Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care.

BACKGROUND: Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs). METHODS: Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications. RESULTS: Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42). CONCLUSIONS: SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.

Recurrent Hyponatremia in the Setting of Autoimmune Disease with Sicca Syndrome: A Case Report.

Sjogren's syndrome is an autoimmune disease associated with xerostomia and xerophthalmia. The association of Sjogren's with hyponatremia has rarely been reported and has been attributed to syndrome of inappropriate antidiuretic hormone secretion. Here, we report a case of polydipsia secondary to xerostomia as a cause of chronic hyponatremia in the setting of Sjogren's syndrome. Analysis of the patient's medical record, including medication reconciliation and dietary habits, revealed several underlying causes of her recurrent hyponatremia. A thorough review of the patient's clinical history and good bedside examination may reduce prolonged hospitalizations and improve the quality of life of a hyponatremic population of patients who are predominantly elderly.

Meloxicam loaded hydroxypropyl methylcellulose (HPMC) microparticulate: Fabrication, characterization and in vivo pharmacokinetic assessment.

Meloxicam (MEL) is an oxicam derivative with low water solubility that is useful in the treatment of colorectal cancer (CRC) as a COX-2 inhibitor. MEL-loaded HPMC micro particles were fabricated using an oil-in-oil (o/o) emulsion solvent evaporation (ESE) method. FTIR, XRD, particle size analysis, DSC, SEM and in vitro dissolution investigation were utilized to evaluate the produced micro particles physiochemically. Finally, rabbits were used as animal models in an in vivo pharmacokinetic study to assess the MEL concentration in the plasma of rabbits. Pure MEL, F1 and F2 were given to rabbits by a single dose for in vivo pharmacokinetic investigations. The XRD and DSC results confirmed the transformation of MEL from its crystalline nature to the amorphous state in micro particles. The formulations F1 and F2 particle sizes were determined 92.43µm and 163.26µm, respectively. The prepared micro particles had a smooth, non-porous and spherical surface. In comparison to the pure drug (22.4%), the F1 and F2 cumulative drug release (%) was 86.19% and 79.57%, respectively. Pure MEL, F1 and F2 have estimated Cmax values of 7.21, 25.41 and 22.38µg/mL, respectively. MEL had a half-life of 19.98 hours, which rose to 22.19 hours and 24.75 hours for F1 and F2, respectively. MEL, F1 and F2 had AUC0-α values of 116.034, 445.95 and 462.72µg/mL*h, respectively. Considering these aspects, MEL-loaded HPMC micro particles may have the potential to better the delivery and control the release of drug that is not easily dissolved in water which could lead to improved therapeutic efficacy and limited side effects.

Evaluation of anti-inflammatory and analgesic effects of Hertia intermedia (Boiss.) Kuntze extract.

Hertia intermedia is a traditional medicinal plant of Balochistan, used for pain management and stomach problems. Current research work was intended to evaluate the anti-inflammatory and analgesic activities of crude ethanolic extract of H. intermedia. Anti-inflammatory activity was determined by the carrageenan-induced and histamine-induce Rat paw edema in rats, analgesic activity was determined by acetic acid-Induced writhing test, formalin-induced hind paw licking in mice and Tail immersion test. H. intermedia crude ethanolic extract showed significant (p<0.05) effect in both carrageenan and histamine-induced rat paw edema at both 250 and 500 mg/kg oral doses. There were significant analgesic activities in comparison with standard drug and control (p<0.05). It is concluded that H. intermedia crude ethanolic extract possesses significant anti-inflammatory and analgesic effects. However further studies may be carried out to isolate the phytochemicals responsible for anti-inflammatory and analgesic activities.

Developed meloxicam loaded microparticles for colon targeted delivery: Statistical optimization, physicochemical characterization, and in-vivo toxicity study.

The study aimed to fabricate and evaluate Meloxicam (MLX) loaded Hydroxypropyl Methylcellulose (HPMC) microparticles for colon targeting because MLX is a potent analgesic used in the treatment of pain and inflammation associated with colorectal cancer (CRC). Nevertheless, its efficiency is limited by poor solubility and gastrointestinal tracts (GIT) associated side effects. Seventeen formulations of MLX loaded HPMC microparticles were fabricated by the oil-in-oil (O/O)/ emulsion solvent evaporation (ESE) technique. A 3-factor, 3-level Box Behnken (BBD) statistical design was used to estimate the combined effects of the independent variables on the dependent variables (responses), such as the percent yield (R1), the entrapment efficiency (EE) (R2), mean particle size (R3) and in vitro percentage of cumulative drug release (R4). For physicochemical characterization FTIR, XRD, DSC, and SEM analyses were performed. Biocompatibility and non-toxicity were confirmed by in-vivo acute oral toxicity determination. The percentage yield and EE were 65.75-90.71%, and 70.62-88.37%, respectively. However, the mean particle size was 62.89-284.55 µm, and the in vitro cumulative drug release percentage was 74.25-92.64% for 24 hours. FTIR analysis showed that the composition of the particles was completely compatible, while XRD analysis confirmed the crystalline nature of the pure drug and its transition into an amorphous state after formulation. DSC analysis revealed the thermal stability of the formulations. The SEM analysis showed dense spherical particles. The toxicity study in albino rabbits showed no toxicity and was found biocompatible. The histopathological evaluation showed no signs of altered patterns. Results of this study highlighted a standard colonic drug delivery system with the ability to improve patient adherence and reduce GIT drug-associated side effects in CRC treatment.

Piroxicam loaded polymer hybrid microspheres based tablets with modified release kinetics: Development, characterization and in vivo evaluation.

Piroxicam (PC) is a non-steroidal anti-inflammatory drug characterized by poor aqueous solubility and reported to cause and impart crucial GIT irritation, bleeding, peptic and duodenal ulcer. Engineering of PC loaded microcapsules and its surface modification using different polymers has become the popular approach to address the said issues. The purpose of the study was to develop new PC loaded gastro-protective polymer hybrid microspheres (PHM) with subsequent conversion to tablet dosage form having modified dissolution rate and improved bioavailability. The crystallinity of the PC loaded PHM were established through powder X-ray diffraction. The optimised microspheres, PC-M1 with particle size 32±3.0µm, entrapment efficiency 83.78±2.5% and in vitro drug release 87.1±2.6% were further subjected to tablets development and in vivo evaluation. The in vitro drug release study conducted for PHM at pH media 1.2 and 6.8 demonstrated retarded and enhanced drug release rates (P<0.001) respectively. Both accelerated and real time stability studies confirmed stability of the PC loaded PHM based tablets. A substantial improvement in the drug plasma concentration 12.6±2.36 (P<0.001) was observed for the produced tablets compared to the marketed formulations.

Clinical indicators for progression of nonalcoholic steatohepatitis to cirrhosis.

Non-alcoholic fatty liver disease (NAFLD), is a disease spectrum characterized by fat accumulation in hepatocytes presenting as hepatic steatosis to advance disease with active hepatic inflammation, known as nonalcoholic steatohepatitis. Chronic steatohepatitis will lead to progressive hepatic fibrosis causing cirrhosis and increased risk for developing hepatocellular carcinoma (HCC). Fatty liver disease prevalence has increased at alarming rates alongside obesity, diabetes and metabolic syndrome to become the second most common cause of cirrhosis after alcohol related liver disease worldwide. Given this rise in prevalence, it is becoming increasingly more important to find non-invasive methods to diagnose disease early and stage hepatic fibrosis. Providing clinicians with the tools to diagnose and treat the full spectrum of NAFLD will help prevent known complications such as cirrhosis and HCC and improve quality of life for the patients suffering from this disease. This article discusses the utility of current non-invasive liver function testing in the clinical progression of fatty liver disease along with the imaging modalities that are available. Additionally, we summarize available treatment options including targeted medical therapy through four different pathways, surgical or endoscopic intervention.

Aggressive primary gastric lymphoma (PGL) masquerading as hepatocellular cancer (HCC) in alcoholic cirrhosis.

BACKGROUND: The gastrointestinal tract is sa well-known site for extranodal Non-Hodgkin lymphomas, with the stomach is known to be the most common site on lymphoma, primary gastric lymphoma (PGL). The lymphoproliferative disorder rarely occurs in patients with cirrhosis. We report a unique case of metastatic PGL in a patient with cirrhosis. CASE PRESENTATION: A middle-aged male with decompensated alcoholic cirrhosis presented with two weeks of epigastric abdominal pain, abdominal distension, and jaundice. Abdominal triple-phase CT scan was consistent with cirrhosis, ascites, and multiple new hypodense liver lesions classified as an intermediate probability for HCC based on the LI-RADS classification system (LI RADS 3). Due to the CT findings in the setting of cirrhosis, a provisional diagnosis of HCC was made. Upper endoscopy revealed new multiple umbilicated submucosal nodules in the gastric body. Biopsy and immunostaining consistent with high-grade B-cell lymphoma. Targeted liver biopsy with similar morphology and immunostaining profile consistent with metastatic primary gastric DLBCL. CONCLUSIONS: The case highlights the importance of recognizing metastatic PGL in patients with underlying cirrhosis to differentiate lymphoma from hepatocellular cancer. Targeted liver biopsies with lymphoma immunostaining are required to make a diagnosis.

The flavonoid 6-hydroxyflavone prevention of cisplatin-induced nephrotoxicity.

In this study, the flavonoid, 6-hydroxyflavone was investigated for its renal protective activity in the cisplatin rat model of nephrotoxicity. Male Sprague-Dawley rats weighing 200-250 g were included in the study. 6-Hydroxyflavone was daily administered at 25 and 50 mg/kg (i.p.), while ascorbic acid was used as a positive control and injected (i.p.) at 50 mg/kg for 15 days. The nephrotoxicity was evoked with a single cisplatin injection at 7.5 mg/kg on the tenth day of treatment. The renal function and levels of oxidative stress markers were assessed. Each tissue slide of different groups was observed under a compound microscope attached with a digital camera. Cisplatin significantly decreased the overall body weight with an increase in serum creatinine and urea and production of severe histopathological and oxidative stress in the kidneys. The daily treatment with 6-hydroxyflavone significantly attenuated the cisplatin associated detrimental changes in the body weight, and serum levels of creatinine and urea at both 25 mg/kg (P<0.05) and 50 mg/kg (P<0.01). The 6-hydroxyflavone treatment also preserved the renal histoarchitecture from the toxicological influence of cisplatin as evident from a significant reduction in the severity of histopathological changes in the renal tissues. Moreover, 6-hydroxyflavone also reduced the cisplatin-induced lipid peroxidation and corrected the renal antioxidant status. A similar protective effect was observed with the positive control, ascorbic acid (50 mg/kg). These findings show that the flavonoid 6-hydroxyflavone has potential nephroprotective properties and can be used for the management of chemotherapy associated renal disturbances.

Design, Preparation and evaluation of various parameters of controlled release matrices of losartan potassium using polymers combination.

Controlled release formulations are administered once a day and reduce frequency of dose and ensuring patient's compliance. In the current research controlled release matrices of losartan potassium formulated with polymeric combinations of ethocel grade 7 with carbopol 934P NF using different concentrations of polymers. In some polymeric tablets, Co-excipients like CMC, Starch, HPMC was added by replacing of 10% of filler in formulations at 10:5. Tablets were prepared by direct compression method and evaluated for physicochemical characteristics. USP Method-1 (rotating basket method) was used to carry out dissolution study in phosphate buffer pH 6.8. Drug release kinetics determined and comparison of dissolution patterns was done with reference tablets. The polymeric combinations well retarded drug release and drug was released by anamolous non-fickian diffusion mechanism. Dissolution profiles of tested tablets and reference tablets were found not similar. Drug release rate was increased by co-excipients. It was concluded from this research work that this polymeric combination can be used efficiently in designing of controlled release martices.

Thiol-disulfide exchange reactions occurring at modified bovine serum albumin detected using ellman's reagent (5, 5'-dithiobis (2-itrobenzoic acid).

Bovine serum albumin (BSA) is usually employed as a model protein because of being homologous with human serum albumin. Cysteine-34 of BSA has been oxidised with Ellman's reagent to produce BSA labelled with an Ellman's moiety (BSA-SE). The BSA-SE was then reacted with glutathione, N-acetylcysteine and D-penicillamine (D-pen). The two were able to release the Ellman's moiety bound at cysteine-34 while D-pen did not. Albumin labeled using Ellman's reagent was used to demonstrate the cleavage of a protein mixed disulphide. The kinetics of thiol disulfide interchange reactions involving formation of a chromophoric thiolate were determined by UV-visible spectroscopy. The reaction of thiolates with excess Ellman's reagent is used for quantitative estimation of thiol by measuring the absorption at λ, 412 nm. The disulfide exchange reactions occurring at Cys-34 of BSA was determined and the reduction of oxidized Cys-34 was studied in order to understand the reverse reaction. Spectroscopic evidence suggested that glutathione and N-acetylcysteine remove the label and produce BSA in a disulfide form. In contrast, D-pen reaction returned BSA to its thiolate form via mediation. It was observed that thio-disulfide exchange occurred at cysteine-34 labelled with Ellman's moiety. The implications to the redox status of plasma are discussed.

Analgesic and neuropharmacological activities of Berberis lycium Royle collected from district Sherani Balochistan, Pakistan.

Berberis lycium (family Berberidaceae) grows in district Sherani, Balochistan, Pakistan. It is used for the treatment of various disorders by the people of Balochistan. The present work was carried out to explore analgesic and neuropharamcological activities of crude methanolic extracts of B. lyceum. The analgesic activity was carried out by acetic acid induced writhing test and formalin test. Open field test, cage crossing test, rearing test, traction test and forced swimming test were carried out in neuropharmacological activities. The results reveal that crude methanolic extracts of B. lyceum showed significant (P<0.05) analgesic activity in acetic acid induced pain as well as with formalin test. In neuropharmacological activities, crude methanolic extracts of B. lyceum showed significant (P<0.05) central nervous system depressant activity and in forced swimming test it showed anxiolytic effects.

Extraction, formulation and characterization of an in vitro and ex-vivo evaluation of Thymus serpyllum L. (Thymus oil) from topical preparations using dialysis cellulose membrane and natural rabbit skin.

Herbal remedies like the Thymus serpyllum L. is useful in traditional medicine for the treatment of many diseases especially congestion, and bronchitis. The purpose of this study was to formulate a micro-emulsion, a gel and an ointment containing the plant hydro distilled thymus oil extracted from Thymus serpyllum L. collected from Ziarat, Balochistan. The prepared formulations were subjected to in-vitro and ex vivo study release, High performance Liquid Chromatography (HPLC), Thin Layer Chromatography (TLC), to justify their suitability for topical use. The in-vitro and ex-Vivo release was studied using Franz Cells and using two different kinds of membrane synthetic dialysis cellulose membrane and natural rabbit skin and the amount of drug released was determined by HPLC at λ 274nm. The three formulations result obtained through dialysis cellulose membrane showed the faster release than the natural rabbit skin. However, the micro-emulsion, gel formulation showed the same release except ointment. The release from the above mentioned formulation can be arranged in the following descending order. micro-emulsion > Gel > Ointment. The best fit of release kinetics was achieved by Krosmeyer- Peppas, the TLC and HPLC identifies the Thymol, isolation and quantification of the marker. This study demonstrates that it is necessary to assess the impact of release and permeability pattern of different formulations. In vitro and ex-vivo diffusion cell experiments can be utilized to develop formulations of traditional medicines identifies.

Teaching medical students to recognise and report errors.

Background: Medical student error reporting can potentially be increased through patient safety education, culture change and by teaching students how to report errors. There is scant literature on what kinds of errors students see during clinical rotations. The authors developed an intervention to better understand what kinds of errors students see and to train them to identify and report errors. Methods: A safety curriculum was delivered during the Medicine clerkship for the academic year 2015-2016. Prior to the workshop, students completed a preintervention survey to determine whether they had reported a clinical error. Subsequently, they participated in an educational workshop. Facilitated discussions about conditions contributing to errors, types of errors, prevention of errors and importance of reporting followed. Students were required to submit a simulated error report about an error they personally observed. An end-of-year survey was sent to students who participated in the curriculum to determine clinical error reporting frequency. Results: Students submitted 282 reports. Near miss errors were seen in 64% and adverse events in 36%. National Quality Forum serious events were reported in 14%, including one death. Recommendations to prevent similar events were weak (62%). Students correctly categorised 93% near miss, 88% adverse events, 67% diagnostic, 81% treatment and 78% preventative errors. On the preintervention survey, 8.5% stated they submitted an error report to their clinical site. On the end-of-year survey, 18% confirmed submitting a formal error report. Conclusion: Training students to recognise and report errors can be successfully integrated into a clinical clerkship and impact clinical error reporting.

Formulation, characterization and in vivo evaluation of Hedera helix L., topical dosage forms.

The purpose of this study was to prepare topical formulations of micro emulsion, gel and ointment containing the Hedera helix L. extracts against asthma and to evaluate the physicochemical characteristics. A validated HPLC method was used for the analysis of blood plasma. In-vivo studies of the drugs were compared in rabbit plasma with oral dosing. Stability studies were performed for 3 months. The results showed that formulations were stable. No Skin irritation observed on rabbits. The optimized micro emulsion and gel showed fast absorption. Maximal plasma concentration (cmax) and the maximal time to reach cmax (tmax) were 70.226µg/mL, 75.26µg/mL and 2 hours for the micro emulsion and gel, 90.11µg/mL and 1 hour for the oral drug syrup respectively. Pharmacokinetic parameters such as tmax, cmax and AUC of the selected formulations and oral dosing were significantly different (P < 0.01).

Thrombotic Thrombocytopenic Purpura Associated with Pazopanib.

A 76-year-old male with metastatic renal carcinoma on day 24 of pazopanib was admitted with complaints of emesis, confusion, and hematuria. Laboratory testing showed acute kidney injury, hyperbilirubinemia, and thrombocytopenia. Scattered schistocytes were seen on peripheral smear, and he was diagnosed with thrombotic microangiopathy (TMA). He was started on daily, one-volume plasma exchange with rapid improvement in thrombocytopenia. ADAMTS13 activity returned as undetectably low with no inhibitor detected. After cessation of plasmapheresis, repeat ADAMTS13 activity returned as normal. Unfortunately, his platelet count started to downtrend within four days after developing septicemia thought to be due to a catheter-associated infection. He was placed on comfort care measures after discussion with his family. An autopsy listed the major cause of death as metastatic renal cell carcinoma. According to two separate systematic reviews, there have been no cases of proven drug-induced TMA where decreased ADAMTS13 activity was the identified mechanism. While pazopanib is also associated with TMA, this unique case suggests a novel potential mechanism for TMA associated with pazopanib and brings forth "drug-induced thrombotic thrombocytopenic purpura" that quickly responds to plasmapheresis as a possible new diagnostic entity requiring prompt recognition and treatment.

Spectrophotometric investigation of Glutathione modulation by Thallium chloride in aqueous medium.

Thallium has been shown to significantly influence various tissues of living organisms; Exposure to Thallium can disturb mitochondrial function, degenerate neurons, and interfere with the function of critical metabolic enzymes and co-enzymes. Glutathione (GSH) an essential biomarker is considered a key factor in harnessing the thallium toxicity. In the present study the interaction of Thallium (Thallium Chloride) and glutathione was investigated spectro-photo-metrically in aqueous media. The renowned Elman's experimental protocol was followed at a wavelength of 412nm for Glutathione quantification in each sample. The pH of each sample was maintained at 7.6 using Phosphate buffer during the entire course of the experiment. A concentration as well as time dependent depletion of glutathione after exposure to various concentration of Thallium metal was observed, revealing chemical interaction between the metal and glutathione. The exact mechanism of interaction of Thallium and glutathione is still to be investigated. However, this piece of research suggests that a decrease in the concentration of Glutathione may be due to Thallium-GSH abduct or oxidize glutathione (GSSG) formation. This study was performed in-vitro as a model of in vivo.