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Iram Haq,1,2 Maryam Almulhem,1 Simone Soars,1 David Poulton,2,3 Malcolm Brodlie1,2 1Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 3Paediatrics, Ninewells Hospital, NHS Tayside, Dundee, UKCorrespondence: Malcolm BrodliePaediatric Respiratory Medicine, Level 3, Clinical Resource Building, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK, Tel +44 191 2336161, Email malcolm.brodlie@ncl.ac.ukAbstract: Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.Keywords: CFTR, ivacaftor, modulator, elexacaftor, tezacaftor

Objective: Assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and of liver fibrosis associated with nonalcoholic steatohepatitis in unselected patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: A total of 561 patients with T2DM (age: 60 ± 11 years; BMI: 33.4 ± 6.2 kg/m 2 ; and HbA 1c : 7.5 ± 1.8%) attending primary care or endocrinology outpatient clinics and unaware of having NAFLD were recruited. At the visit, volunteers were invited to be screened by elastography for steatosis and fibrosis by controlled attenuation parameter (≥274 dB/m) and liver stiffness measurement (LSM; ≥7.0 kPa), respectively. Secondary causes of liver disease were ruled out. Diagnostic panels for prediction of advanced fibrosis, such as AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) index, were also measured. A liver biopsy was performed if results were suggestive of fibrosis., Results: The prevalence of steatosis was 70% and of fibrosis 21% (LSM ≥7.0 kPa). Moderate fibrosis (F2: LSM ≥8.2 kPa) was present in 6% and severe fibrosis or cirrhosis (F3-4: LSM ≥9.7 kPa) in 9%, similar to that estimated by FIB-4 and APRI panels. Noninvasive testing was consistent with liver biopsy results. Elevated AST or ALT ≥40 units/L was present in a minority of patients with steatosis (8% and 13%, respectively) or with liver fibrosis (18% and 28%, respectively). This suggests that AST/ALT alone are insufficient as initial screening. However, performance may be enhanced by imaging (e.g., transient elastography) and plasma diagnostic panels (e.g., FIB-4 and APRI)., Conclusions: Moderate-to-advanced fibrosis (F2 or higher), an established risk factor for cirrhosis and overall mortality, affects at least one out of six (15%) patients with T2DM. These results support the American Diabetes Association guidelines to screen for clinically significant fibrosis in patients with T2DM with steatosis or elevated ALT., (© 2020 by the American Diabetes Association.)

There is no doubt modern genetics have greatly influenced our professional and personal lives during the last decade. Uncovering genetic causes of many medical and dental pathologies is helping to narrow the diagnosis and select a treatment plan that would provide the best outcome. Importantly, having an understanding of multifactorial etiology helps direct our attention toward prevention. We now understand much better our own health problems. In some cases, we can modify our lifestyle and diet in order to prevent "environmental factors" from triggering the mutated genes inherited from our parents. Good examples are diabetes and cardiovascular diseases. If we realize we might have inherited genes for cardiovascular problems from several ancestors who had heart attacks, we already know that these genes will make us only "susceptible" for disease. Those who exercise, watch one's weight, diet, and carefully monitor one's lifestyle will very likely--though possessing "susceptibility genes"--stay healthier and, maybe, will never experience any cardiovascular problems. In principle, the same applies for craniofacial anomalies, especially for nonsyndromic cleft lip and palate. One needs to understand genetic and environmental causes of nonsyndromic orofacial clefts in order to prevent them. With all this in mind, the Pacific Craniofacial Team and Cleft Prevention Program have been established at the Department of Orthodontics, University of the Pacific Arthur A. Dugoni School of Dentistry in San Francisco. A partnership with Rotaplast International, Inc., has made it possible for the faculty, orthodontic residents, and students to participate in 27 multidisciplinary cleft medical missions in underdeveloped and developing countries by donating professional and educational services, and, last but not least, by collecting valuable data and specimens to further research. A significant number of research studies, including 15 master of science theses, have been accomplished in UOP's Craniofacial Genetics Laboratory, with contributions by faculty, undergraduate and graduate students. It has been leading to a better understanding of etiology of nonsyndromic orofacial clefts. It has been learned that genetic factors and environmental factors are ethnicity-specific and, in many places throughout the world, location-specific. Thus, a specific protocol for cleft prevention has to be worked out based on genetic and nutritional studies of each specific population group in order to be effective. This is our ultimate goal.

A zonation technique for sediment samples based upon contaminant ratios of a series of samples is described. The technique is based on the fact that sediment samples of common origin will tend to have similar ratios of concentrations of trace pollutants such as heavy metals, PCBs, etc., despite dilution by variable amounts of inert materials such as silica or calcite. Comparison of these ratios between individual samples yields a matrix of similarity coefficients, which are then analyzed by a hierarchical agglomerative cluster analysis procedure. Sediment samples of similar origin will tend to group together in a single cluster, whereas samples influence by unique factors such as transport patterns or proximity to point source discharges will appear as separate individual clusters. The results of application of this methodology to Great Lakes samples from Hamilton Harbour and Port Hope are presented.