Disease clearance in ulcerative colitis: A new therapeutic target for the future.

Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression. This has fueled the identification of molecular targets, resulting in a rapidly expanding therapeutic armamentarium. Subsequently, management strategies have evolved from symptomatic resolution to well-defined objective endpoints, including clinical remission, endoscopic remission and mucosal healing. While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications, studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures. Current recommendations lack consideration of histological healing. The simultaneous achievement of clinical, endoscopic, and histologic remission has not been fully investigated. This has laid the groundwork for a novel therapeutic outcome termed disease clearance (DC). This article summarizes the concept of DC and its current evidence.

Minimum intervention oral care - incentivising preventive management of high-needs/high caries-risk patients using phased courses of treatment.

This paper demonstrates how person-focused, prevention-based, risk/needs-related, team-delivered, minimum intervention oral care (MIOC) principles and approaches can be integrated into the dental profession for the delivery of environmentally sustainable, optimal care to high-needs and high caries-risk/susceptibility patients. It highlights the potential for NHS remuneration for prevention-based, phased, personalised care pathways/plans (PCPs) within a reformed NHS dental contract system. It emphasises the importance of comprehensive and longitudinal patient risk/susceptibility assessments, prevention and stabilisation of the oral environment before considering more complex, definitive restorative work. This paper forms the first of several components of a suite of educational/information materials needed to instil confidence and implementation protocols within primary care clinical oral health care teams delivering MIOC through phased PCPs, especially when managing patients with high needs and/or disease susceptibility.

Borjeson-Forssman-Lehmann Syndrome: Clinical Features and Diagnostic Challenges.

Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked recessive disorder resulting from mutations in the PHF6 gene. The syndrome is characterized by short stature, obesity, hypogonadism, hypotonia, intellectual disability, distinctive facial features, fleshy ears, and finger and toe abnormalities. However, the diagnostic challenge in identifying BFLS remains a topic of interest. In this case report, we present the clinical characteristics of a proband with BFLS, highlighting the additional features of hypotonia, intellectual disability, and distinctive facial features. While no definitive treatment exists for BFLS, patients benefit from specialized education and ongoing supervision from early childhood through adulthood. Symptomatic treatment, including close follow-up, may be necessary for complications such as seizures and hearing problems. Mastectomy or testosterone replacement therapy may be considered on a case-by-case basis. Genetic counseling for X-linkage should be offered to affected families.

siRNA drug delivery across the blood-brain barrier in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a few FDA-approved drugs that provide modest symptomatic benefits and only two FDA-approved disease-modifying treatments for AD. The advancements in understanding the causative genes and non-coding sequences at the molecular level of the pathophysiology of AD have resulted in several exciting research papers that employed small interfering RNA (siRNA)-based therapy. Although siRNA is being sought by academia and biopharma industries, several challenges still need to be addressed. We comprehensively report the latest advances in AD pathophysiology, druggable targets, ongoing clinical trials, and the siRNA-based approaches across the blood-brain barrier for addressing AD. This review describes the latest delivery systems employed to address this barrier. Critical insights and future perspectives on siRNA therapy for AD are also provided.

Antiplatelet response to clopidogrel is associated with a haplotype in CYP2C19 gene in Pakistani patients.

Clopidogrel, an antiplatelet drug, is frequently prescribed to patients diagnosed with ischemic diseases such as those suffering from acute coronary syndromes or ischemic stroke. Despite the drug being effective in majority of the patients, some still experience ischemic events early in the treatment which might be due to poor platelet inhibition. This study aims to investigate the association of cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms, haplotypes as well as a wide range of clinical and demographic variables with platelet aggregation phenotypes to clopidogrel in a Pakistani cohort. The study comprised of a total of 120 patients diagnosed with cardiovascular diseases and were treated with clopidogrel. Antiplatelet response to clopidogrel was monitored by Helena AggRAM (HL-2-1785P) and patients with maximal platelet aggregation more than 50% were categorized as low responders and those with less than 50% as high responders. Our results show that 56.6% of patients were homozygous for the CYP2C19 wild-type allele, 38.3% of patients possessed one copy of the CYP2C19*2 allele and 5% of patients possessed both CYP2C19*2 alleles. No CYP2C19*3 allele was found in our patient cohort. There was no statistically significant difference between the high and low responder groups to clopidogrel in terms of extensive, intermediate and poor metabolizer genotypes. However, haplotype (H1), leukocyte count, random blood glucose, and history of diabetes mellitus was associated with the antiplatelet response to clopidogrel. The prevalence of clopidogrel resistance in our population was in line with that reported for other regional and global populations.

Vaccine Development against COVID-19: Study from Pre-Clinical Phases to Clinical Trials and Global Use.

As per the World Health Organization (WHO), more than 288 vaccines against COVID-19 are being developed, with an estimated 184 being presently investigated in the pre-clinical phases, while 104 of these vaccine candidates are at various stages of clinical trials. Twelve of these are in the advanced stages of clinical investigation, and promising results in the phase 3 trials have already paved the way for their regulatory approval and subsequent dissemination for global use. Preliminary and interim results of some of these candidate vaccines are being analyzed for public dissemination. Some of these vaccines have already been rolled out to immunize not only the highest risk individuals but also the general population in several countries. Once their safety and efficacy are established, the next limiting step would be their mass manufacturing by the pharmaceutical companies to fulfill the global demand. The challenge of manufacturing billions of doses of high-quality vaccines is under-appreciated at the moment. A massive vaccination drive would be needed to protect people of all ages. The timely and coordinated execution of the vaccination effort would require unprecedented coordination at the national and international levels for generating funds to purchase the required doses of vaccines, fair distribution of doses and managing the mechanics of delivering vaccines throughout the world.

Mechanical behavior of actin and spectrin subjected to high strain rate: A molecular dynamics simulation study.

Recent nanoscopy and super-resolution microscopy studies have substantiated the structural contribution of periodic actin-spectrin lattice to the axonal cytoskeleton of neuron. However, sufficient mechanical insight is not present for spectrin and actin-spectrin network, especially in high strain rate scenario. To quantify the mechanical behavior of actin-spectrin cytoskeleton in such conditions, this study determines individual stretching characteristics of actin and spectrin at high strain rate by molecular dynamics (MD) simulation. The actin-spectrin separation criteria are also determined. It is found that both actin and spectrin have high stiffness when susceptible to high strain rate and show strong dependence on applied strain rate. The stretching stiffness of actin and forced unfolding mechanism of spectrin are in harmony with the current literature. Actin-spectrin model provides novel insight into their interaction and separation stretch. It is shown that the region vulnerable to failure is the actin-spectrin interface at lower strain rate, while it is the inter-repeat region of spectrin at higher strain rate.

Adult Onset Still's Disease: A Retrospective, Single-Center Study.

Background Adult-onset Still's disease (AOSD) is characterized by a classical triad of spiking fever, arthritis, and evanescent rash. It is one of the main causes of hospital admissions for fever of unknown origin and has an extended mean time to diagnosis. Therefore, it remains underdiagnosed relative to its aforementioned time frame. In this study, we attempt to highlight clinical and lab findings associated with AOSD. We then compare our diagnostic results with similar previous studies. Our results should help physicians not to miss this rare entity and make the diagnosis in a reduced time frame. Materials and methods This a retrospective, single-center study conducted at Dow University Hospital in Karachi, Pakistan. Thirty patients were enrolled in this study for six months (July 2019-December 2019). All patients were identified and recruited in the medical outpatient department using Yamaguchi's criteria. Written consent was obtained from all patients to access all their clinical charts. Demographics and prior results of laboratory investigations were retrieved from the chart files. Results In our study, the mean age of patients was 26.6 years. More specifically, males accounted for 53.3% (n=16) of cases, and females accounted for 46.6% (n=14) of total cases. The most common presenting clinical features included arthralgia (100%, n=30), fever (100%, n=30), myalgia (96.6%, n=29), large joint arthritis (66.6%, n=20), sore throat (50%, n=15), hepatomegaly (40%, n=12), splenomegaly (23.3%, n=7), skin rash (36.6%, n=11) and pericarditis (20%, n=6). Furthermore, none of our patients had cervical lymphadenopathy. The most commonly reported laboratory findings include leukocytosis (100%, n=30), hyperferritinemia (90%, n=27), elevated erythrocyte sedimentation rate (100%, n=30) and abnormal liver function tests (76.6%, n=23). Chest x-rays performed in all patients revealed no abnormalities in 83% of patients (n=25). All patients in our study sample (n=30) tested negative for antinuclear antibodies and rheumatoid factor. It was also noted that the mean duration of diagnosis in our patients was 5.98 weeks. The mean hospitalization period in our patients was 12.5 days. Furthermore, 16.7% of patients (n=5) suffered from disease relapse.  Conclusion Our study ascertains that the presence of certain clinical and laboratory findings strongly indicate a diagnosis of adult-onset Still's disease.

The Success Level of Hypospadias Repair in Adults.

Introduction Hypospadias is the abnormal opening of the urethra at the undersurface of the penis. Hypospadias repair is performed in such patients to treat the condition. The success level of hypospadias repair in adults still needs to be established on a larger scale. Therefore, we conducted this study to document the success level of hypospadias repair in adults in our setting to add to the literature. Materials and methods This prospective study was conducted at a major metropolitan hospital in Karachi over a period of six months. A total of 75 male patients aged between 20-50 years and diagnosed with hypospadias of any level with or without mild to moderate chordee were included. Demographic features such as age and the duration of hypospadias were noted. Hypospadias repair using a tubularized incised plate (TIP) urethroplasty technique was performed, and the patients were observed for three days in the ward and for three months in the outpatient department for any complications. The procedure was considered a success if there were no complications and no need for a second surgery; we also took into account patient satisfaction with the procedure to determine the success level. The mean and standard deviation were calculated for patient age and the duration of hypospadias. Frequency and percentages were calculated for distribution of patient age, distribution of the duration of hypospadias, and the success of hypospadias repair. The correlation of patient age and the duration of hypospadias with the success of hypospadias repair was also determined by applying the Chi-square test, and a p-value of ≤0.05 was considered to be statistically significant. Results The mean age and the duration of hypospadias for the study population were the same at 31.43 ± 8.47 years. Distribution of patient age and the duration of hypospadias was also the same with 51 (68%) patients of ≤35 years of age and 24 (32%) patients of >35 years of age. Hypospadias repair was successful in 52 (69.33%) patients but unsuccessful in 23 (30.66%). The stratification of patient age and the duration of hypospadias with the success of hypospadias repair showed a significant inverse relationship (p = 0.017). The data relating to patient age and the duration of hypospadias showed the same values as hypospadias is a birth defect. Conclusion Adult patients undergoing primary hypospadias repair generally show good outcomes. However, the chances of favorable outcomes gradually decrease with age. Hence, patients should be encouraged to undergo the procedure as early in their lives as possible. Patients who are middle-to-old aged should especially be counseled about the relatively higher risk of unsuccessful procedures. Further analysis is needed to confirm the validity of these findings.

Therapeutic Implications of Altered Energy Metabolism in Migraine: A State-of-the-Art Review.

Currently, the management strategies aimed at the resolution of migraine are pharmacological. Most of these therapies are known to alter the serotonin balance of the brain. Furthermore, therapies blocking the calcitonin gene-related peptide (CGRP) have also proven to be quite effective in their treatments. However, apart from being expensive, these therapies do not influence premonitory and aura symptoms. This suggests an incomplete approach and an inadequate understanding of the migraine pathophysiology. Recent metabolic studies have indicated that migraine should be considered as an adaptive response to the mismatch between the cerebral energy reserves and expenditure. Therefore, understanding the underlying metabolism helps derive possible novel therapeutic modalities for migraines. In this review, we highlight the underlying metabolic abnormalities found in migraine patients. This will form the basis of our evidence-based discussion on metabolic therapeutic options for migraines.

Lamin A/C Cardiomyopathy with E203K Pathogenic Mutation.

Lamin A/C (LMNA) cardiomyopathy is an adult-onset, autosomal dominant, rapidly progressive cardiomyopathy which belongs to a spectrum of familial idiopathic cardiomyopathies. It is the most common type of familial dilated cardiomyopathy that is associated with conduction defects. A 76-year-old African American female with second-degree atrioventricular (AV) block presented for evaluation of persistent fatigue. Her family history was significant for sudden deaths of her son and brother at the age of 6 and 48 years, respectively, and AV block in her sister with a pacemaker implant at the age of 64 years. Physical examination was within normal limits. Electrocardiogram showed a Mobitz type II, second-degree AV block. Mild dilated cardiomyopathy was present on echocardiogram. Stress echocardiography had to be stopped due to premature ventricular contractions. Cardiac catheterization, coronary angiography, and cardiac MRI revealed no significant etiology for rhythm disturbance. Holter monitoring revealed intermittent bradycardia with a heart rate falling as low as 28 beats per minute, which led to the decision of dual-chamber pacemaker implantation. RhythmNext genetic testing (Ambry Genetics, Aliso Viejo, CA) was done due to the significant family history of sudden death; it revealed a heterozygous E203K pathologic mutation in the LMNA gene. Sudden death is the most common mode of death in LMNA cardiomyopathy; hence, the implantation of intracardiac cardioverter-defibrillator for primary prophylaxis was discussed with the patient. Clinicians should suspect LMNA cardiomyopathy in patients with rhythm disorders and family history of sudden death, which can help to identify individuals at risk and prevent sudden death by appropriate interventions.

Coronavirus (COVID-19): A Review of Clinical Features, Diagnosis, and Treatment.

Coronavirus (COVID-19) is an enveloped RNA virus that is diversely found in humans and wildlife. A total of six species have been identified to cause disease in humans. They are known to infect the neurological, respiratory, enteric, and hepatic systems. The past few decades have seen endemic outbreaks in the form of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome related coronavirus (SARS-CoV). Yet again, we see the emergence of another outbreak due to a new strain called the SARS-CoV-2 virus. The most recent outbreak initially presented as pneumonia of unknown etiology in a cluster of patients in Wuhan, China. The epicenter of infection was linked to seafood and exotic animal wholesale markets in the city. SARS-CoV-2 is highly contagious and has resulted in a rapid pandemic of COVID-19. As the number of cases continues to rise, it is clear that these viruses pose a threat to public health. This review will introduce a general overview of coronavirus and describe the clinical features, evaluation, and treatment of COVID-19 patients. It will also provide a means to raise awareness among primary and secondary healthcare providers during the current pandemic. Furthermore, our review focuses on the most up-to-date clinical information for the effective management, prevention, and counseling of patients worldwide.

An Atypical Presentation of Myasthenia Gravis: A Case Report.

Myasthenia gravis (MG) belongs to a spectrum of autoimmune diseases in which anti-acetylcholine receptor antibodies damage neuromuscular junctions. It is a relatively rare disease with a higher incidence among the female population. The classical presentation is fatigable fluctuating diplopia or ptosis and, uncommonly, dysphagia or dysphonia. Even though it is rare, this condition can affect any skeletal muscle groups, including the neck or proximal limb muscles. There have been no reported cases of MG presenting as isolated neck weakness. An 81-year-old female patient presented with neck weakness associated with mild discomfort that progressively worsened throughout the day. Examination revealed reduced cervical muscular motor strength only. All imaging and laboratory investigations were within normal limits, except anti-acetylcholine receptor antibodies (binding Ab 12.04 nmol/L, blocking Ab 52% while modulating Ab 84%) with moderately elevated creatine phosphokinase (CPK) levels (350 U/l). The patient was prescribed Mestinon 60 mg QID (pyridostigmine), which led to rapid and significant relief of neck weakness. The patient has been stable on the medication for two years. MG typically presents in middle-aged female populations but, rarely, can also present with atypical symptoms among the elderly. Clinicians should have a high index of suspicion for myasthenia presenting with fatigable muscle weakness to reduce investigative costs and morbidity.

Frightening" Resistant Clostridial Myonecrosis: A Case Report.

Clostridial myonecrosis is a diffuse necrotizing infection of deep soft tissues. It is known for its acute, rapid progression, poor prognosis, and high mortality. We report a case of traumatic clostridial myonecrosis, a 17-year-old, previously healthy female reported to our department with the complaint of pain in her left arm a week after she suffered a fall from her chair on to her left arm. Due to the injury sustained in the incident, under suspicion of a forearm fracture, a cast was applied to her left arm at a local polyclinic. However, after a few days, she reported unbearable pain, which led to the removal of the cast, and that is when diffuse crepitations due to gaseous accumulation were noted in her entire left upper limb. A week later, X-ray studies failed to reveal any fracture or abnormality. The patient was started on broadspectrum antibiotic coverage with intravenous (IV) benzylpenicillin, rifampicin, and clindamycin for a considerable period of time, but there was no improvement in her condition and the infection continued to spread into adjacent soft tissues, requiring intervention with hyperbaric oxygen therapy.

Malignant Thyroid-type Papillary Neoplasm in Struma Ovarii: A Case Report.

Papillary thyroid carcinoma (PTC) arising in a coexistent struma ovarii (SO) is a rare malignancy. It manifests with abdominal symptoms such as palpable mass, pain, distension, and possibly ascites. It is usually diagnosed postoperatively, and its histopathological diagnostic criteria remain identical to that of papillary carcinoma of the thyroid gland. Due to the relative rarity of the disease, definitive guidelines for its overall management are still undefined. We present a case of a 51-year old female with suspicion of a left ovarian tumor due to her presenting symptoms: raised serum CA-125 levels and abnormal abdominopelvic CT scan findings. She underwent complete surgical debulking of the mass (total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), omentectomy, appendectomy, and pelvic lymphadenectomy). The mass was postoperatively diagnosed by histopathology as PTC in SO (stage IA). Furthermore, our patient did not receive any adjuvant treatment. The patient has been disease-free for 24 months post-surgery and is scheduled for regular biannual follow-ups.

Joubert Syndrome: A Rare Radiological Case.

Joubert syndrome is a rare autosomal recessive neurodevelopmental disease characterized by abnormal breathing patterns composed of episodic tachypnea/apnea, hypotonia, ataxia, developmental delay, intellectual impairment, ocular impairment, renal cysts, and hepatic fibrosis. We report the case of a 4-year-old boy who presented with global developmental delay, bilateral nystagmus, and gaze instability with difficulty walking and maintaining an upright posture. A detailed examination revealed facial dysmorphic features with a depressed nasal bridge and deepened orbital sockets. Neurological examination yielded positive results for hypotonia, gait ataxia, bilateral horizontal pendular nystagmus, and a grade 1 ptosis more prominent in the right eye. However, no abnormal breathing patterns were observed in our case. Magnetic resonance imaging revealed the characteristic molar tooth sign and a batwing appearance of the fourth ventricle.

FREQUENCY OF DIFFERENT VALVULAR LESIONS OF RHEUMATIC HEART DISEASE PRESENTING TO A TERTIARY CARE HOSPITAL.

BACKGROUND: Rheumatic Hearth Disease (RHD) is still prevalent in our country and a great source of morbidity. This study was done with an objective to determine relative frequency of different valvular lesions of RHD presenting in a tertiary care hospital. METHODS: This cross sectional study was conducted at the Cardiology Department of Hayatabad Medical Complex, Peshawar. A total of 171 cases of RHD were included through consecutive sampling technique. RESULTS: There were 64.33% females. Mean age was 25.6 +/- 6.95 years ranging from 15 to 40 years. The different percentage of valvular lesions in RHD were MR (59.06%), MS (46.78%), AR (43.85%) and mixed lesions (38.59%). CONCLUSION: Rheumatic heart disease is a very common disease in our community and mitral regurgitation is a predominant lesion at presentation Females are usually affected more than males.