Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic.

BACKGROUND: Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival. PATIENTS AND METHODS: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations. RESULTS: Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs. CONCLUSIONS: Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued.

Challenges in the diagnosis of leptospirosis outwith endemic settings: a Scottish single centre experience.

Background Leptospirosis is a zoonotic infection occurring worldwide but endemic in tropical countries. This study describes diagnostic testing for leptospirosis at our institution in Scotland over a 10-year period. Method We identified patients with blood samples referred to the Public Health England reference laboratory for leptospirosis testing between 2006 and 2016. Results A total of 480 samples were sent for IgM ELISA testing with 26 positive results from 14 patients. Two patients met criteria for 'confirmed' leptospirosis (microscopic agglutination test > 1:320 in one case and a positive PCR in the other) and the remaining 12 were 'probable' on the basis of IgM ELISA positivity, though 9 did not have microscopic agglutination testing performed. Nine infections were imported, mostly from Asia and with a history of fresh water exposure. Three co-infections (respiratory syncytial virus, influenza B and Campylobacter sp.) were identified. Conclusions Practical issues with microscopic agglutination testing (insufficient blood sent to reference laboratory) and PCR (travellers returning > 7 days after illness onset) represent challenges to the laboratory confirmation of a clinical diagnosis of leptospirosis. Co-infection and infectious/auto-immune causes of false positive serology should be evaluated.

Electron transport and room temperature single-electron charging in 10 nm scale PtC nanostructures formed by electron beam induced deposition.

Nanostructures of platinum-carbon nanocomposite material have been formed by electron-beam induced deposition. These consist of nanodots and nanowires with a minimum size ∼20 nm, integrated within ∼100 nm nanogap n-type silicon-on-insulator transistor structures. The nanodot transistors use ∼20 nm Pt/C nanodots, tunnel-coupled to Pt/C nanowire electrodes, bridging the Si nanogaps. Room-temperature single-electron transistor operation has been measured, and single-electron current oscillations and 'Coulomb diamonds' observed. In nanowire transistors, the temperature dependence from 290 to 8 K suggests that the current is a combination of thermally activated and tunnelling transport of carriers across potential barriers along the current path, and that the Pt/C is p-type at low temperature.

Pathologic characterization of genotypes XIV and XVII Newcastle disease viruses and efficacy of classical vaccination on specific pathogen-free birds.

To characterize the clinicopathologic features of recently described genotypes of Newcastle disease virus (NDV), 1 representative strain of genotype XIV and 2 of genotype XVII, all isolated from West Africa, were used to infect groups of ten 4-week-old specific pathogen-free chickens. The pathobiology of these 3 strains was compared to a South African NDV strain classified within genotype VII. All chickens infected with the 4 viruses died or were euthanized by day 4 postinfection due to the severity of clinical signs. Gross and histologic lesions in all infected chickens included extensive necrosis of lymphoid tissues (thymus, spleen, bursa of Fabricius, cecal tonsils, gut-associated lymphoid tissue), gastrointestinal necrosis and hemorrhages, and severe hemorrhagic conjunctivitis. Immunohistochemical staining revealed systemic viral distribution, and the most intense staining was in the lymphoid organs. Results demonstrate that the 3 West African strains from the previously uncharacterized genotypes XIV and XVII are typical velogenic viscerotropic NDV strains with lesions similar to the South African strain. Under experimental conditions, QV4 and LaSota NDV vaccine strains successfully protected chickens from morbidity and mortality against the genotype VII and one genotype XVII NDV strain, with no significant differences in the amount of virus shed when 2 vaccine schemes were compared.

Combined effects of endogenous sex hormone levels and mammographic density on postmenopausal breast cancer risk: results from the Breakthrough Generations Study.

BACKGROUND: Mammographic density and sex hormone levels are strong risk factors for breast cancer, but it is unclear whether they represent the same aetiological entity or are independent risk factors. METHODS: Within the Breakthrough Generations Study cohort, we conducted a case-control study of 265 postmenopausal breast cancer cases and 343 controls with prediagnostic mammograms and blood samples. Plasma was assayed for oestradiol, testosterone and sex hormone-binding globulin (SHBG) concentrations and mammographic density assessed by Cumulus. RESULTS: Oestradiol and testosterone were negatively and SHBG positively associated with percentage density and absolute dense area, but after adjusting for body mass index the associations remained significant only for SHBG. Breast cancer risk was independently and significantly positively associated with percentage density (P=0.002), oestradiol (P=0.002) and testosterone (P=0.007) levels. Women in the highest tertile of both density and sex hormone level were at greatest risk, with an odds ratio of 7.81 (95% confidence interval (CI): 2.89-21.1) for oestradiol and 4.57 (95% CI: 1.75-11.9) for testosterone and high density compared with those who were in the lowest tertiles. The cumulative risk of breast cancer in the highest oestradiol and density tertiles, representing 8% of controls, was estimated as 12.8% at ages 50-69 years and 19.4% at ages 20-79 years, and in the lowest tertiles was 1.7% and 4.3%, respectively. Associations of breast cancer risk with tertiles of mammographic dense area were less strong than for percentage density. CONCLUSIONS: Endogenous sex hormone levels and mammographic density are independent risk factors for postmenopausal breast cancer, which in combination can identify women who might benefit from increased frequency of screening and chemoprophylaxis.

Cranial sutures work collectively to distribute strain throughout the reptile skull.

The skull is composed of many bones that come together at sutures. These sutures are important sites of growth, and as growth ceases some become fused while others remain patent. Their mechanical behaviour and how they interact with changing form and loadings to ensure balanced craniofacial development is still poorly understood. Early suture fusion often leads to disfiguring syndromes, thus is it imperative that we understand the function of sutures more clearly. By applying advanced engineering modelling techniques, we reveal for the first time that patent sutures generate a more widely distributed, high level of strain throughout the reptile skull. Without patent sutures, large regions of the skull are only subjected to infrequent low-level strains that could weaken the bone and result in abnormal development. Sutures are therefore not only sites of bone growth, but could also be essential for the modulation of strains necessary for normal growth and development in reptiles.

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

A simple, reliable M'Fadyean stain for visualizing the Bacillus anthracis capsule.

The simple polychrome methylene blue (PMB) staining procedure for blood or tissue smears from dead animals (M'Fadyean reaction) established in 1903 remained accepted as a highly reliable, rapid diagnostic test for anthrax for six decades while that disease was still common in livestock throughout the world. Improvements in disease control led to anthrax becoming rare in industrialized countries and less frequent in developing countries with the result that quality controlled, commercially produced PMB became hard to obtain by the 1980s. Mixed results with alternative methylene blue-based stains then led to diagnosis failures, confusion among practitioners and mistrust of this procedure as a reliable test for anthrax. We now report that, for laboratories needing a reliable M'Fadyean stain at short notice, the best approach is to have available commercially pure azure B ready to constitute into a solution of 0.03 g azure B in 3 ml of 95% ethanol or methanol to which is then added 10 ml of 0.01% KOH (0.23% final azure B concentration) and which can then be used immediately and through to the end of the tests. Stored in the dark at room temperature, the shelf life is at least 12 months. Smears should be fixed with ethanol or methanol (95-100%), not by heat, and the stain left for 5 min before washing off for optimum effect.

Does an interferon-gamma release assay change practice in possible latent tuberculosis?

BACKGROUND AND AIMS: Suspected latent tuberculosis infection (LTBI) is a common reason for referral to TB clinics. Interferon-gamma release assays (IGRAs) are more specific than tuberculin skin tests (TSTs) for diagnosing LTBI. The aim of this study is to determine if IGRA changes practice in the management of cases referred to a TB clinic for possible LTBI. DESIGN AND METHODS: A prospective study was performed over 29 months. All adult patients who had TST, CXR & IGRA were included. The original decision regarding TB chemoprophylaxis was made by TB team consensus, based on clinical history and TST. Cases were then analysed with the addition of IGRA to determine if this had altered management. An independent physician subsequently reviewed the cases. RESULTS: Of 204 patients studied, 68 were immunocompromised. 120 patients had positive TSTs. Of these, 36 (30%) had a positive QFT and 84 (70%) had a negative QFT. Practice changed in 78 (65%) cases with positive TST, all avoiding TB chemoprophylaxis due to QFT. Of the immunocompromised patients, 17 (25%) underwent change of practice. No cases of active TB have developed. CONCLUSION: This study demonstrates a significant change of clinical practice due to IGRA use. Our findings support the NICE 2011 recommendations.

Correlating the deep inferior epigastric artery branching pattern with type of abdominal free flap performed in a series of 145 breast reconstruction patients.

INTRODUCTION: The deep inferior epigastric perforator (DIEP) flap is currently viewed as the gold standard in autologous breast reconstruction. We studied three-dimensional computed tomography angiography (CTA) in 145 patients undergoing free abdominal flap breast reconstruction to try to correlate deep inferior epigastric artery (DIEA) branching pattern with the type of flap performed and patient outcome. Today, reconstructive breast surgeons have become more experienced in raising DIEP flaps and operative times are becoming more acceptable. However, there remains significant interest in finding ways to aid this challenging dissection. METHODS: We retrospectively evaluated consecutive patients between January 2007 and August 2008. CTAs were analysed using the Moon and Taylor (1988) classification of the DIEA branching pattern. Data gathered included pre-operative morbidity, type of abdominal wall free flap performed, length of operation, length of stay and complications. RESULTS: Some 150 breast reconstructions were performed in 145 patients. There were 67 DIEP flaps, 69 MS-2 transverse rectus abdominis myocutaneous (TRAM) flaps and 14 MS-1 TRAM flaps (where MS-1 spares the lateral muscle and MS-2 spares both lateral and medial segments). Proportionally more DIEP flaps were performed in patients with a type 2 branching pattern. There was one flap loss (0.67%). CONCLUSIONS: In this large CTA series, we found a type 1 (single artery) DIEA pattern most frequently, in contrast to the predominance of the type 2 bifurcating pattern observed previously. The higher proportion of DIEP flaps performed in the type 2 pattern patients is consistent with the documented shorter intramuscular course in this group. We have found CTA useful for faster selection of the best hemiabdomen for dissection and flap loss rates in our unit have reduced from 1.5% to 0.67%.

Tooth and cranial disparity in the fossil relatives of Sphenodon (Rhynchocephalia) dispute the persistent 'living fossil' label.

The tuatara (Sphenodon punctatus) is the only living representative of Rhynchocephalia, a group of small vertebrates that originated about 250 million years ago. The tuatara has been referred to as a living fossil; however, the group to which it belongs included a much greater diversity of forms in the Mesozoic. We explore the morphological diversity of Rhynchocephalia and stem lepidosaur relatives (Sphenodon plus 13 fossil relatives) by employing a combination of geometric morphometrics and comparative methods. Geometric morphometrics is used to explore cranium size and shape at interspecific scale, while comparative methods are employed to test association between skull shape and size and tooth number after taking phylogeny into account. Two phylogenetic topologies have been considered to generate a phylomorphospace and quantify the phylogenetic signal in skull shape data, the ancestral state reconstruction as well as morphological disparity using disparity through time plots (DTT). Rhynchocephalia exhibit a significant phylogenetic signal in skull shape that compares well with that computed for other extinct vertebrate groups. A consistent form of allometry has little impact on skull shape evolution while the number of teeth significantly correlates with skull shape also after taking phylogeny into account. The ancestral state reconstruction demonstrates a dramatic shape difference between the skull of Sphenodon and its much larger Cretaceous relative Priosphenodon. Additionally, DTT demonstrates that skull shape disparity is higher between rather than within clades while the opposite applies to skull size and number of teeth. These results were not altered by the use of competing phylogenic hypotheses. Rhynchocephalia evolved as a morphologically diverse group with a dramatic radiation in the Late Triassic and Early Jurassic about 200 million years ago. Differences in size are not marked between species whereas changes in number of teeth are associated with co-ordinated shape changes in the skull to accommodate larger masticatory muscles. These results show that the tuatara is not the product of evolutionary stasis but that it represents the only survivor of a diverse Mesozoic radiation whose subsequent decline remains to be explained.

Recommendations for the practice of travel medicine.

Travel Medicine has emerged as a distinct entity over the last two decades in response to a very substantial increase in international travel and is now forging its own identity, remit and objectives for care of the traveller. Crucial to the formation of any speciality is the definition of recommendations for its practice. This is particularly important and needed for travel medicine as it overlaps with and forms part of day-to-day work in a number of different medical specialities. This document defines a set of recommendations for the practice of travel medicine from the Faculty of Travel Medicine of the Royal College of Physicians and Surgeons of Glasgow. Their objective is to help raise standards of practice and achieve greater uniformity in provision of services, better to protect those who travel. As travel medicine moves towards applying for speciality status, these standards will also contribute to that process.

The Breakthrough Generations Study: design of a long-term UK cohort study to investigate breast cancer aetiology.

BACKGROUND: The rationale, design, recruitment and follow-up methods are described for the Breakthrough Generations Study, a UK cohort study started in 2003, targeted at investigation of breast cancer aetiology. METHODS: Cohort members have been recruited by a participant referral method intended to assemble economically a large general population cohort from whom detailed questionnaire information and blood samples can be obtained repeatedly over decades, with high completeness of follow-up and inclusion of large numbers of related individuals. 'First-generation' recruits were women contacted directly, or who volunteered directly, to join the study. They nominated female friends and family, whom we contacted, and those who joined ('second generation') nominated others, reiterated for up to 28 generations. RESULTS: The method has successfully been used during 2003-2011 to recruit 112,049 motivated participants with a broad geographic and socioeconomic distribution, aged 16-102 years, who have completed detailed questionnaires; 92% of the participants gave blood samples at recruitment. When eligible, 2½ years after recruitment, >98% completed the first follow-up questionnaire. Thirty percent are first-degree relatives of other study members. CONCLUSION: The 'generational' recruitment method has enabled recruitment of a large cohort who appear to have the commitment to enable long-term continuing data and sample collection, to investigate the effects of changing endogenous and exogenous factors on cancer risk.

Structure and compositional characteristics of caniniform dental enamel in the tuatara Sphenodon punctatus (Lepidosauria: Rhynchocephalia).

OBJECTIVE: The evolution of dental tissues in relation to tooth function is poorly understood in non-mammalian vertebrates. We studied the dentition of Sphenodon punctatus, the sole remaining member of the order Rhynchocephalia in this light. METHODS: We examined 6 anterior maxillary caniniform teeth from adult Sphenodon by scanning electron microscopy, nano-indentation and Raman spectroscopy. RESULTS: The elastic modulus (E) for tuatara enamel was 73.17 (sd, 3.25) GPa and 19.52 +/- 0.76 Gpa for dentine. Hardness (H) values for enamel and dentine were 4.00 (sd, 0.22) and 0.63 +/- 0.02 Gpa respectively. The enamel was thin (100 gm or less), prismless and consisted of grouped parallel crystallites. Incremental lines occurred at intervals of about 0.5 to 1 rm. There were tubular structures along the enamel dentine junction running from the dentine into the inner enamel, at different angles. These were widened at their base with a smooth, possibly inorganic lining. Enamel elastic modulus and hardness were lower than those for mammals. CONCLUSIONS: The presence of enamel tubules in the basal part of the enamel along the EDJ remains speculative, with possible functions being added enamel/dentinal adhesion or a role in mechanosensation.

Evidence that disease-induced population decline changes genetic structure and alters dispersal patterns in the Tasmanian devil.

Infectious disease has been shown to be a major cause of population declines in wild animals. However, there remains little empirical evidence on the genetic consequences of disease-mediated population declines, or how such perturbations might affect demographic processes such as dispersal. Devil facial tumour disease (DFTD) has resulted in the rapid decline of the Tasmanian devil, Sarcophilus harrisii, and threatens to cause extinction. Using 10 microsatellite DNA markers, we compared genetic diversity and structure before and after DFTD outbreaks in three Tasmanian devil populations to assess the genetic consequences of disease-induced population decline. We also used both genetic and demographic data to investigate dispersal patterns in Tasmanian devils along the east coast of Tasmania. We observed a significant increase in inbreeding (F(IS) pre/post-disease -0.030/0.012, P<0.05; relatedness pre/post-disease 0.011/0.038, P=0.06) in devil populations after just 2-3 generations of disease arrival, but no detectable change in genetic diversity. Furthermore, although there was no subdivision apparent among pre-disease populations (θ=0.005, 95% confidence interval (CI) -0.003 to 0.017), we found significant genetic differentiation among populations post-disease (θ=0.020, 0.010-0.027), apparently driven by a combination of selection and altered dispersal patterns of females in disease-affected populations. We also show that dispersal is male-biased in devils and that dispersal distances follow a typical leptokurtic distribution. Our results show that disease can result in genetic and demographic changes in host populations over few generations and short time scales. Ongoing management of Tasmanian devils must now attempt to maintain genetic variability in this species through actions designed to reverse the detrimental effects of inbreeding and subdivision in disease-affected populations.

Determinants of age at menarche in the UK: analyses from the Breakthrough Generations Study.

BACKGROUND: Early menarche increases breast cancer risk but, aside from weight, information on its determinants is limited. METHODS: Age at menarche data were collected retrospectively by questionnaire from 81,606 women aged 16-98, resident in the UK and participating in the Breakthrough Generations Study. RESULTS: Menarche occurred earlier in women who had a low birthweight (P(trend)<0.001), were singletons (P<0.001), had prenatal exposure to pre-eclampsia (P<0.001) or maternal smoking (P=0.01), were not breastfed (P(trend)=0.03), were non-white (P<0.001), were heavy (P(trend)<0.001) or tall (P(trend)<0.001) compared with their peers at age 7 and exercised little as a child (P(trend)<0.001). Menarcheal age increased with number of siblings (P<0.001) independently of birth order, and had an inverse association with birth order after adjustment for sibship size (P<0.001). In a multivariate model, birthweight, ethnicity, weight, height, exercise, sibship size and birth order remained significant, and maternal age at birth became significant (positive association, P<0.001). CONCLUSION: Age at menarche was influenced by both pre- and post-natal factors, and these factors may affect breast cancer risk through this route.