The impact of demonetisation on the utilisation of hospital services, patient outcomes and finances: a multicentre observational study from India.

BACKGROUND: This study assessed trends in healthcare utilisation in relation to the implementation of an economic policy in India wherein 500 and 1000 rupee notes were demonetised. METHODS: In this ambidirectional observational study of private not-for-profit hospitals, data on hospital outpatient and inpatient numbers, surgeries, emergency department (ED) visits, obstetric admissions and mortality were obtained for pre-demonetisation (September/October 2016), early (November/December 2016) and late demonetisation (January/February 2017), and post-demonetisation periods (March/April 2017) and compared with the control period (2015-2016) from 11 centres (three tertiary hospitals; eight secondary). A Bayesian regression analysis was performed to adjust for seasonal (winter) effect. Monthly financial data, including the proportion of cash versus non-cash transactions, were collected. FINDINGS: Overall, at the pooled all-hospital level, Bayesian analysis showed non-significant increase in outpatients (535.4, 95% CI -7097 to 8116) and decrease in deaths (-6.3 per 1000 inpatients, 95% CI -15.45 to 2.75) and a significant decrease in inpatients (-145.6, 95% CI -286.4 to -10.63) during demonetisation. Analysis at the level of secondary and tertiary hospitals showed a variable effect. For individual hospitals, after adjusting for the seasonal effect, some hospitals observed a significant reduction in outpatient (n=2) and inpatient (n=3) numbers, ED visits (n=4) and mortality (n=2) during demonetisation, while others reported significantly increased outpatient numbers (n=3) and ED visits (n=2). Deliveries remained unchanged during demonetisation in the hospitals that provided the service. There was no significant reduction in hospital incomes during demonetisation. In tertiary hospitals, there was a significant increase in non-cash component of transactions from 35% to 60% (p=0.02) that persisted beyond the demonetisation period. CONCLUSIONS: The effect of demonetisation on healthcare utilisation was variable. Some hospitals witnessed a significant reduction in utilisation in some areas, while others reported increased utilisation. There was an increase in non-cash transactions that persisted beyond the period of demonetisation.

Detection of parvovirus B19 in selected high-risk patient groups & their phylogenetic & selection analysis.

Background & objectives: Human parvovirus B19V (B19V) is known to be associated with erythema infectiosum commonly in children, aplastic crisis, especially in persons with underlying haemolytic disorders, hydrops fetalis in pregnancies and arthritis. This cross-sectional study was aimed to determine the presence of B19V infection in childhood febrile illnesses, association of B19V with arthropathies and in adult patients with end-stage renal disease (ESRD) on dialysis. The genetic diversity among the sequences was also analysed. Methods: A nested polymerase chain reaction (nPCR) assay was used for B19V DNA targeting VP1/VP2 region and used for testing 618 patients and 100 healthy controls. Phylogenetic analysis on nucleotide and amino acid sequences was carried out to compare our sequences with other Indian strains and global strains. Results: Among 618 samples tested, seven (1.13%) were found positive. The phylogenetic analysis revealed that all the seven sequences belonged to genotype 1 and showed low genetic diversity. The clustering pattern of seven sequences was similar both by nucleotide and by predicted amino acid sequences. The fixed effects likelihood analysis showed no positive or negatively selected sites. Interpretation & conclusions: Seven samples (4 from non-traumatic arthropathies, 2 from patients with ESRD and 1 from febrile illness patient) were found positive by nPCR. When our seven sequences were compared with global strains, the closest neighbour was other Indian strains followed by the Tunisian strains.

Development & standardization of an in-house IgM indirect ELISA for the detection of parvovirus B19 infections.

BACKGROUND & OBJECTIVES: Parvovirus B19 infections occur worldwide; the infection is acquired early in childhood but could occur later. B19 is reported to cause infection in childhood febrile illnesses, and arthropathies in adults and children and in end-stage renal disease (ESRD) seen in adults. This study was designed to develop an in-house IgM indirect ELISA for serological screening among patients and controls, and to compare ELISA results with those of nested polymerase chain reaction (nPCR) assay. METHODS: An in-house IgM indirect ELISA was standardized using peptide sequence of VP1/VP2 region of parvovirus B19. A total of 201 children and adult with febrile illnesses, 216 individuals with non-traumatic arthropathies, 201 cases of chronic anaemia associated with ESRD and 100 healthy controls were tested. Serum was separated from the blood and subsequently used for DNA extraction. The nested polymerase chain reaction (nPCR) for the detection of B19V DNA was performed using primers targeting the overlapping region of VP1/VP2 capsid protein genes. RESULTS: A total of 618 samples were tested for parvovirus B19 by an in-house IgM indirect ELISA. Among these samples, six were positive by in-house ELISA. The inter-rater agreement between ELISA and PCR assays was calculated using kappa coefficient analysis. The value of κ was 0.77 and the strength of agreement was 'good' (P<0.001). INTERPRETATION & CONCLUSIONS: The in-house IgM indirect ELISA was found to be simple with high sensitivity and specificity when compared with nPCR and could be used as an alternative to expensive commercial kits in resource-poor settings.

A randomized controlled experimental study comparing chitosan coated polypropylene mesh and Proceed™ mesh for abdominal wall defect closure.

BACKGROUND: Abdominal wall defects and hernias are commonly repaired with synthetic or biological materials. Adhesions and recurrences are a common problem. A study was conducted to compare Chitosan coated polypropylene mesh and a polypropylene-polydioxanone composite with oxidized cellulose coating mesh (Proceed™) in repair of abdominal wall defect in a Rabbit hernia model. METHODS: A randomized controlled experimental study was done on twelve New Zealand white rabbits. A ventral abdominal defect was created in each of the rabbits. The rabbits were divided into two groups. In one group the defect was repaired with Chitosan coated polypropylene mesh and Proceed mesh™ in the other. The rabbits were operated in two phases. They were followed up at four weeks and twelve weeks respectively after which the rabbits were sacrificed. They were evaluated by open exploration and histopathological examination. Their efficacy in reducing adhesion and ability of remodeling and tissue integration were studied. RESULTS: There was no statistical significance in the area of adhesion, the force required to remove the adhesions, tissue integration and remodeling between Chitosan and Proceed™ group. Histological analysis revealed that the inflammatory response, fibrosis, material degradation and remodeling were similar in both the groups. There were no hernias, wound infection or dehiscence in any of the studied animals. CONCLUSION: Chitosan coated polypropylene mesh was found to have similar efficacy to Proceed™ mesh. Chitosan coated polypropylene mesh, can act as an anti adhesive barrier when used in the repair of incisional hernias and abdominal wall defects.

RET mutations in a large indian family with medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a tumor arising from the para follicular (C) cells of the thyroid gland and can occur either sporadically or as part of an inherited syndrome. A proportion of these cases carry an autosomal dominant mutation in the RET (REarranged during Transfection) proto-oncogene. Screening for these mutations in the affected patients and the carriers "at risk" which includes the first-degree relatives is of utmost importance for early detection and prompt treatment including prophylactic thyroidectomy in cases that harbor these mutations. RESULTS: This report presents details of screening and subsequent follow-up of a large Indian family, where the index case was found to carry p. Cys634Ser mutation involving exon 11 of the RET gene. These data are of value considering the paucity of information within the region in context of screening large families affected by these mutations.

Our experience with papillary thyroid microcancer.

BACKGROUND: Papillary thyroid microcarcinoma (PTMC) describes a focus of papillary thyroid cancer that is less than 1 cm in size. These tumors are frequently found on histopathological examination of thyroid specimens, operated upon for an indication other than suspected malignancy. MATERIALS AND METHODS: From 2005 to 2012, 94 of 1300 thyroidectomy specimens in our institution were found to have PTMC. Of these, 77 were isolated PTMC while the others were associated with other differentiated cancers. We studied their clinicopathologic features, treatment and long-term outcome. RESULTS: There were 18 men and 59 women (the male: female ratio was 1:3), their mean age was 44 ± 10.5 years (range: 18-72 years). Multinodular goiter was the most common indication for surgery. Malignancy was suspected in only 31.4% cases. The mean tumor size was 4.1 ± 2.3 mm. Nearly 17% cases had slightly larger tumors measuring >6 but <10 mm. Multifocal tumor was found in 44.1% of cases and among these, multifocal disease restricted to a single lobe was found in 19.5%. Eleven patients (14.2%) had cervical lymph node metastasis, 3 (3.9%) had extra thyroid tumor extension and 2 (2.6%) had evidence of vascular invasion. One patient (1.3%) presented with bone metastasis. Majority of the patients (79.2%) underwent total thyroidectomy with or without lymph node dissection. Sixteen patients (20.7%) who had initially undergone hemithyroidectomy went on to have completion thyroidectomy. Twenty nine patients (36.8%) also received radioactive iodine. The mean duration of follow-up was 20.2 ± 13.5 months. On follow-up one patient developed cervical lymph node recurrence and one died due to a second malignancy. CONCLUSIONS: PTMC is often found as an incidental finding on the thyroidectomy specimen. Sometimes they present with regional lymph node metastasis and very rarely with distant metastasis. They have a good prognosis similar to papillary thyroid carcinoma.

The role of urinary fractionated metanephrines in the diagnosis of phaeochromocytoma.

BACKGROUND & OBJECTIVES: Plasma and urinary metanephrines are used as screening tests for the diagnosis of phaeochromocytoma. The recommended cut-off levels are not standardized. This study was conducted to identify a cut-off level for 24 h urinary fractionated metanephrines viz. metanephrine (uMN) and normetanephrine (uNMN) using enzyme immunoassay for the diagnosis of phaeochromocytoma. METHODS: Consecutive patients suspected to have phaeochromocytoma were included in the study. uMN and uNMN in 24 h urinary sample were measured using a commercial ELISA kit. RESULTS: Overall, 72 patients were included over a period of 18 months. Twenty patients had histopathologically confirmed phaeochromocytoma and in 52 patients phaeochromocytoma was ruled out. Using the upper limit of normal stated by the assay manufacturer as the cut-off, uMN >350 µg/day had a low sensitivity and uNMN >600 µg/day had a poor specificity. By increasing the cut-off value of uNMN to twice the upper limit, specificity increased significantly without much loss in sensitivity. Combining uMN and uNMN using a cut-off twice the upper limit improved the diagnostic performance - sensitivity (95%); specificity (92.3%); positive predictive value (PPV - 82.6%); negative predictive value (NPV - 98%). In subsets of patients with a variable pretest probability for phaeochromocytoma, the PPV correlates well with the occurred of these tumors decreased, while the NPV remained at 100 per cent. INTERPRETATION & CONCLUSIONS: ELISA is a simple and reliable method for measuring uMN and uNMN. The test has a good NPV and can be used as an initial screening test for ruling out phaeochromocytoma. Each hospital will have to define the cut-off value for the assay being used, choosing a proper control population.

P.Arg82Leu von Hippel-Lindau (VHL) gene mutation among three members of a family with familial bilateral pheochromocytoma in India: molecular analysis and in silico characterization.

Various missense mutations in the VHL gene have been reported among patients with familial bilateral pheochromocytoma. However, the p.Arg82Leu mutation in the VHL gene described here among patients with familial bilateral pheochromocytoma, has never been reported previously in a germline configuration. Interestingly, long-term follow-up of these patients indicated that the mutation might have had little impact on the normal function of the VHL gene, since all of them have remained asymptomatic. We further attempted to correlate this information with the results obtained by in silico analysis of this mutation using SIFT, PhD-SNP SVM profile, MutPred, PolyPhen2, and SNPs&GO prediction tools. To gain, new mechanistic insight into the structural effect, we mapped the mutation on to 3D structure (PDB ID 1LM8). Further, we analyzed the structural level changes in time scale level with respect to native and mutant protein complexes by using 12 ns molecular dynamics simulation method. Though these methods predict the mutation to have a pathogenic potential, it remains to be seen if these patients will eventually develop symptomatic disease.

A phase 2 study of sequential neoadjuvant chemotherapy with gemcitabine and doxorubicin followed by gemcitabine and cisplatin in patients with large or locally advanced operable breast cancer: results from long-term follow-up.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is being increasingly used for patients with large-size operable breast cancer. This phase 2 study of sequential NACT with gemcitabine and doxorubicin (Gem + Dox) followed by gemcitabine and cisplatin (Gem + Cis) was conducted in women with large or locally advanced breast cancer. The objectives were to evaluate the pathological complete response (pCR) rate, toxicity, pathological and genetic markers predicting response, the proportion of patients undergoing breast conservation surgery, progression-free survival (PFS) and overall survival (OS) after 5 years, and time to treatment failure (TtTF). In this manuscript, we report the long-term OS, PFS, and TtTF results. METHODS: Female patients aged at least 18 years with large T2 (at least 3 cm) or locally advanced (T3, T4, or N2) breast carcinoma were included. Treatment consisted of 4 cycles of Gem + Dox (gemcitabine 1,200 mg/m(2) on days 1 and 8 plus doxorubicin 60 mg/m(2) on day 1 of each 21-day cycle), followed by 4 cycles of Gem + Cis (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus cisplatin 70 mg/m(2) on day 1 of each 21-day cycle), and then surgery. RESULTS: Sixty-five patients were enrolled. The pCR rate was 20%. The 5-year OS probability was 71% (95% CI 56-82%), and the 4-year PFS and TtTF probabilities were 63% (95% CI 48-74%) and 45% (95% CI 32-57%), respectively. CONCLUSIONS: NACT with Gem + Dox followed by Gem + Cis was efficacious in patients with operable breast cancer.

High index of clinical suspicion with optimal surgical techniques and adjuvant radiotherapy is critical to reduce locoregional disease progression in parathyroid carcinoma.

AIMS: We have analyzed the risk factors and the impact of external beam radiotherapy (EBRT) in reducing the locoregional recurrence of parathyroid carcinoma (PTC). METHODS: Various parameters such as clinical presentation, intraoperative findings, surgical methods, and usage of parafibromin were analyzed. Selected endpoints were locoregional progression-free survival and overall survival. RESULTS: Three patients had local recurrence. Two of them received EBRT after the first recurrence but continued to have local recurrence. One patient was lost to follow-up. Six patients with EBRT remain asymptomatic with a locoregional progression-free survival and overall survival of 42 months. The presence of a palpable nodule in the neck, serum calcium >14 mg/dL, and intraoperative substrap adhesion (OR=9.3, 95% confidence interval, 1.76-56.1; P<0.05) should raise suspicion. Four of 5 patients showed a predominantly negative staining with parafibromin. CONCLUSIONS: PTC should be suspected in the preoperative and intraoperative period. EBRT may reduce local recurrence by 65%. Parafibromin staining with no more than 0 to 1+ intensity in 80% to 100% of cells can predict carcinoma with specificity up to 100%.

Discriminating thyroid cancers from benign lesions based on differential expression of a limited set of miRNA using paraffin embedded tissues.

BACKGROUND: Micro-RNAs (miRNAs) are expressed in a tissue-specific manner and are known to demonstrate differential expression even among the various subtypes of a given tumor. This differential expression has been harnessed successfully in the development of diagnostic assays for various malignant tumors. These assays have been found to be relevant and of value as additional diagnostic tools even among thyroid tumors, particularly with regard to thyroid carcinomas of follicular morphology. MATERIALS AND METHODS: A limited set of miRNA have been assessed as part of this study in an effort to use minimal number of miRNA markers (miR-187, miR-221, miR-222, and miR-224) to differentiate the benign from the malignant thyroid tumors using miRNA derived from paraffin embedded material. RESULTS: While miR-221 and miR-222 were found to provide good accuracy as individual markers (86% and 84%), a combination of the two provided slightly better accuracy (91%). Both miR-221 and 222 were able to significantly differentiate malignant tumors from the benign samples (P< 0.001) individually and as a combination of markers. However, inclusion of miR-187 and miR-224 in the panel did not provide any additional benefit. CONCLUSION: While a combination of miR-221 and 222 when used in a diagnostic panel could provide fairly good accuracy additional markers may need to be investigated to augment their diagnostic utility.

Low dose aspirin prevents duodenoesophageal reflux induced mucosal changes in wistar rat esophagus by MAP kinase mediated pathways.

BACKGROUND: Investigations of molecular mechanisms behind the progression of neoplastic changes in the esophagus have uncovered the role of the COX & 5-Lox pathways. Human squamous esophageal mucosa produces relatively large amounts of eicosanoids in the presence of inflammation. Laboratory and epidemiological data suggest that aspirin and non-steroidal anti-inflammatory drugs may be chemo preventive through their inhibitory effect on COX25, 10. Cell culture studies have shown that the members of the mitogen activated protein (MAP) kinase family plays an important role in the development of bile acid-induced carcinogenesis. Differences in MAPK pathways activated by bile exposure were also noted in esophageal squamous cell lines and biopsies from patients with GERD. The protective role of aspirin and its molecular mechanism is not well understood. AIMS: 1. The effect of duodenal reflux on esophageal mucosa. 2. The role of aspirin in preventing duodenal reflux induced esophageal mucosa changes. 3. If it is proven to be preventive, the mechanism of its action. A duodenal reflux rat animal model was used by an end- to-side esophago duodenostomy. METHODS: Total of 56 rats was included. 3 were "Naive control" animals which did not undergo the surgical procedure. The remaining animals were divided into two groups: Surgery alone (experimental) and Surgery + aspirin [therapy group], esophagoduodenostomy. At 40 weeks, the rats were euthanized and appropriate esophageal samples were analysed for histopathology and p38 & ERK MAP kinases, VEGF, protease activity and caspase 3 activities. RESULTS: The presence of gross mucosal nodularity was seen in 21 and 10 rats of the experimental and therapy group respectively (p = 0.03; Table 1). Reflux-associated changes such as basal cell hyperplasia were more common in the experimental group, however this association did not reach statistical significance (p = 0.15; Table 1). Epithelial hyperplasia was seen more in the experimental group, which was prevented by aspirin [p < 0.01]. Papillomatosis, as shown in Fig. 4 was more common in the experimental group (p = 0.02). Activation of p38 & ERK MAP kinases was prevented in aspirin group (p < 0.05, CI -1.796--0.014). Examination of protease activity by zymographic analysis of the esophageal samples revealed a number of gelatinolytic bands in 50% rats of the experimental group, not observed in the therapy group. No significant changes were seen in Caspase 3 [Normal areas -99.74 & nodular areas - 100.34 percent of controls] or VEGF [mean 0.64, sd ± 0.76 Vs 0.69 ± 0.96] activity. CONCLUSIONS: Our data demonstrated that low dose aspirin reduced the incidence of duodenoesophageal reflux induced histological changes in the esophagus by preventing activation of proliferative & anti-apoptotic MAP kinases such as p38 & ER as well as protease activity. Though Barretts' changes and adenocarcinoma have not developed, it could explain the role of duodenoesophageal reflux in the development of different histological but potential premalignant lesions and molecular level changes which are prevented by low dose aspirin.

Mapping the compound muscle action potentials of cricothyroid muscle using electromyography in thyroid operations: a novel method to clinically type the external branch of the superior laryngeal nerve.

OBJECTIVE: Variations of the external branch of the superior laryngeal nerve (EBSLN) are well represented in literature but with conflicting reports about the types and variations. Using EMG, the cricothyroid compound muscle action potential (CMAP) was recorded, to identify the EBSLN and classified them according to clinical variation during routine thyroid operations. SUMMARY BACKGROUND DATA: There is increasing awareness among patients and physicians of the consequences of injury to the external laryngeal nerve in thyroid surgeries. There are at least 4 types, which are described in the literature. The gold standard of nerve identification is EMG, which we used during operations in this study to identify all the EBSLN by demonstrating CMAP and reclassify them. Based on this principle, to avoid injury during thyroidectomy, we propose a new classification. METHODS: This study was a prospective, descriptive study of the EBSLN done during elective thyroidectomy operations. CMAP was demonstrated and EMG was plotted to identify and type them according to clinical variations. The distance between the entry of superior thyroid vessels (STVs) to the lobe and the EBSLN, relationship with the cricothyroid muscle and inferior constrictor muscle were taken into consideration. Based on the possible risk to this during thyroidectomy, we divided them into 4 types. RESULTS: : A total of 70 external laryngeal nerves were dissected and confirmed by the CMAPs in 35 total thyroidectomy patients. Using CMAPs, all the nerves were identified. CONCLUSION: New clinical typing of the EBSLN will give a better understanding of the EBSLN in the intraoperative period. EBSLN need not be identified in routine thyroidectomy operations. Even in large goiters, the incidence of nerve at risk does not increase significantly. Injury to EBSLN can be avoided if the principle of ligating the STVs individually away from the CT muscle and close to the capsule of the gland is followed.

A case of Turner syndrome with hyperparathyroidism in an adult.

Turner syndrome is a hereditary chromosomal anomaly that affects girls and women. A result of gonadal dysgenesis, its primary characteristics are short stature, osteoporosis, neck webbing, and cardiac defects. Turner syndrome may also involve the auditory system and kidneys. We report the case of a woman with Turner syndrome who presented late in adulthood with severe osteoporosis and hypercalcemia. She was subsequently diagnosed with primary hyperparathyroidism secondary to a parathyroid adenoma. After excision of the adenoma, the woman's serum calcium level normalized. To the best of our knowledge, only 4 other cases of Turner syndrome with hyperparathyroidism have been reported in the literature.

Management of insulinomas: analysis from a tertiary care referral center in India.

The aim of this study was to describe the localization and management of patients with pancreatic insulinomas and determine the most effective localization and surgical techniques in the presence of significant financial constraints in the patient population. We retrospectively reviewed the case records of 18 patients with insulinomas treated at our institution over a period of 10 years. The medical records were reviewed for demographic data, clinical presentation, biochemistry, details of localization studies, intraoperative findings, postoperative outcome, and long-term follow-up. The sensitivities of the various localization procedures were calculated using the intraoperative findings as the gold standard. There were 10 men and 8 women in the study, with a median age of 43 years. All patients underwent a supervised 72-hour fast and developed symptomatic hypoglycemia within 48 hours. An average of 1.9 localization procedures was performed per patient. Computed tomography (CT) had a sensitivity of 62% and specificity of 100%. Magnetic resonance imaging and digital subtraction angiography had specificities of 85% and 100%, respectively, with a specificity of 66% and 50%, respectively. Fourteen patients underwent surgery. Intraoperatively the excised tumor was palpable in nine patients, and all patients had postoperative euglycemia. In five patients the tumor was not palpable during the time of surgery; three of these patients underwent blind distal pancreactomy, with two patients having persistent hypoglycemia during the postoperative period. Two patients had a negative exploratory laparotomy. Patients with a surgical cure were followed up for a mean period of 24 months. On the background of financial constraints in connection with patient care, CT scanning is a cost-effective option with good specificity. Intraoperative palpation of the tumor and enucleation is the most effective technique for surgical cure. Blind distal pancreactomy is not advocated for tumors that are not localized intraoperatively.

Extra-adrenal retroperitoneal paraganglioma associated with duplication of inferior vena cava.

Retroperitoneal paragangliomas arise from specialized neural crest cells symmetrically distributed along the aorta in association with the sympathetic chain. If this tissue aggregates in the adrenal medulla pheochromocytoma may arise. When it remains in the paraaortic sites it could develop into extra-adrenal, retroperitoneal paraganglioma. We report a case of extra-adrenal paraganglioma in the renal hilum intimately related to the left side of a double inferior vena cava. To the best of our knowledge such an association has never been described before. The clinical significance of this venous anomaly is reviewed.

Plasmacytoma mimicking mediastinal parathyroid tumour in a patient with primary hyperparathyroidism.

The association of monoclonal gammopathies with primary hyperparathyroidism is well documented. Many case reports have documented the coexistence of primary hyperparathyroidism and multiple myeloma. The cause of this relationship is not known. We report the case of a 49-year-old gentleman who was treated for primary hyperparathyroidism. His initial preoperative nuclear scan had shown persistent activity and retention of tracer in the retrosternal region in addition to the discrete hot spot in the region of the lower pole of the left lobe of the thyroid. During surgery, the enlarged left inferior parathyroid gland was removed. In addition, the retrosternal area was also explored and found to be normal. Ten months later, he developed a mass in the region of the manubrium sternii which was proven to be a plasmacytoma. Were view the literature for similar cases and suggest hypotheses for a possible association. In conclusion, coexisting plasma cell dyscrasias including plasmacytoma should be considered in patients with primary hyperparathyroidism.