Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence

<p>Abstract</p> <p>Background</p> <p>The ATM protein is activated as a result of ionizing radiation, and genetic variants of the <it>ATM </it>gene may therefore affect the level of radiation-induced damage. Individuals heterozygous for <it>ATM </it>mutations have been reported to have an increased risk of malignancy, especially breast cancer.</p> <p>Materials and methods</p> <p>Norwegian breast cancer patients (272) treated with radiation (252 of which were evaluated for radiation-induced adverse side effects), 95 Norwegian women with no known history of cancer and 95 American breast cancer patients treated with radiation (44 of which developed ipsilateral breast tumour recurrence, IBTR) were screened for sequence variations in all exons of the <it>ATM </it>gene as well as known intronic variants by denaturating high performance liquid chromatography (dHPLC) followed by sequencing to determine the nature of the variant.</p> <p>Results and Conclusion</p> <p>A total of 56 variants were identified in the three materials combined. A borderline significant association with breast cancer risk was found for the 1229 T>C (Val>Ala) substitution in exon 11 (P-value 0.055) between the Norwegian controls and breast cancer patients as well as a borderline significant difference in haplotype distribution (P-value 0.06). Adverse side effects, such as: development of costal fractures and telangiectasias, subcutaneous and lung fibrosis, pleural thickening and atrophy were evaluated in the Norwegian patients. Significant associations were found for several of the identified variants such as rs1800058 (Leu > Phe) where a decrease in minor allele frequency was found with increasing level of adverse side effects for the clinical end-points pleural thickening and lung fibrosis, thus giving a protective effect. Overall our results indicate a role for variation in the <it>ATM </it>gene both for risk of developing breast cancer, and in radiation induced adverse side effects. No association could be found between risk of developing ipsilateral breast tumour recurrence and any of the sequence variants found in the American patient material.</p

ATM variants and cancer risk in breast cancer patients from Southern Finland

BACKGROUND: Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N) variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. METHODS: Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. RESULTS: Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. CONCLUSION: Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with increased breast cancer risk or with bilateral breast cancer

Opioid agonist treatment and patient outcomes during the COVID_19 pandemic in south east Sydney, Australia

Introduction In early 2020, many services modified their delivery of opioid treatment in response to the COVID-19 pandemic, to limit viral spread and maintain treatment continuity. We describe the changes to treatment and preliminary analysis of the association with patients' substance use and well-being. Methods A pre-post comparison of treatment conditions and patient self-reported outcomes using data extracted from electronic medical records in the 5 months before (December 2019–April 2020) and after (May 2020–September 2020) changes were implemented in three public treatment services in South Eastern Sydney Local Health District. Results Data are available for 429/460 (93%) patients. Few (21, 5%) dropped out of treatment. In the ‘post’ period there was significantly more use of depot buprenorphine (12–24%), access to any take-away doses (TAD; 24–69%), access to ≥6 TAD per week (7–31%), pharmacy dosing (24–52%) and telehealth services. There were significant reductions in average opioid and benzodiazepine use, increases in cannabis use, with limited group changes in social conditions, or quality of life, psychological and physical health. At an individual level, 22% of patients reported increases in their use of either alcohol, opioids, benzodiazepines or stimulants of ≥4 days in the past 4 weeks. Regression analysis indicates increases in substance use were associated with higher levels of supervised dosing. Discussion and Conclusions These preliminary findings suggest that the modified model of care continued to provide safe and effective treatment, during the pandemic. Notably, there was no association between more TAD and significant increases in substance use. Limitations are discussed and further evaluation is needed

As Few Pediatricians as Possible and as Many Pediatricians as Necessary?

This article discusses the very important issue of the shortage of pediatricains during the next years. A common mantra is “as little as possible and as much as necessary.” This perception can be applied to all kinds of different projects in everyday life in order to help achieve a good outcome. It also applies to medicine, for example, “as little antibiotics as possible and as much/many antibiotics as necessary.” However, does this “rule” also apply to the pediatric workforce, that is, “as few pediatricians as possible and as many pediatricians as necessary”? How can we develop a sustainable pediatric workforce to meet the healthcare needs of children? We previously offered different equations for calculating the needed numbers of annually trained pediatricians to keep the actual number of pediatricians in a country stable in view of variable working conditions such as full-time or part-time working equivalents1,2 and weekly working hours and night shifts.3 We now describe pediatric workforces in 2013-2018 in 16 European countries, 11 European Union and 5 nonEuropean Union countries. National child healthcare systems are embedded in the underlying political and economic systems such as capitalistic, liberal, monarchic, socialistic, or social market system. National pediatric workforces can be analyzed according to the triangle of need–supply–demand. Our analysis neither intended to compare national pediatric workforces with the underlying political systems nor did it investigate the role of different types of health insurance systems, for example, financed by levies to insurance funds (Bismarck system) or by taxes (Beveridge system). We also tried to avoid a singlesided view of pediatricians whose understandable aim is to defend their own needs and to improve working conditions. Instead, we wanted to look at the child healthcare services through the eyes of families and their children. The priority of families is to have an available, adequate/appropriate, affordable, and easily accessible healthcare service provided by highly qualified personnel on all levels ranging from generalists to specialists. Families wish to have a wellfunctioning and competent child healthcare system that—if fragmented—should be well-coordinated. Different bodies and institutions involved in the care of children should communicate and cooperate well, reaching a consensus wherever and whenever possible

PRRT2 mutations: exploring the phenotypical boundaries

Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However it remains unknown whether PRRT2 mutations are causal in other epilepsy syndromes. After we discovered a PRRT2 mutation in a large family with ICCA containing one individual with febrile seizures (FS) and one individual with West syndrome, we analysed PRRT2 in a heterogeneous cohort of patients with different types of infantile epilepsy.status: publishe