Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Routine germline BRCA1 and BRCA2 testing in patients with ovarian carcinoma: analysis of the Scottish real-life experience.

OBJECTIVE: To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy. DESIGN: Retrospective cohort study. SETTING: Four cancer/genetics centres in Scotland. POPULATION: Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria). METHODS: Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. MAIN OUTCOME MEASURES: Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations. RESULTS: Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of <15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged >70 years was 8.2%. CONCLUSIONS: Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate. TWEETABLE ABSTRACT: BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

Investigating the effectiveness of commercially available mouthwash on SARS-CoV-2 in vivo using viable virus titre as the primary outcome. A randomised controlled trial.

This multi-arm, parallel group, single-blinded randomised controlled trial aimed to assess three commercially available mouthwashes effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This manuscript has been written in accordance with the CONSORT statement. Methods. Eligible participants were SARS-CoV-2 positive with a positive test in the last 72 h. All participants had mild to moderate symptoms and could provide five saliva samples over a 60 min period. Participants delivered a baseline saliva sample and then used a mouthwash as per manufacturer's instructions. They provided further saliva samples at minute 1, 10, 30 and 60. Participants were randomised to one of four groups; OraWize+, Total Care Listerine, Cool Mint Listerine and water (control). The lab-based research team were blind to the intervention. The research question was: can SARS-CoV-2 be rendered inactive in saliva by using a mouthwash and how long does this effect last? The primary outcome was the amount of viable infectious SARS-CoV-2 virus in the sample, compared to the baseline sample. The secondary outcome measure was the amount of genetic material from the SARS-CoV-2 virus in the sample, measured via PCR testing. Results. In total 100 participants were recruited (25 per group). Eight participants did not receive the allocated intervention and did not have saliva samples collected. There were no adverse events. In total 42 of the 92 participants had viable virus which could be cultured at baseline. Statistical analysis of the primary outcome was not advised due to the reduced level of viable virus at baseline and the positive skewness present in the distribution of log10(titre) data. Observational data of the primary outcome measure is presented. Analysis of the secondary outcome PCR measure showed that there was strong evidence for a decrease in SARS-CoV-2 RNA levels compared to water for all mouthwashes after 1 min, OraWize+ -0.49 (-0.92, -0.05), p-value 0.029, Cool Mint Listerine -0.81 (-1.25, -0.38), p-value<0.001, Total Care Listerine -1.05 (-1.48, -0.62), p-value<0.001. For the remaining timepoints there was generally no evidence of virus level reduction compared to water although there is weak evidence for a decrease at ten minutes using Total Care Listerine -0.44 (-0.88, 0.01), p-value 0.053. Conclusion. The three mouthwashes included in this trial observationally demonstrated a reduction in virus titre level 1 min after use, with virus levels normalising up to 60 min compared to the control. Although an interesting observation, this result could not be statistically analysed. Using the secondary outcome PCR measure all three included mouthwashes reduced virus levels compared to water at 1 min and these results were statistically significant. Clinically this result does not support the use of the included mouthwashes to reduce SARS-CoV-2 levels in saliva.

Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.

Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland.

In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer's disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom - cognitive decline - is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland's clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers.

AIM: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA125 estimation) in reducing mortality from ovarian cancer in women at increased genetic risk. PATIENTS AND METHODS: A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan-Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement. RESULTS: 64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed in the cohort. 26 tumours were detected at prevalent round; there were 27 incident detected cancers and 11 interval. 65% of cancers were stage 3 or 4, however, stage and survival were little different for prevalent versus post-prevalent cancers. Five year and 10 year survival in 49 BRCA1/2 mutation carriers was 58.6% (95% CI 50.9% to 66.3%) and 36% (95% CI 27% to 45%), which was significantly worse than for 15 non-BRCA carriers (91.8%, 95% CI 84% to 99.6%, both 5 and 10 year survival p = 0.015). However, when borderline tumours were excluded, the difference in survival between carriers and non-carriers was no longer significant. CONCLUSION: Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.

The Birmingham Hip Resurfacing: 5-year clinical and radiographic results from a District General Hospital.

We prospectively examined the functional and radiographic outcomes of a serial cohort of 104 Birmingham Hip Resurfacings in an independent centre. Final follow-up was to a mean of 61 months, and six cases were lost to follow-up. Excellent results were obtained in 91%, but obese patients had significantly (p < 0.03) poorer post-operative outcomes. Whilst there were no cases of neck fracture neck narrowing of up to 20 mm was noted. Radiolucent lines were present in a single zone in 9.4% (9/96) acetabular and 3.1% (3/96) femoral components. However, no components were definitely loose and there were no revisions for any reason during the period of the study. This independent series confirms that the Birmingham Hip Resurfacing gives excellent early clinical results and little early evidence of radiographic failure. The high rate of neck narrowing gives us cause for concern and we would recommend regular radiographic follow-up.

Virtual arthroplasty follow-up: five-year data from a district general hospital.

INTRODUCTION: Follow-up after hip and knee arthroplasty is advocated to identify asymptomatic loosening and improve patient satisfaction. There are, however, financial and time implications associated with regular clinic appointments. Assessment through virtual means has been suggested as an alternative. MATERIALS AND METHODS: At the West Suffolk Hospital, following arthroplasty surgery of the lower limb, patients are followed-up via a questionnaire at one and five years postoperatively, then subsequently at five-yearly intervals. Patients are recalled based on the outcome of these assessments. Using a locally compiled data base we identified all patients reviewed between 2011 and 2015 using this virtual assessment process and examined their outcomes. RESULTS: During the five years of follow-up, 5,380 patients were eligible for assessment. Compliance varied from 77% follow up for hips and 83% for knees. Ten patients were recalled following total hip replacement, eight for x-ray changes and one for a poor satisfaction score. Five went on to undergo revision surgery. Some 56 recalls to clinic following knee arthroplasty were seen; 42 due to a poor Oxford Knee Score, 6 with associated x-ray abnormalities and 6 isolated abnormal x-rays. Five subsequently underwent revision surgery; 30 (54%) were discharged after initial review and 18 (32%) were referred to different subspecialties.As a result of the virtual review process, 4,219 clinic appointments were avoided, with no documented admissions as a result of a missed complication from virtual review. DISCUSSION: A virtual arthroplasty clinic significantly reduces the number of patients attending regular follow-up clinics, without compromising safe practice.

Moving into the mainstream: healthcare professionals' views of implementing treatment focussed genetic testing in breast cancer care.

A proportion of breast cancers are attributable to BRCA1 or BRCA2 mutations. Technological advances has meant that mutation testing in newly diagnosed cancer patients can be used to inform treatment plans. Although oncologists increasingly deliver treatment-focused genetic testing (TFGT) as part of mainstream ovarian cancer care, we know little about non-genetics specialists' views about offering genetic testing to newly diagnosed breast cancer patients. This study sought to determine genetics and non-genetics specialists' views of a proposal to mainstream BRCA1 and 2 testing in newly diagnosed breast cancer patients. Qualitative interview study. Nineteen healthcare professionals currently responsible for offering TFGT in a standard (triage + referral) pathway (breast surgeons + clinical genetics team) and oncologists preparing to offer TFGT to breast cancer patients in a mainstreamed pathway participated in in-depth interviews. Genetics and non-genetics professionals' perceptions of mainstreaming are influenced by their views of: their clinical roles and responsibilities, the impact of TFGT on their workload and the patient pathway and the perceived relevance of genetic testing for patient care in the short-term. Perceived barriers to mainstreaming may be overcome by: more effective communication between specialities, clearer guidelines/patient pathways and the recruitment of mainstreaming champions.

Cascade genetic testing for mismatch repair gene mutations.

Mismatch repair gene mutation carriers have a high risk of developing colorectal cancer, and can benefit from appropriate surveillance. A combined population based ascertainment cascade genetic testing approach provides a systematic and potentially effective strategy for identifying such carriers. We have developed a Markov Chain computer model system which simulates various factors influencing cascade genetic testing; including demographics, uptake, genetic epidemiology and family size. This was used to evaluate cascade genetic testing for mismatch repair gene mutations in theory and practice. Simulations focussed on the population of Scotland by way of illustration, and were based on a 20-year programme in which index cases were ascertained from colorectal cancer cases aged<55 years at onset. Results indicated that without practical barriers to cascade genetic testing, 545 (95% CI=522, 568) carriers could be identified; 42% of the population total. This comprised approximately 140 index cases, 302 asymptomatic relatives and 104 previously affected relatives. However, when realistic ascertainment and acceptance rates were used to inform simulations, only 257 (95% CI=246, 268) carriers, about 20% of the carrier population, were identifiable. Of these approximately 112 were index cases, 108 were asymptomatic relatives, and 37 were previously affected relatives. This contrast emphasises the importance of ascertainment and acceptance rates. Likewise the low number of index cases shows that case identification is a limiting factor. In the absence of robust data from epidemiological studies, these findings can inform decisions about the use of cascade genetic testing for mismatch repair gene mutations.

Spinocerebellar ataxia type 8 in Scotland: frequency, neurological, neuropsychological and neuropsychiatric findings.

OBJECTIVES: The objectives of this study were to: (i) establish whether the spinocerebellar ataxia type 8 (SCA 8) expansion is associated with ataxia in Scotland; (ii) test the hypothesis that SCA 8 is associated with neuropsychological impairment; and (iii) review neuroradiological findings in SCA 8. METHODS: The methods included: (i) measurement of SCA 8 expansion frequencies in ataxic patients and healthy controls; (ii) comprehensive neuropsychological assessment of patients with SCA 8 and matched controls, neuropsychiatric interview; and (iii) comparison of patient and matched control magnetic resonance imaging (MRI) scans. RESULTS: (i) 10/694 (1.4%) unrelated individuals with ataxia had combined CTA/CTG repeat expansions >100 compared to 1/1190 (0.08%) healthy controls (P < 0.0005); (ii) neuropsychological assessment revealed a dysexecutive syndrome among SCA 8 patients, not readily explained by motor or mood disturbance; neuropsychiatric symptoms occurred commonly; (iii) cerebellar atrophy was the only salient MRI abnormality in the patient group. CONCLUSIONS: The SCA 8 expansion is associated with ataxia in Scotland. The disorder is associated with a dysexecutive syndrome.

Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia.

Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. A large four-generation family in which the affected males have striking clinical features of Fried syndrome were investigated for linkage to X-chromosome markers; the results showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. In total, 60 candidate genes located in this region, including AP1S2, which was recently shown to be involved in mental retardation, were screened for mutations. A mutation in the third intron of AP1S2 was found in all affected male subjects in this large French family. The mutation resulted in skipping of exon 3, predicting a protein with three novel amino-acids and with termination at codon 64. In addition, the first known large Scottish family affected by Fried syndrome was reinvestigated, and a new nonsense mutation, p.Gln66X, was found in exon 3. Using CT, both affected patients from the French family who were analysed had marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognise this syndromic disorder. It may be possible to use this feature to identify families with X-linked mental retardation that should be screened for mutations in AP1S2.

Fetal Dysmorphology-Still an Essential Art. Analysis of the Limitations of Microarray in a Fetal Population and a Look Toward the Genome Sequencing Era.

Cytogenomic microarray allows assessment of the genome at higher resolutions than traditional karyotyping. The objective of this study is to evaluate the utility of microarray in a routine fetal autopsy setting before the advent of routine fetal exome/genome sequencing and the issues these technologies may generate. A systematic review of fetal postmortems at 12-24 weeks gestation between January 2011 and December 2014 was undertaken. Cases where there was no consent for audit, research, or genetic testing were excluded as were cases referred to the Procurator Fiscal, stillbirths, and neonatal deaths. Copy number variations were detected in 16 cases. In addition, there was 1 case of uniparental disomy; not all of these were related to the phenotype. There were a number of cases with phenotypic abnormalities and normal array results. Five of these underwent directed mutation analysis-3 were positive. Genetic laboratory investigations such as microarray and Quantitative Fluorescent-Polymerase Chain Reaction may increase the diagnostic yield in the assessment of fetal dysmorphology. However, this study shows that genetic results not only require careful review given the potential uncertain significance but also require phenotypic assessment of the fetus by a competent fetal dysmorphologist to determine the likely causative effect of any detected anomaly. This best practice will also extend to next generation sequencing and interpretation of variants of unknown significance. Fetal medicine teams should ideally include specialists well versed in assessment of fetal anomaly to provide families with the best possible information about the cause of their pregnancy loss and their options for future pregnancies.

Assessing clarity and erasability of commercially available pens for surgical site marking: a comparative study in human volunteers.

BACKGROUND: Marking the surgical site is a well-established part of pre-operative protocol and errors in marking have been implicated in wrong site surgery incidents and are a significant patient safety issue. There are many commercially available marker pens and anecdotally very little consistency in which pen is used or the clarity of marking. Previous studies have shown subjective differences between different pens and the current paper sought to support this evidence with objective data and widen the investigation of commercially available pens. METHODS: Eight marker pens were used to mark two separate sites on three caucasian volunteers. These marks were photographed and assessed by six observers before and after the application of chlorhexidine skin preparation. The observers were blinded to which pen was used for each mark, and rated the clarity of the marks subjectively. The photographs were assessed using image analysis software to give an objective measure of clarity against the skin. RESULTS: There was a wide variation between the clarity of marks made by the different pens, and also a wide variation in the resistance to skin preparation. The Pentel N50 pen was the outstanding best performing pen across all categories. CONCLUSIONS: It is recommended that the Pentel N50 black marker pen be used for surgical site marking to improve patient safety and avoid adverse events.

The manufacture of generic replicas of implants for arthroplasty of the hip and knee: is it regulated and will it save money?

Joint replacement of the hip and knee remain very satisfactory operations. They are, however, expensive. The actual manufacturing of the implant represents only 30% of the final cost, while sales and marketing represent 40%. Recently, the patents on many well established and successful implants have expired. Companies have started producing and distributing implants that purport to replicate existing implants with good long-term results. The aims of this paper are to assess the legality, the monitoring and cost saving implications of such generic implants. We also assess how this might affect the traditional orthopaedic implant companies. Cite this article: Bone Joint J 2016;98-B:892-900.

Evidence based medicine in practice: lessons from a Scottish clinical genetics project.

OBJECTIVE: To establish national clinical guidelines and integrated care pathways for five conditions (tuberous sclerosis (TS), Huntington's disease (HD), myotonic dystrophy (MD), neurofibromatosis type 1 (NF1), and Marfan syndrome (MS)) and audit their use in Scotland. DESIGN: Systematic review of published reports followed by consensus conferences to prepare clinical guidelines and integrated care pathways. Structured review of medical records before and after introduction of integrated care pathways to document changes in practice. Survey of staff views on procedures adopted. SETTING: All four clinical genetics centres in Scotland. RESULTS: Project resulted in reduced variation in practice across centres, improved data recording in medical records, and improved communication with other professional groups. A very poor evidence base for management of patients with the conditions studied was found. CONCLUSIONS: A collaborative structure for undertaking clinical research would improve the evidence base for current practice. National discussion of the boundaries of responsibility of care for the long term management of patients with these disorders is required. The integrated care pathway approach shows promise as a means of facilitating the development of audit within clinical genetics services.