The Cost-Effectiveness of an Advanced Hybrid Closed-Loop System in People with Type 1 Diabetes: a Health Economic Analysis in Sweden.

INTRODUCTION: Swedish National Diabetes Registry data show a correlation of improved glycemic control in people with type 1 diabetes (T1D) with increased use of diabetes technologies over the past 25 years. However, novel technologies are often associated with a high initial outlay. The aim of the present study was to evaluate the long-term cost-effectiveness of the advanced hybrid closed-loop (AHCL) MiniMed 780G system versus intermittently scanned continuous glucose monitoring (isCGM) plus self-injection of multiple daily insulin (MDI) or continuous subcutaneous insulin infusion (CSII) in people with T1D in Sweden. METHODS: Outcomes were projected over patients' lifetimes using the IQVIA CORE Diabetes Model (v9.0). Clinical data, including changes in glycated hemoglobin (HbA1c) and hypoglycemia rates, were sourced from observational studies and a randomized crossover trial. Modeled patients were assumed to receive the treatments for their lifetimes, with HbA1c kept constant following the application of treatment effects. Costs were accounted from a societal perspective and expressed in Swedish krona (SEK). Utilities and days off work estimates were taken from published sources. RESULTS: The MiniMed 780G system was associated with an improvement in life expectancy of 0.16 years and an improvement in quality-adjusted life expectancy of 1.95 quality-adjusted life years (QALYs) versus isCGM plus MDI or CSII. These clinical benefits were due to a reduced incidence and a delayed time to onset of diabetes-related complications. Combined costs were estimated to be SEK 727,408 (EUR 72,741) higher with MiniMed 780G, with treatment costs partially offset by direct cost savings from the avoidance of diabetes-related complications and indirect cost savings from the avoidance of lost workplace productivity. The MiniMed 780G system was associated with an incremental cost-effectiveness ratio of SEK 373,700 per QALY gained. CONCLUSIONS: Based on a willingness-to-pay threshold of SEK 500,000 per QALY gained, the MiniMed 780G system was projected to be cost-effective versus isCGM plus MDI or CSII for the treatment of T1D in Sweden.

Insertion of a vacuum based drain for post-parotidectomy non-resolving seroma in an outpatient setting.

We describe a novel technique for the insertion of a vacuum drain, in an outpatient setting, for persistent seroma post-parotidectomy. This is a retrospective case series of a single academic centre. The complete medical records of all patients who underwent parotidectomy between 2014 and 2019 were reviewed. Data regarding demographics, comorbidities, and intraoperative and postoperative courses were extracted for patients for whom a vacuum drain was inserted due to persistent seroma. A size 8 Fr drain was inserted using a novel approach through the parotidectomy incision using 'Biovac' (Biometrix) 50ml, Trocar kit, that had been adjusted and modified for this purpose. Two hundred and eighteen patients had had parotidectomy during the study period. Eight patients (3.6%) underwent insertion of the drain due to persistent seroma. In three patients (37.5%) no drain was inserted during the initial surgery. The mean (SD) time between surgery and insertion of the outpatient vacuum drain was 10 (5) days. All drain insertions were uneventful and no complications were noted. The mean (SD) time for outpatient vacuum drain removal was 12.75 (4.3) days. A single patient (12.5%) underwent additional needle aspiration of 5cc few days following removal of the drain. Persistent seromas may be managed in an outpatient clinic with good results and a high safety profile.

Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer.

BACKGROUND: Little is known about mechanisms of resistance to poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. PATIENTS AND METHODS: We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARPi or platinum chemotherapy. Whole exome sequencing was carried out on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was carried out for functional assessment of intact homologous recombination (HR). RESULTS: Pre- and post-resistance tumor samples were sequenced from eight patients (four with BRCA1 and four with BRCA2 mutation; four treated with PARPi and four with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy. CONCLUSIONS: Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

Prevalence and mutational determinants of high tumor mutation burden in breast cancer.

BACKGROUND: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. PATIENTS AND METHODS: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. RESULTS: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pembrolizumab-based therapies derived an objective and durable response to therapy. CONCLUSION: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

Pseudo-anticipation in Creutzfeldt-Jakob disease is due to a rhomboid-shaped artifact.

BACKGROUND AND PURPOSE: Previous studies have reported conflicting results regarding possible anticipation in familial E200K Creutzfeldt-Jakob disease (fCJD). Our objective was to use a large database to assess the age of disease onset (AODO) in CJD. METHODS: The study population included 477 CJD patients [266 with fCJD, 145 with sporadic CJD (sCJD) and 66 patients of Libyan origin but negative family history] from the Israeli registry of CJD conducted since 1954. In all patients, AODO in relatives and family trees was documented. Comparison of AODO was done using a paired t test and regression using Pearson correlation for birth and year of onset. RESULTS: The initial analysis in 52/73 families in which more than one generation was affected revealed an AODO of 63.30 ± 9.44 in the first generation compared to 56.96 ± 8.99 in the second generation (P < 0.001). However, inspection of individual AODO values plotted by year of birth showed a clear rhomboid methodological artifact generated by missing data of many young onset CJD patients who died before the database began to function in 1954 and of many late onset CJD patients missing at the present time since they will only develop the disease in the future. The 'generation' effect completely disappears if analysis is performed by year of disease onset or for the periods in which complete data are available. CONCLUSIONS: In this very large dataset, true anticipation in fCJD patients was not detected. It is plausible that previous reports supporting the presence of anticipation are biased by a rhomboid-shaped data availability artifact.

Improving techniques for diagnostics of laser pulses by compact representations.

We propose and demonstrate, numerically and experimentally, use of sparsity as prior information for extending the capabilities and performance of techniques and devices for laser pulse diagnostics. We apply the concept of sparsity in three different applications. First, we improve a photodiode-oscilloscope system's resolution for measuring the intensity structure of laser pulses. Second, we demonstrate the intensity profile reconstruction of ultrashort laser pulses from intensity autocorrelation measurements. Finally, we use a sparse representation of pulses (amplitudes and phases) to retrieve measured pulses from incomplete spectrograms of cross-correlation frequency-resolved optical gating traces.

Anatomic variations of the paranasal sinuses in the general pediatric population.

BACKGROUND: The prevalence of sinuses' anatomic variations in the healthy pediatric population has not been studied. The study describes the prevalence of known anatomic variations with regard to gender and age in this population. METHODS: A single academic institute observational cohort study. A total of 200 head CT scans were reviewed, subdivided into five equal age subgroups (0-4.99; 5-7.99; 8-10.99; 11-13.99; 14-17 years), with an equal male to female ratio. Different subgroups were randomly assigned to two senior residents (100 CTs each). A senior rhinologist and radiologist were randomly selected to review 100 CTs each. Consensus was reached after a joint review. Each CT was evaluated for the presence of sinuses and the following variations: deviated septum, frontoethmoidal, infraorbital, posterior-ethmoid cells (Kuhn, Haller, and Onodi cells, respectively) and concha bullosa. Definitions were made according to the European Position on Rhinosinusitis 2012. RESULTS: Gender did not affect sinus development or anatomical variations. The frontal and sphenoid sinuses were significantly less developed in the 0-4.99 years group. The point prevalence of concha bullosa and deviated septum significantly increased with age. The point prevalence of Haller cells demonstrated borderline significance among age groups, with children 0-4.99 demonstrating the lowest point prevalence. A significant association was found between the existence of Haller cells to Kuhn and Onodi cells. CONCLUSIONS: Anatomical variations should be expected in the pediatric population. Familiarity with their point prevalence and associations may assist pediatric endoscopic sinus surgery planning.

Intravenous opioid drug abuse as an independent risk factor for supraglottic squamous cell carcinoma-A case-control study.

OBJECTIVES: Intravenous opioid drug abuse (IVDA) was previously correlated with laryngeal cancer. However, discrimination of this correlation by anatomical subsites has not yet been described. In this study, we aim to further establish the association between IVDA and laryngeal squamous cell carcinoma (SCC) and to indicate the laryngeal subsites that are predisposed for this correlation. DESIGN: A retrospective matched case-control study. SETTING AND PARTICIPANTS: Patients diagnosed with supraglottic SCC (SG-SCC) between 1996 and 2016 treated in a tertiary academic referral centre were enrolled to the case group. The control group comprised of matched patients diagnosed with glottis SCC (G-SCC). Matching was based on gender, age and socio-economic rank. MAIN OUTCOME MEASURES: Variables studies as risk factors included the following: smoking, alcohol consumption, history of IVDA and infectious diseases. The variables were tested for association with the 2 groups and with each other. RESULTS: Forty-eight patients with SG-SCC were matched with 48 patients with G-SCC. IVDA rates significantly increased among patients with SG-SCC. Of the SG-SCC group, 18.8% had a positive history for IVDA compared with 2.1% of the G-SCC (P = .008). A history of IVDA was found to be a risk factor for SG-SCC, independent of smoking, excessive alcohol and socio-economic status. The odds ratio for patients with an IVDA history to have SG-SCC relatively to G-SCC was 10.846 (95% CI: 1.3-89.4). CONCLUSIONS: Intravenous opioid drug abuse represents an independent risk factor for SG-SCC. The pathogenesis should be investigated not just as a risk factor, as opioids are commonly used for pain management in oncologic patients.

Surgeon-performed thyroid ultrasound-proving utility and credibility in selecting patients for fine needle aspiration according to the American thyroid association guidelines. A retrospective study of 500 patients.

DESIGN: Case series with chart review. SETTING: Single academic centre. PARTICIPANTS: The data of all patients who underwent surgeon-performed ultrasound (SUS) between 7/2009 and 9/2012 were retrospectively reviewed. MAIN OUTCOME MEASURES: A correlation between sonographic features and a non-benign cytology\malignant pathology. RESULTS: Four hundred ninety-eight nodules were included. Solid texture, irregular margins, hypo-echogenicity and intranodular vascularity were significantly associated with malignancy when benign to non-benign cytology was compared, and when compared to malignant pathology. Lack of suspicious features was significantly associated with benign lesions, with a negative predictive value of 94%. Except for taller than wider shape, malignancy odds ratio was significantly higher for known suspicious features, reaching 4.81 for irregular borders (CI 2.42-9.55, P < .001). CONCLUSIONS: SUS has proven to be a reliable and consistent tool to assess the thyroid nodule risk stratification. Surgeons should recognise the potential of this tool and its implementation.

Temperature changes of one-piece implants during the setting of acrylic resin temporary crown. The effect of implant diameter. An in vitro study.

The purpose of this work is to evaluate changes in temperature of one-piece titanium implant surface during the setting of acrylic resin temporary crowns and to correlate thermal changes to implant diameter. Thirty-three one-piece implants (ARRP, Alpha-Biotec) were divided into 3 groups according to diameter size (G1=3 mm, G2=3.3 mm, G3=3.6 mm). Implants were mounted on an acrylic glass apparatus. Thermocouples were positioned at the most coronal thread. Lower incisor temporary polycarbonate crowns were filled with 80 µL of self-curing acrylic resin and positioned immediately on the implant abutment. Thermal changes of the implant surface were recorded continuously for 10 min. Data were statistically analyzed using one-way analysis of variance. The mean initial temperature (C0) of groups G1, G2 and G3 was similar (24.79±0.78ºC, 25.26±0.63ºC, 24.97±1.06ºC, respectively). The setting of the acrylic resin temporary crown resulted in a significant increase in the implant surface temperature of all groups. The mean thermal amplitude (ΔC) for groups G1, G2 and G3 were 6.79±1.02ºC, 6.61±0.94ºC, 6.65±1.26ºC, respectively. The mean time to maximum temperature (Tmax) for groups G1, G2 and G3 were 337.38±42.91 sec, 324.69±41.46 sec and 317.98±37.91 sec respectively (P>0.05). Direct application of auto-polymerizing resin to the titanium abutment of one-piece implants significantly increased the cervical implant surface temperature. Implant diameter did not influence the temperature changes.

Should high BMI be a reason for IVF treatment denial?

Our aim was to examine the influence of BMI on the live-birth rate following IVF/ICSI and evaluate its specific contribution among other factors thus enabling accurate reproductive policy development. All patients that underwent IVF/ICSI at our center during January 2012-July 2015 were included in this retrospective study. A total of 1654 ICSI cycles were divided into four groups according to the patient's BMI (kg/m2): group I (normal weight): <25 (943 cycles); group II (overweight): 25-30 (403 cycles); group III (obese): 30-35 (212 cycles); group IV (morbid obesity): >35 (96 cycles). Comparing the four groups of BMI, mean age and number of previous ART cycles was significantly lower in group I compared to groups II, III and IV. Length of treatment was significantly shorter in group I compared to groups II, III and IV. Ovarian response to COH was comparable in terms of mean estradiol and progesterone levels on the day of hCG administration mean number of oocytes retrieved, fertilized and number of embryos transferred. Endometrial thickness was significantly lower in group IV. Outcome measures, such as implantation rate, clinical pregnancy rate (CPR) per cycle and per ET, as well as live-birth rates did not differ significantly between the groups, although in group IV LBR per cycle and per ET was lower. Multivariate logistic regression stepwise analysis found a significant correlation between age and BMI but did not find correlation between BMI and clinical pregnancy (p = 0.436) or LB (p = 0.206). The results of our relatively large retrospective study did not demonstrate a significant impact of BMI on the ART cycle outcome. Therefore, BMI should not be a basis for IVF treatment denial.

Effect of noise on tasks in operating theatres: a survey of the perceptions of healthcare staff.

Noise in the operating theatre has an adverse impact on healthcare professionals, both physically and psychologically. It can be distracting, make communication difficult, and contribute to a perceived increase in stress. Staff in theatre must deliver high quality care, and overlook noise as a potentially damaging influence. The aim of this survey was to obtain further information about the perspective of healthcare professionals on how noise can affect their practice and whether it affects their work in theatre. We distributed six closed-ended questions in the form of a Survey Monkey® questionnaire to about 50 hospitals across the UK and target groups such as medical students, the Leeds Advanced Trauma Life Support faculty group, the Court of Examiners of the Royal College of Surgeons of England, and surgical trainees sitting the Member of the Royal College of Surgeons examination. We received 519 responses of which 415 respondents (83%) thought that noise contributed to human errors. A total of 282 participants (57%) thought that the theatre was the noisiest area within the theatre suite. Both communication among staff (n=400, 80%) and concentration (n=384, 77%) were thought to be adversely affected by noise. However, 385 (78%) did not feel that music adversely affected their performance. The results provide insights into the interplay of noise and its effect on people. Although the role of music remains contentious, our results suggest that it might have a calming influence.

Religiosity: Its Impact on Coping Styles Among Women Undergoing Fertility Treatment.

The Israeli worldview places great significance on childbearing. This could create emotional and ethical difficulties for women coping with fertility issues in addition to their treatments. This study examined the relations between coping strategies and level of religiosity in 159 women undergoing infertility treatment. Statistically significant relations were found between the problem-solving coping style and religious observance (p < 0.01) and religious beliefs (p < 0.05). An inverse correlation was found between the emotional coping style and religious beliefs (p < 0.001). Health professionals should recognize the patient's coping styles and understand the patient's religious belief system as part of an ongoing fertility treatment.

Fatty acid-related modulations of membrane fluidity in cells: detection and implications.

Metabolic homeostasis of fatty acids is complex and well-regulated in all organisms. The biosynthesis of saturated fatty acids (SFA) in mammals provides substrates for ß-oxidation and ATP production. Monounsaturated fatty acids (MUFA) are products of desaturases that introduce a methylene group in cis geometry in SFA. Polyunsaturated fatty acids (n-6 and n-3 PUFA) are products of elongation and desaturation of the essential linoleic acid and α-linolenic acid, respectively. The liver processes dietary fatty acids and exports them in lipoproteins for distribution and storage in peripheral tissues. The three types of fatty acids are integrated in membrane phospholipids and determine their biophysical properties and functions. This study was aimed at investigating effects of fatty acids on membrane biophysical properties under varying nutritional and pathological conditions, by integrating lipidomic analysis of membrane phospholipids with functional two-photon microscopy (fTPM) of cellular membranes. This approach was applied to two case studies: first, pancreatic beta-cells, to investigate hormetic and detrimental effects of lipids. Second, red blood cells extracted from a genetic mouse model defective in lipoproteins, to understand the role of lipids in hepatic diseases and metabolic syndrome and their effect on circulating cells.

Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12-month data from the OpT2mise randomized trial.

AIMS: To compare insulin pump therapy and multiple daily injections (MDI) in patients with type 2 diabetes receiving basal and prandial insulin analogues. METHODS: After a 2-month dose-optimization period, 331 patients with glycated haemoglobin (HbA1c) levels ≥8.0% and ≤12% were randomized to pump therapy or continued MDI for 6 months [randomization phase (RP)]. The MDI group was subsequently switched to pump therapy during a 6-month continuation phase (CP). The primary endpoint was the between-group difference in change in mean HbA1c from baseline to the end of the RP. RESULTS: The mean HbA1c at baseline was 9% in both groups. At the end of the RP, the reduction in HbA1c was significantly greater with pump therapy than with MDI (-1.1 ± 1.2% vs -0.4 ± 1.1%; p < 0.001). The pump therapy group maintained this improvement to 12 months while the MDI group, which was switched to pump therapy, showed a 0.8% reduction: the final HbA1c level was identical in both arms. In the RP, total daily insulin dose (TDD) was 20.4% lower with pump therapy than with MDI and remained stable in the CP. The MDI-pump group showed a 19% decline in TDD, such that by 12 months TDD was equivalent in both groups. There were no differences in weight gain or ketoacidosis between groups. In the CP, one patient in each group experienced severe hypoglycaemia. CONCLUSIONS: Pump therapy has a sustained durable effect on glycaemic control in uncontrolled type 2 diabetes.