Overview of pathogenic Escherichia coli, with a focus on Shiga toxin-producing serotypes, global outbreaks (1982-2024) and food safety criteria.

Classification of pathogenic E. coli has been focused either in mammalian host or infection site, which offers limited resolution. This review presents a comprehensive framework for classifying all E. coli branches within a single, unifying figure. This approach integrates established methods based on virulence factors, serotypes and clinical syndromes, offering a more nuanced and informative perspective on E. coli pathogenicity. The presence of the LEE island in pathogenic E. coli is a key genetic marker differentiating EHEC from STEC strains. The coexistence of stx and eae genes within the bacterial genome is a primary characteristic used to distinguish STEC from other pathogenic E. coli strains. The presence of the inv plasmid, Afa/Dr adhesins, CFA-CS-LT-ST and EAST1 are key distinguishing features for identifying pathogenic E. coli strains belonging to EIEC, DAEC, ETEC and EAEC pathotypes respectively. Food microbiological criteria differentiate pathogenic E. coli in food matrices. 'Zero-tolerance' applies to most ready-to-eat (RTE) foods due to high illness risk. Non-RTE foods' roles may allow limited E. coli presence, which expose consumers to potential risk; particularly from the concerning Shiga toxin-producing E. coli (STEC) strains, which can lead to life-threatening complications in humans, including haemolytic uremic syndrome (HUS) and even death in susceptible individuals. These findings suggest that decision-makers should consider incorporating the separate detection of STEC serotypes into food microbiological criteria, in addition to existing enumeration methods. Contamination of STEC is mainly linked to food consumption, therefore, outbreaks of E. coli STEC has been reviewed here and showed a link also to water as a potential contamination route. Since their discovery in 1982, over 39,787 STEC cases associated with 1,343 outbreaks have been documented. The majority of these outbreaks occurred in the Americas, followed by Europe, Asia and Africa. The most common serotypes identified among the outbreaks were O157, the 'Big Six' (O26, O45, O103, O111, O121, and O145), and other serotypes such as O55, O80, O101, O104, O116, O165, O174 and O183. This review provides valuable insights into the most prevalent serotypes implicated in STEC outbreaks and identifies gaps in microbiological criteria, particularly for E. coli non-O157 and non-Big Six serotypes.

From Oncogenesis to Theranostics: The Transformative Role of PSMA in Prostate Cancer.

Prostate cancer, a leading cause of cancer-related mortality among men, is characterized by complex genetic and epigenetic alterations, dysregulation of oncogenic pathways, and a dynamic tumor microenvironment. Advances in molecular diagnostics and targeted therapies have significantly transformed the management of this disease. Prostate-specific membrane antigen (PSMA) has emerged as a critical biomarker, enhancing the precision of prostate cancer diagnosis and treatment. Theranostics, which integrates PSMA-targeted imaging with radioligand therapies, has shown remarkable efficacy in detecting and treating advanced prostate cancer. By leveraging the dual capabilities of PSMA-based diagnostics and therapeutic agents, theranostics offers a personalized approach that improves patient outcomes. This comprehensive review explores the latest developments in PSMA-targeted theranostics and their impact on the future of prostate cancer management, highlighting key clinical trials and emerging therapeutic strategies.

RETRACTED: Teklemariam et al. Isolation and Characterization of a Novel Lytic Phage, vB_PseuP-SA22, and Its Efficacy against Carbapenem-Resistant Pseudomonas aeruginosa. Antibiotics 2023, 12, 497.

The journal retracts the article, "Isolation and Characterization of a Novel Lytic Phage, vB_PseuP-SA22, and Its Efficacy against Carbapenem-Resistant Pseudomonas aeruginosa", cited above [...].

Presentation of Acute Pancreatitis in Sickle Cell Disease Patients: A Single Hospital Experience.

INTRODUCTION: Sickle cell disease (SCD) is a haemoglobinopathy that leads to the formation of distorted sickle-shaped red blood cells that are prone to vaso-occlusion. This may lead to vaso-occlusive crises that may affect any organ. Acute pancreatitis (AP) in SCD patients may be mimicked by a vaso-occlusive crisis in the abdomen. The objective of this article is to analyse the clinical profiles of SCD patients with AP and understand the differences in the presentation of AP compared to an abdominal vaso-occlusive crisis and the difference between its presentation in SCD patients in comparison to other patients. MATERIALS AND METHODS: Twenty-eight SCD patients who were diagnosed with AP during their admission to the paediatric department at a tertiary hospital between January 2012 and December 2020 were retrospectively studied. Patients aged older than 14 years were excluded. The data collected concerned: demographics, the clinical course and the hospital course. The diagnosis and severity protocols followed the revised Atlanta Criteria. RESULTS: The patients were aged with a mean of 9.61 years. There were 15 males and 13 females. Demographics were not significantly correlated to complication rates (P > 0.05). The mean duration of hospitalisation was 6.43 days. The most common clinical presentations were abdominal pain, fever, then vomiting and nausea. Three patients experienced complications and they were all cases of cholangitis (10.71%). There were no cases of pseudocysts, acute necrotic collections, pancreatic or peripancreatic necrosis or walled-off necroses. All of the cases of AP in SCD children were mild according to the revised Atlanta classification. Leucocytosis was present in 29.29% of patients and 17.8% of patients had high C-reactive proteins (CRPs). There was no significant correlation between leucocyte counts, CRP levels, serum or urinary amylase levels and complications (P > 0.05). All patients had haemoglobin (Hb) levels above 7 g/dL. The levels of sickle Hb ranged from 40 to 70 g/dL and reticulocyte counts averaged at 3.57%. Haematologic parameters were not significantly correlated with complication rates (P > 0.05). There were no recurrences. CONCLUSION: AP in SCD patients presented with classic signs and symptoms. There were no associations between demographics and complications. The levels of leucocytes, CRP counts and serum and urinary amylase were not correlated with complications. The level of Hb and sickle cell Hb was not associated with complication rates. Reticulocytes were slightly elevated in SCD patients with AP. More studies are needed to demarcate factors distinguishing AP in SCD from abdominal vaso-occlusive crises.

Saudi Initiative of Bronchiolitis Diagnosis, Management, and Prevention 2024 updated consensus on the prevention of respiratory syncytial virus.

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis among children under 5 years of age worldwide, accounting for a prevalence of 25%-88% in Saudi Arabia. Although no effective treatment for the virus exists, passive immunoprophylaxis reduced RSV hospitalizations in high-risk children. With recent advances in immunization, the Saudi Initiative of Bronchiolitis Diagnosis, Management, and Prevention panel screened recent relevant international guidelines, locally published data, and expert consensus to update guidelines for RSV prevention, taking into consideration the resources, timing, varying health profiles, and RSV burden in Saudi Arabia. The panel updated its recommendations to include immunization of infants, mothers, and older adults. Practical guidelines were prepared to facilitate the administration of the short-acting and newly developed long-acting RSV monoclonal antibodies (mAb) during the regular follow-ups of high-risk infants in specialized clinics. In addition, long-acting mAb was highlighted as all-infant protection in the routine immunization calendar.

Strong effect of demographic changes on Tuberculosis susceptibility in South Africa.

South Africa is among the world's top eight tuberculosis (TB) burden countries, and despite a focus on HIV-TB co-infection, most of the population living with TB are not HIV co-infected. The disease is endemic across the country, with 80-90% exposure by adulthood. We investigated epidemiological risk factors for (TB) in the Northern Cape Province, South Africa: an understudied TB endemic region with extreme TB incidence (926/100,000). We leveraged the population's high TB incidence and community transmission to design a case-control study with similar mechanisms of exposure between the groups. We recruited 1,126 participants with suspected TB from 12 community health clinics and generated a cohort of 774 individuals (cases = 374, controls = 400) after implementing our enrollment criteria. All participants were GeneXpert Ultra tested for active TB by a local clinic. We assessed important risk factors for active TB using logistic regression and random forest modeling. We find that factors commonly identified in other global populations tend to replicate in our study, e.g. male gender and residence in a town had significant effects on TB risk (OR: 3.02 [95% CI: 2.30-4.71]; OR: 3.20 [95% CI: 2.26-4.55]). We also tested for demographic factors that may uniquely reflect historical changes in health conditions in South Africa. We find that socioeconomic status (SES) significantly interacts with an individual's age (p = 0.0005) indicating that protective effect of higher SES changed across age cohorts. We further find that being born in a rural area and moving to a town strongly increases TB risk, while town birthplace and current rural residence is protective. These interaction effects reflect rapid demographic changes, specifically SES over recent generations and mobility, in South Africa. Our models show that such risk factors combined explain 19-21% of the variance (r2) in TB case/control status.

Germline Variants in Sporadic Pituitary Adenomas.

Context: Data on germline genetics of pituitary adenomas (PAs) using whole-exome sequencing (WES) are limited. Objective: This study investigated the germline genetic variants in patients with PAs using WES. Methods: We studied 134 consecutive functioning (80.6%) and nonfunctioning (19.4%) PAs in 61 female (45.5%) and 73 male patients (54.5%). Their median age was 34 years (range, 11-85 years) and 31 patients had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes. Results: We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: AIP:c.767C>T (p.S256F), CDH23:c.906G>C (p.E302D), CDH23:c.1096G>A (p.A366T), DICER1:c.620C>T (p.A207V), MLH1:c.955G>A (p.E319K), MSH2:c.148G>A (p.A50T), SDHA:c.869T>C (p.L290P) and USP48 (2 patients): c.2233G>A (p.V745M). Conclusion: This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. These findings need further studies to confirm them.

EPAS1-related pheochromocytoma/paraganglioma.

In 2012, somatic EPAS1 pathogenic variants were found to cause a triad of pheochromocytoma/paragangliomas (PPGLs), polycythemia, and somatostatinoma. Since then, a limited number of studies on this subject have been reported, and data on the long-term outcome of metastatic disease are not available on this rare syndrome. We comprehensively reviewed EPAS1-related PPGL and describe an unusual patient who has been living with an EPAS1-related metastatic PPGL for 47 years. The results of this work show that EPAS1 pathogenic variants are rare, more in females and patients without pathogenic variants in other PPGL susceptibility genes. PPGLs are the most common manifestation followed by polycythemia and somatostatinoma. The EPAS1 pathogenic variants are often postzygotic, and the timing of their acquirement during embryonic development seems to correlate with the number and timing of development of the disease manifestations. Although recurrent and multifocal disease is common in EPAS1-related PPGL, distant metastases are uncommon and usually indolent. This is illustrated by a case of a man who was diagnosed at the age of 9 years and is currently 56 years old, alive, and well for 47 years with these metastases. He was found to have a somatic EPAS1 pathogenic variant (c.1592C>A, p.Pro531His) in bilateral pheochomocytoma and a pancreatic NET (somatostatinoma) but not in genomic DNA isolated from peripheral leukocytes. This and previous reports suggest that distant metastases are uncommon and less aggressive in EPAS1-related PPGLs compared to those found in other hereditary PPGLs.

LncRNA GAS8-AS1 dinucleotide genetic variantn.713A>G, n.714T>C is associated with early-stage disease, lymph node, and distant metastasis in differentiated thyroid cancer.

PURPOSE: Long noncoding RNAs (lncRNAs) play an essential role in the epigenetic regulation of various key genes involved in vital cellular functions. A somatic dinucleotide mutation in the lncRNA GAS8-AS1 was reported in Chinese papillary thyroid cancer. However, GAS8-AS1 dinucleotide alteration and its impact have never been explored in differentiated thyroid cancers and other populations. METHODS: We extracted genomic DNA from 265 DTCs and 97 normal healthy subjects, PCR amplified and Sanger sequenced to examine the GAS8-AS1 dinucleotide alteration. Calculated genotype/allele frequency to test Hardy-Weinberg Equilibrium (HWE) and performed a genetic model of inheritance to determine its association with DTC risk. Correlated the GAS8-AS1 dinucleotide variant distribution with clinical characteristics to find the association. Predicted GAS8-AS1 RNA secondary structure for wild type and variant using RemuRNA and RNAfold to assess the conformational changes. RESULTS: GAS8-AS1 dinucleotide alteration (n.713A > G, rs55742939; n.714T > C, rs61118444) identified in DTCs is a germline variant not somatic. The GAS8-AS1 genotype and allele frequency significantly deviated for HWE in DTCs (χ2 = 37.954; p = 0.0001) though not associated with its risk. Dinucleotide variant distribution was remarkably associated with early-stage disease (p = 0.002), lymph node (p = 0.01), and distant metastasis (p = 0.01) in DTCs. The GAS8-AS1 bearing dinucleotide variant markedly showed conformational change compared to that of its wild type. CONCLUSIONS: These findings indicate that GAS8-AS1 is genetically deregulated and implicated in several stages of DTC tumorigenesis suggesting it could be a promising prognostic biomarker in DTCs.

Respiratory Syncytial Virus (RSV) Burden in Infants in the Kingdom of Saudi Arabia and the Impact of All-Infant RSV Protection: A Modeling Study.

INTRODUCTION: Respiratory syncytial virus (RSV) represents a considerable burden on the healthcare system and hospital resources. This study explored the impact of universal immunoprophylaxis with long-acting monoclonal antibody (nirsevimab) during infants' first RSV season on RSV-induced health events and related costs in the Kingdom of Saudi Arabia (KSA). METHODS: The burden of RSV-induced health events and related costs under the current standard of practice (SoP) and the impact of universal immunoprophylaxis with nirsevimab was estimated using a static decision-analytic model in a cohort of infants experiencing their first RSV season in the KSA. The model estimated hospital admissions (including pediatric intensive care unit [PICU] admissions and mechanical ventilation [MV]), emergency room (ER) visits, primary care (PC) visits, long-term sequelae, and RSV mortality. RESULTS: The model estimated that under the current SoP, RSV results in 17,179-19,607 hospitalizations (including 2932-3625 PICU and 172-525 MV admissions), 57,654-191,115 ER visits, 219,053-219,970 PC visits, 14 deaths, 12,884-14,705 cases of recurrent wheezing, and a total cost of SAR 480-619 million. Universal nirsevimab immunoprophylaxis was estimated to avert 58% of hospitalizations (58% PICU admissions, 58% MV episodes), 53% of ER visits, 53% of PC visits, 58% of episodes of recurrent wheezing, 8 deaths, and result in savings of SAR 274-343 million in total healthcare cost. CONCLUSION: Compared with current SoP, an nirsevimab immunoprophylaxis strategy in the KSA for all infants during their first RSV season was estimated to dramatically decrease healthcare resource use, and economic burden associated with RSV.

The residency levels' effect on pediatric dental rehabilitation operation time.

BACKGROUND: Postgraduate pediatric dental residents' competency, to perform dental rehabilitation procedures under General anesthesia (GA), at different levels of training is challenging for operation time control. An adequate operation time (OT) for children decreases morbidity risk and improves hospital time utilization efficiency. The aim of the study is to assess the effect of pediatric dental resident training level on OT for pediatric dental rehabilitation procedures under GA at King Abdulaziz Medical City (KAMC). METHODS: A cross-sectional study included pediatric dental rehabilitation performed under GA by pediatric dental residents at (KAMC) -Jeddah from October/2015 to September/2022. The primary outcome was OT, and the predictive variable was resident training levels. A linear regression analysis was used to compare OT between procedures performed by junior (years 1-2) or senior (years 3-4) trainees, adjusting for patient and operative factors. RESULTS: One thousand seven pediatric dental rehabilitation cases were performed under GA by junior (13) and senior (31) residents. The univariant analysis indicated that OT for senior residents was significantly longer (13 min) than for junior residents. However, the linear regression analysis showed that senior residents had a significantly shorter OT when considering the more dental procedures performed per case under GA than junior residents. Senior residents took significantly more radiographs and performed more primary pulp therapies and multi-surface anterior colored restorations under GA than junior residents. CONCLUSIONS: The OT for pediatric dental rehabilitation procedures under GA is associated with resident training level. The total OT was significantly longer based on procedure number, type, and resident level. The study indicated that senior residents could manage more complex cases in a shorter time. The finding emphasizes the importance of assigning GA cases to residents based on their level and the case's complexity. Additionally, it helps standardize the resident privileges under GA and understand the impact of residency training on hospital efficiency.

Prevalence of sodium-glucose transporter 2 inhibitor-associated diabetic ketoacidosis in real-world data: A systematic review and meta-analysis.

BACKGROUND: The U.S. Food and Drug Administration (FDA) revised the labels of sodium-glucose transporter 2 (SGLT2) inhibitors in December 2015 to inform users regarding the risk of diabetic ketoacidosis (DKA). As more drugs of this class are approved and their indications are expanded, this serious adverse effect has been increasingly reported. OBJECTIVE: This review evaluated observational studies to inform the prevalence of SGLT2-inhibitor-associated DKA compared with other antihyperglycemic agents. METHODS: A systematic review was conducted in PubMed and EMBASE until 19 July 2022 (PROSPERO: CRD42022385425). We included published retrospective cohort active comparator/new user (ACNU) and prevalent new user studies assessing SGLT2-inhibitor-associated DKA prevalence in adult patients with type 2 diabetes mellitus (T2DM) against active comparators. We excluded studies which lacked 1:1 propensity score matching. The JBI Checklist for Cohort Studies guided the risk-of-bias assessments. Meta-analysis was conducted based on the inverse variance method in R software. RESULTS: Sixteen studies with a sample of 2,956,100 nonunique patients met the inclusion criteria. Most studies were conducted in North America (n = 9) and adopted the ACNU design (n = 15). Meta-analysis of 14 studies identified 33% higher DKA risk associated with SGLT2 inhibitors (HR = 1.33, 95% CI: 1.14-1.55, P < 0.01). Meta-regression analysis identified the study location (P = 0.02), analysis principle (P < 0.001), exclusion of chronic comorbidities (P = 0.007), and canagliflozin (P = 0.04) as significant moderator variables. CONCLUSIONS: Despite limitations related to heterogeneity, generalizability, and misclassification, the results of this study show that SGLT2 inhibitors increase the prevalence of DKA among adult T2DM patients in the real world. The findings supplement evidence from randomized controlled trials (RCTs) and call for continued vigilance.

Expanding the phenotypic and genotypic spectrum of GGPS1 related congenital muscular dystrophy.

Congenital muscular dystrophies are a group of progressive disorders with wide range of symptoms associated with diverse cellular mechanisms. Recently, biallelic variants in GGPS1 were linked to a distinct autosomal recessive form of muscular dystrophy associated with hearing loss and ovarian insufficiency. In this report, we present a case of a young patient with a homozygous variant in GGPS1. The patient presented with only proximal muscle weakness, and elevated liver transaminases with spared hearing function. The hepatic involvement in this patient caused by a novel deleterious variant in the gene extends the phenotypic and genotypic spectrum of GGPS1 related muscular dystrophy.

Noninvasive Neurally Adjusted Ventilation versus Nasal Continuous or Intermittent Positive Airway Pressure for Preterm Infants: A Systematic Review and Meta-Analysis.

The noninvasive neurally adjusted ventilatory assist (NIV-NAVA) is a newly developed noninvasive ventilation technique with promising clinical and ventilatory outcomes for preterm infants. This systematic review and meta-analysis aimed to investigate whether NIV-NAVA has better clinical and ventilatory outcomes than nasal continuous airway pressure (NCPAP) or noninvasive positive pressure ventilation (NIPP) on premature infants. MEDLINE, Embase, and CENTRAL were searched, and randomized controlled trials (RCTs) that compared NIV-NAVA with NCPAP or NIPP for preterm infants (gestational age: <37 weeks) were included. We evaluated the following outcomes in the neonatal intensive care unit: the desaturation rate, failure of noninvasive modality requiring intubation when received as the primary mode or the need for re-intubation after extubation from mechanical ventilation in the secondary mode (weaning), length of stay, and fraction of inspired oxygen. The mean difference and risk ratio were used to represent continuous and dichotomous outcomes, respectively. We included nine RCTs involving 339 preterm infants overall. NIV-NAVA showed similar clinical and ventilatory outcomes to NCPAP or NIPP, except for the maximum diaphragmatic electrical activity. The rate of failure of the noninvasive modality was not statistically different between NIV-NAVA and NCPAP. The pooled estimates for the maximum electrical activity were significantly reduced in NIV-NAVA compared with those in NIPP. The findings suggest that NIV-NAVA may be as safe and effective as NCPAP and NIPP for preterm neonates, particularly those who may not tolerate these alternative noninvasive methods. However, further trials are recommended for greater evidence.

An aggressive cabergoline-resistant, temozolomide-responsive macroprolactinoma due to a germline SDHB pathogenic variant in the absence of paraganglioma or pheochromocytoma.

Context: Germline succinate dehydrogenase subunit B (SDHB) pathogenic variants are characteristic of familial paraganglioma (PGL) syndrome type 4. This syndrome frequently presents with abdominal PGL and has high tendency for locally aggressive behavior and distant metastasis. The vast majority of pituitary adenomas (PAs) are sporadic. However, PAs can be part of a number of familial tumor syndromes such as multiple endocrine neoplasia type 1 (MEN 1) or more rarely in association with pheochromocytoma and PGL (referred to as 3P syndrome). Only a limited number of PAs in association with SDHB-related PGL has been reported and the vast majority occurred subsequently or simultaneously with pheochromocytoma/PGL (collectively abbreviated as PPGL). In this report, we describe a young patient who had a giant pituitary macroprolactinoma resistant to large doses of cabergoline (CBG) and external beam radiotherapy (XRT). The patient did not have personal history of PPGL but was found to carry a germline SDHB pathogenic variant. Case report: A 38-year-old woman presented with headache, visual disturbances and galactorrhea and was found to have a 34-mm macroprolactinoma. She was treated with CBG 3-4 mg per week but PA continued to grow and caused significant cranial pressure symptoms. She underwent two transsphenoidal surgeries with rapid tumor recurrence after each one. She received XRT but PA continued to grow. She was finally treated with temozolomide with excellent response. Whole exome and subsequent Sanger sequencing confirmed that she has a pathogenic monoallelic SDHB mutation (NM_003000:c.C343T, p.R115*). PA tissue showed loss of heterozygosity for the same mutation and absent SDHB immunostaining confirming the pathogenic role of this SDHB mutation. Conclusion: Germline SDHB mutations can rarely cause PA in the absence of PPGL. They should be considered as a possible cause of aggressiveness and resistance to dopamine agonists in similar cases.

Strong Effect of Demographic Changes on Tuberculosis Susceptibility in South Africa.

South Africa is among the world's top eight TB burden countries, and despite a focus on HIV-TB co-infection, most of the population living with TB are not HIV co-infected. The disease is endemic across the country with 80-90% exposure by adulthood. We investigated epidemiological risk factors for tuberculosis (TB) in the Northern Cape Province, South Africa: an understudied TB endemic region with extreme TB incidence (645/100,000) and the lowest provincial population density. We leveraged the population's high TB incidence and community transmission to design a case-control study with population-based controls, reflecting similar mechanisms of exposure between the groups. We recruited 1,126 participants with suspected TB from 12 community health clinics, and generated a cohort of 878 individuals (cases =374, controls =504) after implementing our enrollment criteria. All participants were GeneXpert Ultra tested for active TB by a local clinic. We assessed important risk factors for active TB using logistic regression and random forest modeling. Additionally, a subset of individuals were genotyped to determine genome-wide ancestry components. Male gender had the strongest effect on TB risk (OR: 2.87 [95% CI: 2.1-3.8]); smoking and alcohol consumption did not significantly increase TB risk. We identified two interactions: age by socioeconomic status (SES) and birthplace by residence locality on TB risk (OR = 3.05, p = 0.016) - where rural birthplace but town residence was the highest risk category. Finally, participants had a majority Khoe-San ancestry, typically greater than 50%. Epidemiological risk factors for this cohort differ from other global populations. The significant interaction effects reflect rapid changes in SES and mobility over recent generations and strongly impact TB risk in the Northern Cape of South Africa. Our models show that such risk factors combined explain 16% of the variance (r2) in case/control status.

How do BRAFV600E and TERT promoter mutations interact with the ATA and TNM staging systems in thyroid cancer?

Context: The American Thyroid Association risk stratification (ATA) and the American Joint Committee on Cancer Tumor Node Metastases (TNM) predict recurrence and mortality of differentiated thyroid cancer (DTC). BRAFV600E and TERT promoter mutations have been shown to correlate with the histopathological features and outcome of DTC. Our objectives were to study the correlation of these molecular markers with these clinicopathological-staging systems. Patients and methods: We studied 296 unselected patients, 214 females and 82 males with a median age of 36 years (IQR 23.3-49.0). BRAFV600E and TERT promoter mutations were tested by PCR-based Sanger sequencing. Data were extracted from medical records and analysed using Chi-Square and Fisher Exact tests and Kaplan Meier analysis. Results: Of 296 patients tested, 137 (46.3%) had BRAFV600E-positive tumors and 72 (24.3%) were positive for TERT promoter mutations. The BRAFV600E mutation did not correlate with the ATA and TNM staging, being non-significantly different in various stages of these systems and did not predict the development of persistent disease (PD) (P 0.12). Unlike BRAFV600E, TERT promoter mutations were more frequent in the ATA high-risk than in intermediate- or low-risk tumors (P 0.006) and in TNM stages III and IV than lower stages (P <0.0001). TERT promoter mutations also predicted the outcome, being present in 37.2% of patients with PD compared to only 15.4% in those without evidence of disease (P <0.0001). The same pattern was also seen when BRAFV600E and TERT promoter mutations were combined. Conclusion: TERT promoter mutations alone or in combination with BRAFV600E mutation, but not BRAFV600E mutation alone, correlated well with the ATA and TNM staging and predicted development of PD, especially in higher stages of these systems.

Persistence of Matrilocal Postmarital Residence Across Multiple Generations in Southern Africa.

Factors such as subsistence turnover, warfare, or interaction between different groups can be major sources of cultural change in human populations. Global demographic shifts such as the transition to agriculture during the Neolithic and more recently the urbanization and globalization of the twentieth century have been major catalysts for cultural change. Here, we test whether cultural traits such as patri/matrilocality and postmarital migration persist in the face of social upheaval and gene flow during the past 150 years in postcolonial South Africa. The recent history of South Africa has seen major demographic shifts that resulted in the displacement and forced sedentism of indigenous Khoekhoe and San populations. During the expansion of the colonial frontier, the Khoe-San admixed with European colonists and enslaved individuals from West/Central Africa, Indonesia, and South Asia, introducing novel cultural norms. We conducted demographic interviews among Nama and Cederberg communities representing nearly 3,000 individuals across three generations. Despite the history of colonial expansion, and the subsequent incorporation of Khoe-San and Khoe-San-descendant communities into a colonial society with strong patrilocal norms, patrilocality is the least common postmarital residence pattern in our study populations today. Our results suggest that more recent forces of integration into the market economy are likely the primary drivers of change in the cultural traits examined in our study. Birthplace had a strong effect on an individual's odds of migration, distance moved, and postmarital residence form. These effects are at least partially explained by the population size of the birthplace. Our results suggest that market factors local to birthplaces are important drivers of residence decisions, although the frequency of matrilocal residence and a geographic and temporal cline in migration and residence patterns also indicate the persistence of some historic Khoe-San cultural traits in contemporary groups.