Neutrophil to lymphocyte ratio as a prognostic marker for cardiovascular outcomes in patients with ST-segment elevation myocardial infarction after percutaneous coronary intervention: A systematic review and meta-analysis.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) has been considered a prognostic biomarker of mortality and other major cardiac events. This study investigates NLR's efficacy in predicting in-hospital and long-term outcomes in patients with ST-segment elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). METHODS: Electronic databases (PUBMED, Cochrane CENTRAL, ERIC, Embase, Ovid, and Google Scholar) were searched till June 2022 to identify studies having STEMI patients who underwent PCI. Risk ratios and mean differences (MDs), along with their corresponding 95% confidence intervals (Cis) and standard deviations (SDs), were pooled using a random-effect model. This meta-analysis has been registered on Prospero (ID: CRD42022344072). RESULTS: A total of 35 studies with 28,756 patients were included. Pooled estimates revealed an increased incidence of primary outcomes; in-hospital all-cause mortality (RR = 3.52; 95% CI = 2.93-4.24), long-term all-cause mortality (HR = 1.07; 95% CI = 1.00-1.14), (RR = 3.32; 95% CI = 2.57-4.30); in-hospital cardiovascular mortality (RR = 2.66; 95% CI = 2.04-3.48), long-term cardiovascular mortality (RR = 6.67; 95% CI = 4.06-10.95); in-hospital major adverse cardiovascular events (MACE) (RR = 1.31; 95% CI = 1.17-1.46), long-term MACE (RR = 2.92; 95% CI = 2.16-3.94); length of hospital stay (WMD = 0.60 days; 95% CI = 0.40-0.79) in patients with high NLR compared to those with a low NLR. CONCLUSION: NLR might be a valuable tool for prognostication (in-hospital) and stratification of patients with STEMI who underwent PCI.

Low triiodothyronine (T3) levels predict worse outcomes in autoimmune encephalitis-A meta-analysis of current literature.

INTRODUCTION: An unusual association between thyroid dysfunction and autoimmune encephalitis (AE) was noticed when patients presented with low free triiodothyronine (fT3) levels and antithyroid antibodies. We conducted a meta-analysis to investigate whether thyroid dysfunction, that is, lower fT3 levels are associated with worsening clinical manifestations and prognosis in patients with AE. METHODS: Literature search of five electronic databases was performed till April 5, 2023. Inclusion criteria were as follows: Observational studies reporting patients with all subtypes of AE and assessing thyroid dysfunction categorized as low fT3 and non-low fT3. Primary endpoints included modified Rankin scale (mRS) at admission, abnormal magnetic resonance imaging, length of stay, seizures, and consciousness declination. RESULTS: Comprehensive literature search resulted in 5127 studies. After duplicate removal and full-text screening, six observational studies were included in this analysis. Patients with low fT3 were 2.95 times more likely to experience consciousness declination (p = .0003), had higher mRS at admission (p < .00001), had 3.14 times increased chances of having a tumor (p = .003), were 3.88 times more likely to experience central hypoventilation, and were 2.36 times more likely to have positivity for antithyroid antibodies (p = .009) as compared to patients with non-low fT3. CONCLUSION: The findings of our study suggest that low fT3 levels might be related to a more severe disease state, implying the significance of thyroid hormones in AE pathogenesis. This finding is crucial in not only improving the early diagnosis of severe AE but also in the efficient management of the disease.

Cardiovascular outcomes of emergent vs elective transcatheter aortic valve replacement in severe aortic stenosis: regression matched meta-analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been highly increased as the recommended option for patients with a high surgical risk. This study aims to commit a systematic review and meta-analysis to assess the outcomes in severe aortic stenosis patients following emergency transcatheter aortic valve replacement (emergent TAVR) compared to elective TAVR or eBAV followed by elective TAVR. METHODS: We conducted a systematic literature search of PubMed, Embase, Cochrane CENTRAL, CINAHL, Science Direct, and Google Scholar. We included nine studies in the latest analysis that reported the desired outcomes. Outcomes were classified into primary outcomes: 30-day all-cause mortality and 30-day readmission rate, and secondary outcomes, which were further divided into (a) peri-procedural outcomes, (b) vascular outcomes, and (c) renal outcomes. Statistical analysis was performed using Stata v.17 (College State, TX) software. RESULTS: A total of 44,731 patients with severe aortic stenosis were included (emergent TAVR n = 4502; control n = 40045). 30-day mortality was significantly higher in the emergent TAVR group (OR: 2.62; 95% CI = 1.76-3.92; P < 0.01). Regarding post-procedural outcomes, the length of stay was significantly higher in the emergent TAVR group (Hedges's g: +4.73 days; 95% CI = +3.35 to +6.11; P < 0.01). With respect to vascular outcomes, they were similar in both groups. Regarding renal outcomes, both acute kidney injury (OR: 2.52; 95% CI = 1.59-4.00; P < 0.01) and use of renal replacement therapy (OR: 2.33; 95% CI = 1.87-2.91; P < 0.01) were significantly higher in emergent TAVR group as compared to the control group. CONCLUSION: Our study demonstrated that despite increased 30-day mortality and worse renal outcomes, the post-procedural outcomes were similar in emergent and elective TAVR groups. The increased mortality and worse renal outcomes are likely due to hemodynamic instability in the emergent group. The similarity of post-procedural outcomes is evidence of the safety of TAVR even in emergent settings.

Hump-Nosed Viper Bite-Associated Thrombotic Thrombocytopenic Purpura: A Rare Complication.

Thrombotic thrombocytopenic purpura (TTP) is one of the rarely encountered complications of hump-nosed viper bites, which requires early detection and specific management. Hump-nosed viper bites are well known to affect multiple systems, and it is imperative to identify and manage each complication simultaneously. A 48-year-old patient presented to the hospital following a hump-nosed viper bite, where he subsequently developed local necrosis, acute kidney injury (AKI), and TTP. A diagnosis of TTP was made using the PLASMIC score (which refers to the score's seven components: platelet count; combined hemolysis variable; absence of active cancer; absence of stem-cell or solid organ transplant; mean corpuscular volume (MCV); international normalized ratio (INR); and creatinine) and supporting blood picture findings despite the diagnostic difficulties encountered due to the misleadingly normal automated platelet counts. The patient underwent multiple blood transfusions, 12 cycles of hemodialysis, and two cycles of therapeutic plasma exchange, the latter contributing to a significant improvement in his overall clinical and biochemical markers. In this case presentation, we report a rare case of TTP occurring after a hump-nosed viper bite, with the outcome of the report focusing on the diagnostic difficulties and available therapeutic modalities.

Acute Psychosis Presenting With Dengue Fever Complicated by Dengue Encephalitis.

Dengue is an infection with a wider spectrum of disease manifestations, ranging from simple dengue fever to expanded dengue syndrome. Expanded dengue syndrome encompasses multiorgan involvement, including neurological manifestations such as dengue encephalitis, seizures, encephalopathy, coma, hemiparesis, etc. Herein, we present a case of a 50-year-old female with a background history of well-controlled type 2 diabetes mellitus and hypertension for five years on oral medication. The patient presented with a one-day history of altered levels of consciousness, agitation, and aggressive behavior. Before admission, she had a history of high-grade fever with chills and rigors for three days. Serial investigations were performed, and the diagnosis of dengue encephalitis was made amidst the absence of positive findings for encephalitis in most of the imaging modalities except in electroencephalogram (EEG), making this case unique. Initially, it was presumed to be meningoencephalitis. Hence, the patient was initiated on intravenous acyclovir and cefotaxime. After the definitive diagnosis of dengue encephalitis, the given medication was stopped after seven days of administration, and with supportive management, the patient made a successful recovery within 10 days.

Pyrexia of Unknown Origin Caused by Non-Hodgkin's Lymphoma: A Diagnostic Challenge for Clinicians.

Non-Hodgkin's lymphomas (NHLs) are a group of lymphoproliferative diseases that originate from different cell types, namely B cells, T cells, or natural killer cells. Herein, we report the case of a 69-year-old male patient who presented with a gradual-onset, intermittent, low-grade fever for four months and a right-sided neck lump for two months. On examination, a right-sided enlarged lymph node sized 1 × 1 cm2 was noted, which was mobile, hard in consistency, and non-tender. No other lymphadenopathy was noted in other parts of the body. Imaging and biochemical studies done at the initial stages did not reveal features in favor of any lymphoproliferative disorders, and the two lymph node biopsies done two weeks apart were inconclusive as well. An extended panel of investigations was done in view of excluding other infective and inflammatory pathologies, which was negative, making the patient undiagnosed of any disease state despite being symptomatic for four months. Finally, the third lymph node biopsy tested positive, which paved the way for the diagnosis of NHL. This diagnosis underlines the importance of this case. Following the diagnosis, the patient was initiated on a few chemotherapeutic agents, after which a mild symptomatic improvement was achieved.

Dengue Cases Presenting to the Emergency Department of a Tertiary Care Hospital in Late 2021: A Cross-Sectional Study in Karachi.

Objectives: Dengue Fever (DF) is an arboviral disease caused by the Dengue virus (DENV). This study aims to assess the association of dengue prevalence with patients' residential areas and hematological laboratory findings (Total platelet count, immunoglobulins, and dengue antigens) during COVID-19 pandemic. Methods: A retrospective study was conducted at the Emergency department of Jinnah Postgraduate Medical Center, Karachi from October to December 2021. All the patients irrespective of their ages presenting to the ED with either of the following complaints: fever; GIT problems; vomiting; body ache; bleeding were included in our study. Results: Our study comprised 189 patients in total in which the females (n = 172) outnumbered the males (n = 17). Out of all, 84.7% of the patients were febrile having a low-grade fever on average. Korangi district had the most dengue cases, while Keamari had the fewest. There was no significant association reported between mean platelet count, mean TLC, and mean hemoglobin levels with dengue positivity. Conclusion: There is a concerning rise in DF cases in Karachi, particularly in the Korangi district. Despite the COVID-19 pandemic, DF demands urgent attention.

A Rare Presentation of Wegener's Granulomatosis With Perinuclear Antineutrophil Cytoplasmic Antibody Positivity.

Wegener's granulomatosis (WG), also termed granulomatosis with polyangiitis, is a vasculitic condition with numerous systemic manifestations. It is mainly a pauci-immune vasculitis which involves small and medium-sized vessels. Herein, we report a case of a 72-year-old female with a background history of type 2 diabetes mellitus and hypertension. She presented to the hospital with recurrent nasal congestion, headache, and intermittent facial pain for two months' duration. At the initial presentation, she was diagnosed with pansinusitis, for which she was treated with antibiotics and was discharged. Two weeks later, she presented with progressively worsening bilateral lower limb numbness and weakness for one week's duration. With serial investigations, she was diagnosed with WG and was treated with intravenous methylprednisolone along with cyclophosphamide, after which she made a significant improvement in her clinical status.

Transcatheter Edge-to-Edge Repair for Tricuspid Regurgitation-A Systematic Review and Meta-Analysis.

Transcatheter edge-to-edge repair (TEER) has emerged as a widely accepted procedure for tricuspid regurgitation (TR) as gauged by echocardiographic parameters and clinical outcomes. Our study aims to assess TR severity and other echocardiographic outcomes in patients undergoing TEER with TriClip, MitraClip, and PASCAL devices. A literature search of 5 databases was performed until 1st June 2023. Randomized controlled trials (RCTs) or observational studies with moderate to severe (grade III-V) TR patients undergoing isolated TEER were considered eligible. Echocardiographic, and quality of life determining outcomes such as improvement in TR severity grade ≥3, New York Heart Association (NYHA) class ≥3, procedural success, 6-minute walking distance (6MWD), and adverse outcomes were analyzed. Grade assessment was performed and studies were assessed for risk of bias and publication bias. We included 15 studies (14 observational and 1 RCT) in our paper. Analysis revealed a substantial reduction in TR volume (P < 0.00001), TR grading (P < 0.00001), tricuspid annular diameter (P < 0.00001), proximal isovelocity surface area radius (P < 0.00001), effective regurgitant orifice area (P < 0.00001), and improvement in NYHA class (P < 0.00001) at 30 days from baseline, postprocedurally. A significant increase in 6MWD at 1 year (P = 0.001) was also recorded. No significant differences in left ventricular ejection fraction (P = 0.87), fractional area change (P = 0.37), or tricuspid annular plane systolic excursion (P = 0.76) were observed. TEER procedural success was 97%. TEER produced a significant reduction in TR grade and volume, NYHA class, 6MWD, and showed prominent procedural success. Large scale RCTs comparing the TEER devices are needed to strengthen the present findings.

Odds of HIV among incarcerated drug users: a systematic review and meta-analysis of Asian countries.

Background: HIV makes up a large portion of infectious diseases globally. People injecting drugs in prisons are at high risk for contracting HIV infection. Prisons house ~10.2 million people globally, making them a high-risk setting for HIV transmission. This systematic review summarizes the available data on the odds of developing HIV infection among imprisoned people who inject drugs (PWIDs) in Asian regions. Methods: The authors electronically assessed published studies from January, 2000 to December, 2022, including studies that investigated the odds of HIV in imprisoned PWIDs. We extensively searched PubMed, ERIC, and Cochrane Central and Google Scholar with no constraints in language or time. All the observational studies evaluating the chances of HIV in Asian prisoners with an exposure group of PWIDs and a control group of non-injecting-drug users were included in our analysis. Results: The databases search yielded 254 potential studies, 10 observational studies of which having a total of 17 333 participants were included. A low or moderate risk of bias was reported in all the studies except one case-control. The pooled analysis showed a significant association between PWIDs and the chances of contracting HIV infection (Odds ratio=6.40; 95% CI=3.89-10.52; P<0.00001; I2=53%). Conclusion: This study found a vital correlation between injecting-drug usage during imprisonment and HIV transmission speed. The results of this meta-analysis support the need to prevent HIV and conducting treatment programs in high-risk settings like prisons.

Workplace violence against healthcare workers in Pakistan; call for action, if not now, then when? A systematic review.

BACKGROUND: Workplace violence (WPV) is a global problem that affects healthcare workers' physical and mental health and impairs work performance. Pakistan's healthcare system is not immune to WPV, which the World Health Organization recognises as an occupational hazard. OBJECTIVES: The primary objective of this systematic review is to determine the prevalence of physical, verbal, or other forms of WPV in healthcare workers in Pakistan. Secondary objectives include identifying the associated risk factors and perpetrators of WPV. METHODS: A systematic review of six electronic databases was conducted through August 2022. Studies were included if they met the following criteria: 1) healthcare workers (HCWs), including physicians, nurses, and paramedic staff working in the private or public sector of Pakistan; 2) exposure to physical, verbal, or any type of violence. Data were extracted and analysed for the prevalence of WPV, types of violence, associated risk factors, and perpetrators of violence. RESULTS: Twenty-four studies including 16,070 HCWs were included in this review. Verbal violence was the most common form of violence levied, with its highest prevalence (100%) reported in Islamabad and lowest verbal violence prevalence (25%) in Karachi. Verbal abuse was preponderant against female HCWs, while physical abuse was directed more towards males. The most common perpetrators were patient attendants, followed by the patients. CONCLUSION: Our review determines a 25-100% prevalence of WPV against HCWs in Pakistani medical setups. This occupational hazard needs the attention of relevant authorities in the country to put protective enforcement policies in place. Large-scale surveys should be conducted to better gauge the current plight of HCWs in the nation.

Role of soluble urokinase type plasminogen activator receptor (suPAR) in predicting mortality, readmission, length of stay and discharge in emergency patients: A systematic review and meta analysis.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker that is used to predict mortality, readmission, early discharge, and LOS, thus, serves as a useful tool for ED physicians. Our study aims to analyze the efficacy of suPAR in predicting these prognostic markers in ED. METHODS: We performed a comprehensive search on 6 databases from the inception to 30th November 2022, to select the following eligibility criteria; a) observation or triage trial studies investigating the role of suPAR levels in predicting: 30 day and 90-day mortality, 30-day readmission, early discharge (within 24hr), and LOS in patients coming to AMU. RESULTS: A total of 13 studies were included, with a population size of 35,178, of which 52.9% were female with a mean age of 62.93 years. Increased risk of 30-day mortality (RR = 10.52; 95% CI = 4.82-22.95; I2 = 38%; P < .00001), and risk of 90-day mortality (RR = 5.76; 95% CI = 3.35-9.91; I2 = 36%; P < .00001) was observed in high suPAR patients. However, a slightly increased risk was observed for 30-day readmission (RR = 1.50; 95% CI = 1.16-1.94; I2 = 54%; P = .002). More people were discharged within 24hr in the low suPAR level group compared to high suPAR group (RR = 0.46; 95% CI = 0.40-0.53; I2 = 41%; P < .00001). LOS was thrice as long in high suPAR level patients than in patients with low suPAR (WMD = 3.20; 95% CI = 1.84-4.56; I2 = 99%; P < .00001). CONCLUSION: suPAR is proven to be a significant marker in predicting 30-day and 90-day mortality in ED patients.

A Rare Presentation of Hypereosinophilic Syndrome With Loffler's Endomyocarditis, Encephalopathy, and Multiple Thromboembolic Strokes.

Idiopathic hypereosinophilic syndrome is a disorder with a high eosinophilic count for which no identifiable cause is evident. Herein we report a case of a 47-year-old male with a background history of hypereosinophilia, who presented with sudden onset altered level of consciousness and drowsiness for 1-day duration associated with a gradual onset progressive memory loss for 1-month duration. Based on clinical, biochemical, and imaging studies, a diagnosis of Loffler's endomyocarditis was made for which he was treated with albendazole with diethylcarbamazine along with high-dose steroids. He made a successful recovery after 2 months of treatment.

Perioperative selenium administration in cardiac surgery patients, a way out to reduce post surgical adversities? A meta analysis.

Introduction: The oxidative damage suffered in cardiac surgery is associated with declining trace elements which lead to the development of multi organ dysfunction (MOD), acute kidney injury (AKI), or increased length of hospital stay (LOS). Recent evidence shows the cardioprotective role of the trace element selenium as it mitigates worsening outcomes post cardiac surgery. Hence, this meta analysis aims to investigate the role of selenium in lowering cardiac surgery related adverse outcomes. Methods: Literature search of five electronic databases was performed from the inception of the paper till 29th July, 2023. Eligibility criteria included; (a) randomized clinical trials with Adult patients (≥18 years) undergoing cardiac surgery (b) intervention with selenium pre or/and postoperatively; (c) a control group of a placebo, normal saline, or no selenium. Outcomes of interest include postoperative mortality, LOS in the hospital and Intensive Care Unit (ICU), AKI, troponin I, and Creatinine Kinase-MB (CK-MB). The Cochrane bias assessment tool was used to evaluate the risk of bias. Outcomes were pooled with the Mantel-Haenszel Random-effects model using Review Manager. Results: Seven RCTs with 2,521 patients and 65% of males were included in this paper. No noticable differences were observed between selenium and control groups in terms of postoperative AKI, mortality, LOS in hospital and ICU, troponin I, and CK-MB levels. All studies had a low risk of bias on quality assessment. Discussion: Our meta analysis demonstrated no discernible effects of selenium infusion on post operative complications among patients undergoing cardiac surgery. Further large scale multi centered studies comparing the protective role of selenium with combined therapy of other bioactive agents are needed to provide convincing explanations. Systematic Review Registration: PROSPERO Identifier: 424920.

Pituitary Apoplexy as a Complication of COVID-19 Infection.

Pituitary apoplexy (PA) is a complication occurring due to hemorrhage and/or infarction in a pituitary adenoma due to various pathophysiological mechanisms. Herein, we report a case of a 47-year-old previously healthy male who presented with fever and reduced level of consciousness for one day. During the hospital stay, he was diagnosed with PA in a background of pituitary macroadenoma along with positive nasopharyngeal swabs for SARS-CoV-2 infection. Even though the PA was successfully managed, the patient succumbed four days after admission due to respiratory failure caused by severe COVID-19 pneumonia.

Therapeutic and safety outcomes of intracoronary nicardipine in coronary artery disease patients: a systematic review.

Aim: This systematic review aimed to shed light on the efficacy of intracoronary (IC) nicardipine in treating no reflow with CAD undergoing revascularization. Methods: Literature search was performed on databases with following eligibility criteria: adult patients with CAD; clinical trials or observational studies; IC nicardipine as intervention; therapeutic and safety outcome reported. Results: A total of 1249 papers were yielded during the literature search. Of these, 11 studies were finalized for this systematic review. Complete restoration of TIMI 3 flow was observed in 98.6% of the patients receiving IC nicardipine. A significant increase in the CBF after infusion of IC nicardipine (p < 0.05) was also observed. Conclusion: IC nicardipine significantly increases CBF and decreases coronary vascular resistance.

Coronary artery disease (CAD) is a condition that results in the narrowing or blockage of heart arteries. Arteries are blood vessels that bring oxygen-rich blood from your heart to the rest of your body's cells. We aimed to evaluate the effects of intracoronary (IC) nicardipine, a drug that blocks calcium from entering the muscle cells and blood vessels of the heart, which causes the vessels to relax and widen, allowing for blood to flow more easily, on a phenomenon known as coronary slow flow (CSF). CSF is defined as a delayed widening of the blood vessels of the heart. CSF or the no reflow phenomenon is a major negative complication associated with surgical procedures such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), both of which are used to open up blocked arteries. The systematic search identified studies that evaluated the effect of IC nicardipine in patient during CAD treatment, undergoing PCI, CABG, or having confirmed or suspected narrowing of the aortic valve or one of the four valves of the heart, which results in restricted blood flow from the heart to the body. From the results of studies discussed in the review, it can be concluded that IC nicardipine significantly increases blood flow to the heart and can help prevent the no reflow phenomenon in patients undergoing PCI. Nicardipine proved to be a safe and effective option in the management of complications such as no reflow in patients receiving therapies to restore blood flow following CAD.

Can velmanase alfa be the next widespread potential therapy for alpha-mannosidosis?

Alpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.

Association of adverse childhood experiences with adulthood multiple sclerosis: A systematic review of observational studies.

INTRODUCTION: Adverse childhood experiences (ACEs) are proposed to increase the risk of developing multiple sclerosis (MS) later in life. This systematic review aimed to explore the correlation between ACEs and MS development, age of onset, quality of life in MS patients and MS relapse rates. METHODS: We searched a total of six databases in June 2022 and retrieved the relevant studies. The population included adult (18+) individuals who either had been diagnosed or were at risk for developing MS and also had exposure to ACEs. Our primary outcomes include the risks of MS development, age of MS onset, and MS relapse rate in patients who were exposed to different types of ACEs. RESULTS: A total of 11 studies were included in our review. A study reported that among 300 women diagnosed with MS, 71 (24%) reported a history of childhood abuse; moreover, with further research, it was concluded that ACEs were associated with the development of MS. Abuse that occurred 2-3 times per week was associated with an 18.81-fold increased risk of having MS when compared to the unexposed sample. The relapse rate of MS was found to be substantially greater in severe cases of ACEs compared to individuals who did not report any ACEs. CONCLUSIONS: Results support a significant association between ACEs and the development of MS; individuals with a positive history of ACEs develop MS symptoms earlier. Moreover, the severity of ACEs is also linked with increased relapse rates of MS.