 dose of pirtobrutinib monotherapy (n=725). Data cut was 31 January 2022. Results: Of 57 RT patients (median age: 67 years), 91% (n=52) received at least 1 prior RT-directed therapy. Median lines of prior RT therapy were 2: (anti-CD20 antibody [86%, n=49], chemotherapy [79%, n=45], BCL-2 inhibitor [35%, n=20], BTKi [28%, n=16], PI3K inhibitor [12%, n=7], CAR-T [9%, n=5], immunomodulator [5%, n=3], stem cell transplant [4%, n=2], other systemic therapy [33%, n=19]) and median lines of prior CLL were 2: (BTKi [60%, n=34], anti-CD20 antibody [60%, n=34], chemotherapy [47%, n=27], BCL-2 inhibitor [42%, n=24], immunomodulator [9%, n=5], PI3K inhibitor [7%, n=4], stem cell transplant [7%, n=4], CAR-T [2%, n=1], other systemic therapy [11%, n=6]). ORR for patients within phase 2 (n=56, 200mg once/day starting dose) was 54% (95% CI, 39-68): 5 complete responses, 22 partial responses. Median DoR was 8.6 months (95% CI, 1.9-NE, 63% censored) and median OS was 13.1 months (95% CI, 7.1-NE) at a median follow up time of 5.5 months and 9.7 months respectively. Six patients electively discontinued pirtobrutinib to pursue curative-intent therapy (allogeneic transplant, n=6, 3.8 months median time-on-therapy). The most frequent TEAEs were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). Of Grade≥3 TEAEs, neutropenia (20%, n=143) was the most frequent and hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were of low grade. Fifteen (2%) patients discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib demonstrated promising preliminary efficacy and was well tolerated for patients who received prior RT-directed chemoimmunotherapy and covalent BTKi. Presented:ASH2022. Citation Format: Joanna Rhodes, David Lewis, Paolo Ghia, Nirav N. Shah, Catherine C. Coombs, Chan Y. Cheah, Jennifer Woyach, Nicole Lamanna, Marc S. Hoffmann, Shuo Ma, Toby A. Eyre, Talha Munir, Manish R. Patel, Alvaro J. Alencar, Constantine S. Tam, John F. Seymour, Wojciech Jurczak, Ewa Lech-Maranda, Lindsey E. Roeker, Philip A. Thompson, Paolo B. Abada, Chunxiao Wang, Binoj Nair, Hui Liu, Donald E. Tsai, Anthony R. Mato, William G. Wierda. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT167.

Objective: To assess the diagnostic accuracy of rapid diagnostic kits test for diagnosis of malaria taking microscopy as gold standard Methodology: A total of 375 cases with age range 18-65 years of either gender as suspected for malaria were included in the study. We excluded all those cases already taking anti-malarial drugs. The study was conducted at Chughtais Lahore Lab, Lahore. Required blood sample were obtained following aseptic measures. Malaria RDT SD Bioline Malaria Antigen Pf/Pan (Catalogue No. 05FK60, Standard Diagnostics Inc, Hagal-Dong, Korea, from now on referred as “SD RDT”) was used. Patients were labeled as positive or negative on the basis of reports from hematology department assessed by microscopy and patients were labeled as positive or negative Results: The mean age of the patients was 41.84±13.44 years, male to female ratio of the patients was 1.01:1. The sensitivity, specificity, and diagnostic accuracy of the RDT for diagnosing malaria was 96.79%, 96.28% and 96.53% respectively taking microscopy as gold standard Conclusion: Rapid diagnostic kits is very useful reliable test with high diagnostic accuracy for diagnosis of malaria taking microscopy as gold standard Keywords: Microscopy, Rapid Diagnostic kits, Malaria