A Review of Parathyroid Surgery for Primary Hyperparathyroidism from the United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS).

BACKGROUND: The United Kingdom Registry of Endocrine and Thyroid Surgeons is a national database holding details on > 28,000 parathyroidectomies. METHODS: An extract (2004-2017) of the database was analysed to investigate the reported efficacy, safety and use of intra-operative surgical adjuncts in targeted parathyroidectomy (tPTx) and bilateral neck exploration (BNE) for adult, first-time primary hyperparathyroidism (PHPT). RESULTS: 50.9% of 21,738 cases underwent tPTx. Excellent short-term (median follow-up 35 days) post-operative normocalcaemia rates were reported overall (tPTx 96.6%, BNE 94.5%, p  0.05), nor any difference in VC dysfunction when formally examined (4.9% vs 4.1%, p > 0.05). CONCLUSIONS: In image-positive, first time, adult PHPT cases, tPTx is as safe and effective as BNE, with both achieving excellent short-term results with minimal complications

A minimally invasive immunocytochemical approach to early detection of oral squamous cell carcinoma and dysplasia

Squamous dysplasia of the oral cavity indicates increased risk of progression to squamous cell carcinoma (SCC). An important advance would be the development of a minimally invasive assay for identification of oral SCC and dysplasia. We have investigated the suitability in this context of immunostaining oral smears for minichromosome maintainance proteins (MCMs), sensitive and specific biomarkers of cell cycle entry. Immunohistochemical examination of 66 oral tissue samples showed a greater frequency of Mcm-2 expression in surface layers of moderate/severe dysplasia and SCC compared to benign keratosis/mild dysplasia. Immunocytochemistry for Mcm-2/Mcm-5 was performed on 101 oral smears. Conventional smears included 23 from normal mucosa, benign proliferative disease and mild dysplasia, all of which were MCM negative. Of 52 conventional smears of SCC tissue samples, 18 were inadequate. However, MCM-positive cells were present in 33/34 adequate samples. Of 26 liquid-based cytology smears, 19 out of 20 smears from SCC were adequate and all were MCM positive. Six smears from benign lesions were adequate and MCM negative. We conclude that MCMs are promising markers for early detection of oral SCC and dysplasia, particularly in a liquid-based cytology platform. Detection of MCMs would be amenable to automation and potentially applicable in the developing world. Further studies are now warranted

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10−4) compared with either PBF- (P=1.5 × 10−3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10−5) and disease-free survival (P=4.9 × 10−5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome

A prospective study of monitoring practices for metabolic disease in antipsychotic-treated community psychiatric patients

<p>Abstract</p> <p>Background</p> <p>Patients with severe mental illness are at increased risk for metabolic and cardiovascular disease. A number of recent guidelines and consensus statements recommend stringent monitoring of metabolic function in individuals receiving antipsychotic drugs.</p> <p>Methods</p> <p>We conducted a prospective cohort study of 106 community-treated psychiatric patients from across the diagnostic spectrum from the Northeast of England to investigate changes in metabolic status and monitoring practices for metabolic and cardiovascular disease. We undertook detailed anthropometric and metabolic assessment at baseline and follow-up, and examined clinical notes and hospital laboratory records to ascertain monitoring practices.</p> <p>Results</p> <p>A high prevalence of undiagnosed and untreated metabolic disease was present at baseline assessment. Mean follow-up time was 599.3 (SD ± 235.4) days. Body mass index (p < 0.005) and waist circumference (p < 0.05) had significantly increased at follow-up, as had the number of individuals who were either overweight or obese. Fifty-three per cent of individuals had hypertriglyceridemia, and 31% had hypercholesterolemia, but only 7% were receiving lipid-lowering therapy. Monitoring practices were poor. Recording of measures of adiposity occurred in 0% of individuals, and > 50% of subjects had neither blood glucose nor lipids monitored during the follow-up period.</p> <p>Conclusion</p> <p>This cohort has a high prevalence of metabolic disease and heightened cardiovascular risk. Despite the publication of a number of recommendations regarding physical health screening in this population, monitoring rates are poor, and physical health worsened during the follow-up period.</p

Tumours and tumour-like lesions of the lower face at Korle Bu Teaching Hospital, Ghana – an eight year study

<p>Abstract</p> <p>Background</p> <p>The oro-facial region including the jawbones, the maxilla and mandible and related tissues can be the site of a multitude of neoplastic conditions. These tumours have a predilection for the entire facial region; however, odontogenic tumours tend to affect the mandible more than the maxilla, especially, in West African children. We report results from a retrospective study spanning eight years on the frequency, clinical presentation, sites and character of lower face tumours seen in the main referral hospital in Ghana.</p> <p>Patients and methods</p> <p>Records of consecutive patients of all age and sex seen by the first author's team at the Department of Oral and Maxillofacial Surgery, Korle-Bu Teaching Hospital with tumours affecting the lower part of the face from January 1996 to December 2003 were retrieved, coded and entered into a database. The data were then analyzed by age, sex, presenting signs and symptoms, site of lesion, and their histology.</p> <p>Results</p> <p>A total of 394 patients with oro-facial swellings were retrieved from the registry out of which 210 had lower face tumour and tumour-like lesions. The complete data set was obtained for 171 patients, comprising 99 (58%) males and 72 (42%) females. The most common clinical presenting features were mandibular facial swelling (63%), intra-oral swelling (55%), pain (41%) and ulceration (29%). The tumours were predominantly found in the right (43%), anterior (19%) and left (18%) aspects of the lower face. The remainder making up 20% were found in the floor of the mouth, tongue and lips. Seventy eight (45.6%) of the patients presented with lesions that were classified as malignant of which 54 (62%) were diagnosed as squamous cell carcinoma (SCC). Sixty-two (36.3%) had benign odontogenic tumours and thirty-one (18.1%) had non-odontogenic tumour-like lesions. Fifty-four (62%) of malignant tumours were squamous cell carcinoma; 58 (93.6%) of the benign odontogenic tumours were classified as ameloblastoma. The mean age at presentation of all lesions was 40.4 years with over 50% of benign lesions in patients aged between 11 and 30 years. Malignant tumours were more commonly detected in patients between 41 and 70 years (63%).</p> <p>Conclusion</p> <p>Tumours and tumour-like lesions of the lower face comprising the mandible, tongue and adjacent structures are a diverse group of neoplasm and are seen commonly in practice of Maxillofacial surgery. Both malignant and benign tumours are seen in the Ghanaian population. In the present study, SCC and ameloblastoma were the commonest malignant and benign odontogenic tumours seen respectively; the two representing more than 65% of all tumours.</p

Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC

The human leukocyte antigen (HLA) class II genes HLA-DRB1, -DQA1 and -DQB1 are the strongest genetic factors for type 1 diabetes (T1D). Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region’s high gene density and complex linkage disequilibrium (LD). To facilitate the association analysis, two novel algorithms were implemented in this study: one for phasing the multi-allelic HLA genotypes in trio families, and one for partitioning the HLA strata in conditional testing. Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case–Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families. After imputation, the two datasets have 1,941 common SNPs in the MHC, of which 22 were successfully tested and replicated based on the statistical testing stratifying on the detailed DRB1 and DQB1 genotypes. Further conditional tests using the combined dataset confirmed eight novel SNP associations around 31.3 Mb on chromosome 6 (rs3094663, p = 1.66 × 10−11 and rs2523619, p = 2.77 × 10−10 conditional on the DR/DQ genotypes). A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association

Immunohistochemical estimation of cell cycle phase in laryngeal neoplasia

We previously developed an immunohistochemical method for estimating cell cycle state and phase in tissue samples, including biopsies that are too small for flow cytometry. We have used our technique to examine whether primary abnormalities of the cell cycle exist in laryngeal neoplasia. Antibodies against the markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67, and putative markers of cell cycle phase, cyclin D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis) were applied to paraffin-embedded sections of normal larynx (n=8), laryngeal dysplasia (n=10) and laryngeal squamous cell carcinoma (n=10). Cells expressing each marker were determined as a percentage of total cells, termed the labelling index (LI), and as a percentage of Mcm-2-positive cells, termed the labelling fraction (LF). The frequency of coexpression of each putative phase marker was investigated by confocal microscopy. There was a correlation between Mcm-2 and Ki67 LIs (ρ=0.93) but Mcm-2 LIs were consistently higher. All cells expressing a phase marker coexpressed Mcm-2, whereas Ki67 was not expressed in a proportion of these cells. The putative phase markers showed little coexpression. Labelling index values increased on progression from normal larynx through laryngeal dysplasia to squamous cell carcinoma for Mcm-2 (P=0.001), Ki67 (P=0.0002), cyclin D1 (P=0.015), cyclin A (P=0.0001) and cyclin B1 (P=0.0004). There was no evidence of an increase in the LF for any phase marker. Immunohistochemistry can be used to estimate cell cycle state and phase in laryngeal biopsies. Our data argues against primary cell cycle phase abnormalities in laryngeal neoplasia

Coupled, Physics-Based Modeling Reveals Earthquake Displacements are Critical to the 2018 Palu, Sulawesi Tsunami

The September 2018, Mw 7.5 Sulawesi earthquake occurring on the Palu-Koro strike-slip fault system was followed by an unexpected localized tsunami. We show that direct earthquake-induced uplift and subsidence could have sourced the observed tsunami within Palu Bay. To this end, we use a physics-based, coupled earthquake–tsunami modeling framework tightly constrained by observations. The model combines rupture dynamics, seismic wave propagation, tsunami propagation and inundation. The earthquake scenario, featuring sustained supershear rupture propagation, matches key observed earthquake characteristics, including the moment magnitude, rupture duration, fault plane solution, teleseismic waveforms and inferred horizontal ground displacements. The remote stress regime reflecting regional transtension applied in the model produces a combination of up to 6 m left-lateral slip and up to 2 m normal slip on the straight fault segment dipping 65∘ East beneath Palu Bay. The time-dependent, 3D seafloor displacements are translated into bathymetry perturbations with a mean vertical offset of 1.5 m across the submarine fault segment. This sources a tsunami with wave amplitudes and periods that match those measured at the Pantoloan wave gauge and inundation that reproduces observations from field surveys. We conclude that a source related to earthquake displacements is probable and that landsliding may not have been the primary source of the tsunami. These results have important implications for submarine strike-slip fault systems worldwide. Physics-based modeling offers rapid response specifically in tectonic settings that are currently underrepresented in operational tsunami hazard assessment