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Purpose: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain., Methods: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study., Results: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases., Conclusion: Panel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary., Competing Interests: Conflict of Interest Professor Gareth Evans has received consultancy fees from AstraZeneca and Everything Genetic Ltd. Professor Gordon Jayson has received research funding from AstraZeneca. Dr Andrew Clamp has received research funding from AstraZeneca. Dr Rosemary Lord has performed advisory work for GSK. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Evidence on the value of minimally invasive pancreatic surgery (MIPS) has been increasing but it is unclear how this has influenced the view of pancreatic surgeons on MIPS., Methods: An anonymous survey was sent to members of eight international Hepato-Pancreato-Biliary Associations. Outcomes were compared with the 2016 international survey., Results: Overall, 315 surgeons from 47 countries participated. The median volume of pancreatic resections per center was 70 (IQR 40-120). Most surgeons considered minimally invasive distal pancreatectomy (MIDP) superior to open (ODP) (94.6%) and open pancreatoduodenectomy (OPD) superior to minimally invasive (MIPD) (67.9%). Since 2016, there has been an increase in the number of surgeons performing both MIDP (79%-85.7%, p = 0.024) and MIPD (29%-45.7%, p < 0.001), and an increase in the use of the robot-assisted approach for both MIDP (16%-45.6%, p < 0.001) and MIPD (23%-47.9%, p < 0.001). The use of laparoscopy remained stable for MIDP (91% vs. 88.1%, p = 0.245) and decreased for MIPD (51%-36.8%, p = 0.024)., Conclusion: This survey showed considerable changes of MIPS since 2016 with most surgeons considering MIDP superior to ODP and an increased use of robot-assisted MIPS. Surgeons prefer OPD and therefore the value of MIPD remains to be determined in randomized trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Bone marrow transplantation (BMT) has significantly improved survival rates in various hematological malignancies. However, this has led to an increased prevalence of long-term cardiotoxicity, particularly in those with prior anthracycline (AC) therapy., Objectives: To evaluate changes in left atrial (LA) volume and function, including LA strain, in BMT patients with prior AC exposure and evaluate its utility as a marker of diastolic dysfunction., Methods: This was a cross-sectional analysis of 79 BMT patients with prior AC exposure who underwent a comprehensive surveillance transthoracic echocardiogram compared to age-matched healthy volunteers. Left ventricular (LV) and LA parameters were evaluated between the 2 groups. BMT patients were stratified using traditional measures of diastolic function and additionally utilizing LA strain., Results: LV systolic dysfunction with reduced LVEF (13/79) or global longitudinal strain (29/79) was present in BMT patients. There were no differences in LA volumes between the two groups. LA reservoir strain (30.1 ± 11.2% vs 34.1 ± 9.6%, p < 0.001) and LA conduit strain (13.6 ± 8.4% vs 17.0 ± 10.5%, p < 0.001) were reduced in the BMT group compared to controls. LA reservoir strain had modest correlation with mitral annular e' velocity (r = 0.468, p < 0.001). Using current diastolic function guidelines, 26/79 BMT patients had evidence of diastolic dysfunction. However, utilizing LA reservoir strain, an additional 35 patients were identified., Conclusions: LA strain can identify early diastolic dysfunction in BMT patients with prior AC treatment. With diastolic dysfunction known to precede systolic dysfunction post AC, changes in LA reservoir strain may identify more patients with cardiac dysfunction, prompting increased surveillance and treatment., (Copyright © 2022. Published by Elsevier B.V.)

Background: We conducted a cohort study of adult patients presenting for orthopaedic trauma surgery at a statewide trauma centre, with the aims of determining (i) the incidence and risk factors for severe acute pain in the PACU, and (ii) the incidence and risk factors for persistent post-surgical pain at 3 months., Methods: Data were collected before operation, in the PACU, 72 h after surgery and 3 months after surgery, and included numerical rating scale (NRS) scores for pain, and modified Brief Pain Inventory-Short Form, Kessler Psychological Distress Scale, World Health Organization Disability Assessment Schedule, and Pain Catastrophizing Scale scores., Results: Severe acute pain in the PACU was reported by 171 (56%; 95% confidence interval [CI]: 51%, 62%) of the 303 included patients. Female sex (odds ratio [OR]: 1.86; 95% CI: 1.06, 3.26) and prior post-injury surgery (OR: 2.21; 95% CI: 1.11, 4.41) remained associated with severe acute pain after multivariable adjustment. Persistent post-surgical pain at 3 months was reported by 149 (65%; 95% CI: 59%, 71%) of the 229 included patients. The preoperative NRS score (OR: 1.17; 95% CI: 1.03, 1.32) remained associated with persistent pain after multivariable adjustment., Conclusions: We identified three easy-to-measure risk factors: female sex, prior post-injury surgery for severe acute pain, and preoperative NRS scores for persistent pain. Further research is required to identify pain management strategies and psychosocial interventions to reduce the burden of pain, disability, and distress in these patients., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Correct graft placement is critical to the success of anterior cruciate ligament reconstructions (ACLR). Whilst current trend is to insert the graft in an anatomical location, synthetic grafts have shown to better perform when they are located in an isometric position. Placement, however, is largely dependent on the surgeon and no consensus has been reached for synthetic grafts. Kinematic flexion-extension data of four separate cadaveric knees was obtained using an optical tracking system. Knees were CT-scanned and computer models were developed for each specimen. Three different graft insertion techniques were simulated in each of the computer models. Kinematic data obtained from the optical tracking was applied to the 3D computer models to simulate knee flexion-extension, and virtual change in ACL graft length was measured over the cycle for each insertion technique. Length changes were plotted onto the Radiological-Quadrant. The isometric region on the femur was found to be a band spreading from the mid to deep end of the Blumensaat's line down to the shallow-inferior end of the femoral condyle. The JP Laboureau isometric point technique was consistently located in the isometric zone, with the following coordinates on the Radiographic-Quadrant: t=0.375 (SD 0.0066), h=0.227 (SD 0.0266). The Bernard-Hertel and Charlie Brown anatomical placement methods were located (13%, -6%) and (8%, -15%) away, from the JP Laboureau isometric point, respectively, based on t- and h- coordinates of the Radiographic-Quadrant. This study has determined the isometric region using three-dimensional analysis relative to the Radiographic-Quadrant. The JP Laboureau method best finds the isometric point. This information is useful for synthetic graft placement., (© 2013 Elsevier Ltd. All rights reserved.)

Background: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing., Patients and Methods: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS)., Results: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value., Conclusions: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.

Background: Increasing the threshold to define a positive D-dimer could reduce unnecessary computed tomographic pulmonary angiography (CTPA) for a suspected pulmonary embolism (PE) but might increase rates of a missed PE and missed pneumonia, the most common non-thromboembolic diagnosis seen on CTPA., Objective: Measure the effect of doubling the standard D-dimer threshold for 'PE unlikely' Revised Geneva (RGS) or Wells' scores on the exclusion rate, frequency and size of a missed PE and missed pneumonia., Methods: Patients evaluated for a suspected PE with 64-channel CTPA were prospectively enrolled from emergency departments (EDs) and inpatient units of four hospitals. Pretest probability data were collected in real time and the D-dimer was measured in a central laboratory. Criterion standard was CPTA interpretation by two independent radiologists combined with clinical outcome at 30 days., Results: Of 678 patients enrolled, 126 (19%) were PE+ and 93 (14%) had pneumonia. Use of either Wells' ≤ 4 or RGS ≤ 6 produced similar results. For example, with RGS ≤ 6 and standard threshold (< 500 ng mL(-1)), D-dimer was negative in 110/678 (16%), and 4/110 were PE+ (posterior probability 3.8%) and 9/110 (8.2%) had pneumonia. With RGS ≤ 6 and a threshold < 1000 ng mL(-1) , D-dimer was negative in 208/678 (31%) and 11/208 (5.3%) were PE+, but 10/11 missed PEs were subsegmental and none had concomitant DVT. Pneumonia was found in 12/208 (5.4%) with RGS ≤ 6 and D-dimer < 1000 ng mL(-1)., Conclusions: Doubling the threshold for a positive D-dimer with a PE unlikely pretest probability could reduce CTPA scanning with a slightly increased risk of missed isolated subsegmental PE, and no increase in rate of missed pneumonia., (© 2012 International Society on Thrombosis and Haemostasis.)

Background: Generic medicines are commonly used in New Zealand; however, Pharmaceutical Management Agency of New Zealand (PHARMAC) has indicated a need for better information to the public. Studies on consumers' perceptions suggest that pharmacists play an important role in consumers' choice; hence, "quality use of generic medicines" can be promoted with a better understanding of pharmacists' views, knowledge, and perception., Objectives: (1)To evaluate pharmacists' perceptions, views, and knowledge of and willingness to recommend generic medicines. (2) To explore pharmacists perceptions of the safety, quality, and efficacy of generic medicines. (3) To assess pharmacists' views on current policy with respect to substitution of generic medicines., Methods: A cross-sectional survey using a postal questionnaire was conducted, and questionnaires were sent to 625 randomly selected pharmacists from a list of 1594 pharmacists who had agreed to release their details for research purposes., Results: Three-hundred and sixty pharmacists responded to the questionnaire (a response rate of 58%). Seventy percent of pharmacists stated there is no difference in safety between original brand and generic medicines. However, 65% stated that original brand medicines were of higher quality than their generic counterparts, and half stated that generic medicines and original brand medicines are equally effective. A large number of pharmacists reported concerns regarding brand substitution and offered suggestions, such as the need for advertising campaigns, patient pamphlets, updating prescribers' software, and distinct packaging for generic medicines. It was found that pharmacists' perceptions of generic medicines are primarily driven by PHARMACs policies and their experiences with consumers., Conclusions: About one-third of pharmacists correctly defined the term "generic medicines," suggesting discrepancies in pharmacists' knowledge and perceptions of generic medicines. Concerns were raised regarding: quality, safety, and effectiveness; however, most of the pharmacists acknowledged the economic benefits to the health care system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

DNA polymerase θ (POLQ, polθ) is a large, multidomain DNA polymerase encoded in higher eukaryotic genomes. It is important for maintaining genetic stability in cells and helping protect cells from DNA damage caused by ionizing radiation. POLQ contains an N-terminal helicase-like domain, a large central domain of indeterminate function, and a C-terminal polymerase domain with sequence similarity to the A-family of DNA polymerases. The enzyme has several unique properties, including low fidelity and the ability to insert and extend past abasic sites and thymine glycol lesions. It is not known whether the abasic site bypass activity is an intrinsic property of the polymerase domain or whether helicase activity is also required. Three "insertion" sequence elements present in POLQ are not found in any other A-family DNA polymerase, and it has been proposed that they may lend some unique properties to POLQ. Here, we analyzed the activity of the DNA polymerase in the absence of each sequence insertion. We found that the pol domain is capable of highly efficient bypass of abasic sites in the absence of the helicase-like or central domains. Insertion 1 increases the processivity of the polymerase but has little, if any, bearing on the translesion synthesis properties of the enzyme. However, removal of insertions 2 and 3 reduces activity on undamaged DNA and completely abrogates the ability of the enzyme to bypass abasic sites or thymine glycol lesions., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Structure-based protein sequence alignments of family B DNA polymerases revealed a conserved motif that is formed from interacting residues between loops from the N-terminal and palm domains and between the N-terminal loop and a conserved proline residue. The importance of the motif for function of the bacteriophage T4 DNA polymerase was revealed by suppressor analysis. T4 DNA polymerases that form weak replicating complexes cannot replicate DNA when the dGTP pool is reduced. The conditional lethality provides the means to identify amino acid substitutions that restore replication activity under low-dGTP conditions either by correcting the defect produced by the first amino acid substitution or by generally increasing the stability of polymerase complexes; the second type are global suppressors that can effectively counter the reduced stability caused by a variety of amino acid substitutions. Some amino acid substitutions that increase the stability of polymerase complexes produce a new phenotype-sensitivity to the antiviral drug phosphonoacetic acid. Amino acid substitutions that confer decreased ability to replicate DNA under low-dGTP conditions or drug sensitivity were identified in the new motif, which suggests that the motif functions in regulating the stability of polymerase complexes. Additional suppressor analyses revealed an apparent network of interactions that link the new motif to the fingers domain and to two patches of conserved residues that bind DNA. The collection of mutant T4 DNA polymerases provides a foundation for future biochemical studies to determine how DNA polymerases remain stably associated with DNA while waiting for the next available dNTP, how DNA polymerases translocate, and the biochemical basis for sensitivity to antiviral drugs., (2010 Elsevier Ltd. All rights reserved.)

Background: Emergency physicians rely on the interpretation of radiologists to diagnose and exclude pulmonary embolism (PE) on the basis of computerized tomographic pulmonary angiography (CTPA). Few data exist regarding the interobserver reliability of this endpoint., Objective: To quantify the degree of agreement in CTPA interpretation between four academic hospitals and an independent reference reading (IRR) laboratory., Methods: Hospitalized and emergency department patients who had one predefined symptom and sign of PE and underwent 64-slice CTPA were enrolled from four academic hospitals. CTPA results as interpreted by board-certified radiologists from the hospitals were compared against those from the IRR laboratory. CTPAs were read as indeterminate, PE(-) or PE(+), and percentage obstruction was computed by the IRR laboratory, using a published method. Agreement was calculated with weighted Cohen's kappa., Results: We enrolled 492 subjects (63% female, age 54 +/- 1 years, and 16.7% PE(+) at the site hospitals). Overall agreement was 429/492 (87.2%; 95% confidence interval 83.9-90.0). We observed 13 cases (2.6%) of complete discordance, where one reading was PE(+) and the other reading was PE(-). Weighted agreement was 92.3%, with kappa = 0.75. The median percentage obstruction for all patients was 9% (25th-75th percentile interquartile range: 5% to -30%). For CTPAs interpreted at the site hospitals as PE(-) or indeterminate but read as PE(+) by the IRR laboratory, the median of percentage obstruction was 6% (4-7%)., Conclusion: We found in this sample a good level of agreement, with a weighted kappa of 0.75, but with 2.6% of patients having total discordance. Overall, a large proportion of clots were distal or minimally occlusive clots.

Background: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype., Methods: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype., Results: We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001)., Conclusions: The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.

Unlabelled: With increasing numbers of cystic fibrosis (CF) patients surviving to adulthood, issues related to vocation inevitably arise and warrant specific attention. We examined the percentage of participants with CF currently working and explored risk factors for work disability among adults with CF., Method: We recruited 50 consecutive patients from an adult cystic fibrosis service. Demographic, employment history, illness severity indicators and CF-attributed work disability factors were evaluated. Demographic risk factors for work disability using the illness severity measures of FEV(1), S-K score, CRDQ, and recent hospitalisation as independent variables were determined., Results: Factorial analysis of a disability index (DI) indicated no dependency on FEV(1) or S-K score, but dependency on quality of life indices (p<0.05), age (p<0.05) and hospital admission rate (p<0.05). Hours worked per week were dependent on quality of life (p<0.01) (mastery of disease domain), fewer hospital admissions (p<0.01) and age (p<0.05). Sixty-eight percent of the sample reported that CF resulted in significant impediments to employment. However, few had sought vocational guidance (6%)., Conclusion: Determinants of workforce participation shows that hours worked and perceived disability are more dependent on mastery of disease, age, and time in hospital, than on clinical severity scores. Health professionals may assist productivity through career counselling or tailored programs.

An exceptional unilateral right double popliteal artery was discovered by chance. After a review of the possible causes of embryological developmental abnormalities, the most likely hypothesis is that of persistent sciatic artery.

The performance of an infra-red analyser (Beckman LB-2) in sampling alveolar gas at ventilatory frequencies and volumes occuring in the human neonate has been examined. The optimum sampling flow rate was found to be 300 ml/min; at this flow the 90% response time of the analyser-catheter system was 140 ms. Correlation of estimated alveolar PCO2 and arterial PCO2 was performed in the rabbit which has a ventilatory rate and tidal volume similar to those of the human neonate. There was a good correlation between maximum end-expired PCO2 (PE'CO2) and arterial PCO2 over a wide range of ventilatory rates (10-100 b.p.m.); maximum PE'CO2 was a better index than mean PE'CO2 or alveolar plateau PE'CO2.

The intermittent intravenous administration of narcotic analgesics had advantages over intramuscular administration, but is often impracticable. The design of a prototype apparatus is described, from which analgesic, pethidine, can be self-administered intravenously during labour. The apparatus consists of a syringe pump and control system from which the patient can demand an increment of analgesic. The minimum interval between increments and the dose of the increment are preset. A demand for analgesia is only successful when the patient passes a reaction-time test, subsequently modified. The apparatus has been used by forty-two mothers in labour. The mean total dose self-administered (2.2 mg/kg) was well within the prescribed limits, suggesting that mothers regulated their demand. The apparatus appears acceptable and safe in labour. The apparatus will probably be of value in comparative studies of analgesics.

A system is described for measuring carbon dioxide output and alveolar carbon dioxide concentration in the neonate and for deriving the volume of alveolar ventilation. Air is drawn through a soft rubber face mask applied loosely to the face so that all expired gas is entrained. A fraction of the flow is sampled by an infra-red analyser, the signal from which is integrated to provide a measure of carbon dioxide output. Alveolar carbon dioxide concentration is measured by continuous sampling of expired gas through a nasal catheter. The response time of the catheter-analyser system is 140 ms. In 20 healthy 1-day-old neonates the mean carbon dioxide excretion was 5.86 ml/min. kg-1 (STPD) and the mean alveolar PCO2 was 4.85 kPa. From these measurements mean alveolar ventilation 147 ml/min. kg-1 (BTPS) was calculated. These results are similar to those obtained by other methods.

In mothers nursed in a semi-recumbent position, arterial oxygen tension was measured at the beginning and END OF AN an intermittent period of inhalation, Lasting for six contractions, during the first stage of labour. Ten mothers had methoxyflurane 0.35 per cent and air, followed by methoxyflurane 0.35 per cent with approximately 50 per cent oxygen. Another 10 mothers had 50 per cent nitrous oxide and 50 per cent oxygen (Entonox). The mean values of PaO2 at the beginning of periods of inhalation in those who received methoxyflurane in air, methoxyflurane in 50 per cent oxygen, and nitrous oxide in oxygen were 109, 120 and 106 mm Hg respectively. The mean increases in PaO2 by the ends of periods of inhalation were 18, 43 and 63 mm Hg respectively. On average, increasing the inspired concentration of oxygen to 50 per cent significantly and substantially increased maternal PsO2 with both agents by the emd pf inhalation. There would therefore be some increase in available oxygen during the phase of higher blood flow following a uterine contraction. However, the lowest maternal PaO2 measured was 72 mm Hg; therefore additional oxygen is unlikely to offer much advantage except in patients with respiratory or cardiac deficiencies. In the intervals between inhalations of the analgesic mixture the PaO2 decreased to about the level found during air breathing. Consequently it would be necessary to breather additional oxygen continuously, between as well as during contractions, to ensure an increased maternal PaO2 throughout labour.

In seven neonates, whose mothers were given pethidine during labour, urine was collected for the first 24-40 h of life. Urinary volume and pH, and concentrations of pethidine and norpethidine in the urine were measured. Urine flow rate was low for the first 7-22 h, and then high for about 12 h. The rate of excretion of pethidine and norepethidine was approximately parallel to the urine flow rate. However, the ratio of the rate of excretion of norpethidine to that of pethidine increased with time and the concentration of norpethidine in urine decreased first and then, after 18 h, increased significantly. These findings that the neonate can metabolize pethidine, although the rate of metabolism is probably less than in the adult. The total amounts of pethidine and norpethidine excreted in the first 24 h after birth were positively related to the dose-delivery interval in the mother for intervals up to at least 5 h. From the data it is estimated that 95% of the total pethidine transferred from the mother would be eliminated by the baby by the 2nd to 3rd day after birth.