The Journey and Excitement Following the Development of the First Peptide in a Pill: A Brief Overview of Pharmacology and Clinical Trials of Oral Semaglutide

Oral semaglutide is the newest discovery, the first in class peptide in a pill. Sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC), a small fatty acid, has been co-formulated with semaglutide, which facilitates its absorption from the gastric mucosa. It has 94% homology with human glucagon-like peptide 1 (GLP-1). It comes in three dose forms – 3 mg, 7 mg and 14 mg. It is given as once daily dosing and is recommended in adult type 2 diabetes mellitus patients as monotherapy when metformin is contraindicated or not tolerated and in combination with other oral antidiabetic drugs (OADs). In a phase 3 trial, it has been shown to reduce glycated hemoglobin (HbA1c) up to 1.5%, with weight reduction up to 5 kg with a 14 mg dose. There was nonsignificant risk reduction of 21% in 3-point major adverse cardiovascular events (MACE) and 51% and 49% risk reduction in cardiovascular (CV) deaths and all-cause mortality, respectively. Oral semaglutide was found to be superior to empagliflozin, sitagliptin and liraglutide in both glycemic control and weight reduction. It also exhibits many pleiotropic effects – reduced energy intake, anti-inflammatory and anti-atherosclerotic effect, to name a few. Nausea was the most common side effect which was experienced by only 15% to 20% of patients. It was mild-to-moderate and transient. Overall, oral semaglutide has shown its efficacy both early and late in the management of diabetes, irrespective of renal and hepatic impairment.

Vitamin B12 Deficiency Presenting as Acute Psychosis.

Psychiatric symptoms attributable to vitamin B12 deficiency have been described for decades. Vitamin B12 deficiency is common in developing countries and its prevalence ranges up to 67% among Indian population.1 The earlier reports are for the most part in accordance with more recent ones, despite being diagnostically less specific in psychiatric and haematological terms. These symptoms seem to fall into several clinically separate categories like slow cerebration, confusion, memory changes, delirium, with or without hallucinations and/or delusions, depression, acute psychotic states, and (more rarely) reversible manic and schizophreniform states.2 Apart from these conditions, some cases of dementia, violent behaviour and fatigue have also been documented to be caused by vitamin B12 deficiency.3 Reports of patients initially presenting to psychiatric facilities without associated haematological manifestations are rare. There are a few case reports of acute psychosis attributed to vitamin B12 deficiency, but more evidence is required to substantiate and establish this association.4 We describe three patients who developed acute psychosis accompanied by features suggestive of organic aetiology. They were found to have cobalamin deficiency in the absence of typical neurological or haematological abnormalities.

Distal End Radius Fracture Treatment by Different Modalities: A Comparative Study at Tertiary Hospital In Western Maharashtra.

Background: A retrospective study was conducted in the department of orthopaedic surgery in a tertiary care hospital of western Maharashtra. Methods: Data of all the patients with fracture of distal end radius with or without ulna fracture who were admitted in our centre over a period of 4 years were recorded from case files, casuality admission register and operative records. A total of 204 patients were included in our study and mode of treatment was compared among the various available treatment modality such as cast/slab; percutation fixation with k-wire, external fixation & plate osteosynthesis. Results: Out of the total number of cases (n=204) for fracture distal end radius, nearly 10% case were managed with cast (n=21), 22% with percutaneous fixation with k-wire (n=45), 23.5% with external fixature (n=48), 19% with both external fixator and k-wire (n=38) and 25% with plate osteosynthesis (n=52). Hence when we assess the modality of treatment of distal end radius year wise from 2011 to 2014, the incidence of surgery by plate osteosynthesis has increased over a span of period. Conclusion: Retrospective study conducted at our tertiary care hospital concludes that incidence of plating for distal end radius fracture has increased over a period of time as compared to cast, percutaneous k -wire fixation and external fixator.

Comparison of interferon gamma release assay & tuberculin skin tests for diagnosis of latent tuberculosis in patients on maintenance haemodialysis.

Background & objectives: Tuberculosis (TB) is a common infection in patients on haemodialysis. There is a definite role of treatment of latent TB (LTB) in these patients. However, diagnosis of LTB in these patients by tuberculin skin test (TST) is unreliable. There is suggestion that interferon gamma release assay (IGRA) will be more reliable test for diagnosis of LTB in this setting. Thus, we evaluated value of IGRA and TST for the diagnosis of LTB in patients on dialysis in an Indian setting. Methods: Patients with end stage kidney disease on dialysis were included. Patients with active TB were excluded. Each patient was subjected to TST (induration of ≥10 mm was taken as positive) and QuantiFERON TB Gold In-Tube test (QFT-GIT) for diagnosis of LTB. Results: A total of 185 patients were included; 129 (69.7%) were males and mean age was 36.7 ± 12.3 yr. Past history of TB was present in 18 (9.7%) patients. One hundred and thirty four (72.4%) patients had scar of BCG vaccination. QFT-GIT test was positive in 66 (36%), TST in 32 (17%) and both in 13 (7%) patients. Of the 66 patients positive with QFT-GIT, only 13 (19.6%) were positive for TST. Of the 32 patients positive with TST, only 13 (40.6%) were positive with QFT-GIT; 100 (54%) patients were negative for both the tests. Overall, 85 (45.9%) patients were positive for either of the two tests. Poor agreement was shown between the two methods. On logistic regression analysis, odds of QFT-GIT to be positive in patients with BCG vaccination was 1.23 and with history of TB 0.99, both being insignificant. odds of tuberculin skin test to be positive in patients with BCG vaccination was 1.04 and with history of TB 0.99, both again being insignificant. Interpretation & conclusions: Our findings showed that more number of patients (36%) on haemodialysis were positive for QuantiFERON Gold In-Tube test as compared to TST (17%). There was poor agreement between the two tests. no significant effect of BCG vaccination and history of TB in past was observed on both tests.

Intra-pulmonary teratoma: A rare case.

A 28-year-old female, home-maker presented to our department with a four-year history of intermittent episodes of cough and haemoptysis. She had no history of fever, weight loss or expectoration. Physical examination was unremarkable.

Crescentic glomerulonephritis: A clinical and histomorphological analysis of 46 cases.

Background: Crescentic glomerulonephritis (CrGN), defined as crescents involving more than 50% of the glomeruli, includes pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease. Objectives: The present study was aimed at evaluating the various clinical, biochemical and histological parameters in CrGN with respect to these categories and clinical outcome. Materials and Methods: Renal biopsies diagnosed as CrGN between Jan 2008 and Feb 2010 were included. Clinical and laboratory parameters were retrieved along with the therapeutic approach and clinical outcome, wherever available. Renal biopsy slides were evaluated for various glomerular, tubulo-interstitial and arteriolar features. Appropriate statistical tests were applied for significance. Results: A total of 46 cases of CrGN were included; majority (71.7%) of cases were pauci-immune (PI) while 28.3% were immune complex-mediated (IC). Among clinical features, gender ratio was significantly different between PI and IC groups (P = 0.006). The various histological parameters, including proportion of cellular crescents, tuft necrosis and Bowman's capsule rupture, were similar in both the groups. Four unusual associations, including idiopathic membranoproliferative glomerulonephritis (MPGN), multibacillary leprosy, acute lymphoblastic leukemia and C1q nephropathy were detected. Adequate follow-up information was available in 21 (46%) of the patients. Of these, 11 (52.4%) were dialysis-dependent at the last follow-up. Adult patients required renal replacement therapy more frequently than pediatric cases (P = 0.05). Presence of arteriolar fibrinoid necrosis also showed association with poor clinical outcome (P = 0.05). Conclusions: Crescentic glomerulonephritis remains one of the main causes of acute renal failure with histological diagnosis. Immunohistologic examination is essential for accurate classification into one of the three categories. This condition should be considered in rare causal associations like leprosy or MPGN with renal failure, to allow for timely performed renal biopsy and appropriate aggressive therapy.

Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies.

Background: Calcineurin inhibitors (cyclosporine and tacrolimus) are important constituents of post renal transplant immunosuppression. However, renal toxicity limits their utility. Histological features of calcineurin inhibitor toxicity (CNIT) have been the subject of few studies using protocol biopsy samples, and consensus on diagnostic criteria is still evolving. Aims: To analyze the spectrum of histological changes in protocol renal allograft biopsies with evidence of CNIT and identify additional features that are likely to help the pathologist in arriving at a diagnosis. Materials and Methods: One hundred and forty protocol allograft biopsies performed at 1, 6 and 12 months post renal transplant were studied. The defining features of CNIT included: isometric vacuolization of proximal tubular cells, arteriolar hyalinosis with medial/peripheral nodules and striped pattern of tubular atrophy/interstitial fibrosis. Other features such as global glomerulosclerosis, vacuolization of smooth muscle cells of arterioles, tubular microcalcinosis, ischemic shrinkage of glomeruli and hyperplasia of juxtaglomerular apparatus (JGA) were also analyzed and graded semiquantitatively. Results: CNIT was seen in 17/140 protocol biopsies (12.1%). In addition to the diagnostic criteria, arteriolar hyalinosis, smooth muscle cell vacuolization of arterioles and hyperplasia of JGA were found to be useful indicators of CNIT. Conclusions: There is a relatively high incidence of CNIT in protocol allograft biopsies. A critical analysis of renal biopsy in adequate number of serial step sections to identify these features is mandatory, as many of these features are subtle and are likely to be missed if not specifically sought.

Use of different primer directed sequence amplification by polymerase chain reaction for identification of Pneumocystis jirovecii in clinical samples.

BACKGROUND: Pneumocystis carinii pneumonia (PCP), caused by opportunistic agent Pneumocystis jirovecii (formerly, Pneumocystis carinii is one of the most serious respiratory infection in immunocompromised patients. AIM: The present study was conducted to compare polymerase chain reaction (PCR) assays targetting three different genes of Pneumocystis to study their application in its diagnosis. METHODS: One hundred and eighty (n = 180) clinical samples from 145 immunocompromised patients with clinical suspicion of PCP and 35 samples from control group of 30 immunocompetent individuals with respiratory infections other than PCP were prospectively examined for the presence of Pneumocystis jirovecii (P. jirovecii). All the samples were subjected to microscopic examination, one single [major surface glycoprotein, (MSG)] and two nested [mitochondrial large subunit ribosomal ribonucelic acid, (mtLSU rRNA) and internal transcribed spacer (ITS) region], polymerase chain reaction assays. RESULTS: Microscopic examination was positive in only six (n = 6) patients, whereas single round MSG PCR detected P. jirovecii deoxyribonucleic acid (DNA) in 16 cases. When the clinical samples were tested by mtLSU rRNA and ITS nested PCR assays, it was possible to detect seven additional cases of PCP, making it to a total of 23 cases. None of the clinical specimens in control group (n = 30) were positive by any of the above-mentioned techniques. Amongst the 81 bronchoalveolar lavage (BAL) samples tested, 16 were positive by MSG PCR, while 20 were positive by both nested, i.e., mtLSU rRNA and ITS PCR assays. Similarly, out of 50 sputum samples, only three were positive by MSG, seven by mtLSU rRNA and six by ITS nested PCR assays. CONCLUSION: It has been observed that MSG is relatively more sensitive when single round PCR assay is used for detection of human Pneumocystosis compared to the first (single) rounds of either ITS or mtLSU rRNA nested PCRs. However, the two nested PCRs using ITS and mtLSU rRNA have been found to be more sensitive. On comparison of two nested PCR assays, the results have been more or less comparable.

Multiple myeloma presenting as collapsing glomerulopathy.

A 54 year old male patient was admitted with advanced renal failure of recent onset. Serology was noncontributory. Renal biopsy showed collapsing glomerulopathy with interstitial fibrosis. Bone marrow examination confirmed the diagnosis of multiple myeloma. With chemotherapy multiple myeloma went into remission. However he continued to remain dialysis dependent and a repeat kidney biopsy showed progression to endstage renal disease.