Surgery under siege: A case study of leg amputation in 18th century Louisbourg, Nova Scotia, Canada.

OBJECTIVE: Paleopathological analysis of a below-knee amputation was conducted to explore the sociocultural reasons why the amputation took place. MATERIALS: Older adolescent male (18-21 years) from the New Englander mass burial at the 18th century Fortress of Louisbourg. METHODS: Macroscopic assessment and archival data. RESULTS: A surgical amputation of the right tibia and fibula, distal to the knee was identified. The cross-sectional diaphysis of the leg has kerf marks and a splinter (breakaway point) at the posterior-lateral border of the tibia suggesting the leg gave way from its own weight or was manually removed once most of the sawing was complete. CONCLUSIONS: Archival records suggest frostbite from prolonged exposure to freezing temperatures and trauma from unsafe working conditions at the Fortress were the main causes that led to amputation. SIGNIFICANCE: This case study highlights the importance of contextualizing cases of amputation to understand factors leading to the amputation procedure and techniques used in the past, and the social and living conditions of the individual. LIMITATIONS: Observations were restricted to skeletal material as soft tissue decomposed and there was no material evidence suggestive of amputation associated with this individual in their grave. SUGGESTIONS FOR FUTURE RESEARCH: Full trauma assessment of the Fortress of Louisbourg skeletal collection to provide additional insight into injury sustained at Louisbourg and 18th century surgical practices.

Experiences of UK and Irish family carers of people with profound and multiple intellectual disabilities during the COVID-19 pandemic.

BACKGROUND: People with profound and multiple intellectual disabilities (PMID) have high and intensive support needs that ordinarily place significant strain on family carers. This was further heightened by the removal of many external supports during the COVID-19 pandemic. We sought to explore the experiences of family carers of people with PMID during the COVID-19 pandemic and understand what the longer-term impact might be on their lives. METHODS: Focus group interviews (n = 32) were conducted with family carers (n = 126) from the four countries of the UK and the Republic of Ireland. Participants were asked questions relating to their experiences of the COVID-19 pandemic, coping strategies, and challenges faced. All focus groups were conducted using the online platform, Zoom. These were audio recorded, transcribed verbatim and analysed employing inductive thematic analysis. FINDINGS: Three main themes were generated from the data including (1.0) COVID-19 as a double-edged sword (2.0), The struggle for support (3.0), Constant nature of caring. These included 11 subthemes. (1.1) 'COVID-19 as a catalyst for change', (1.2) 'Challenges during COVID-19: dealing with change', (1.3) 'Challenges during COVID-19: fear of COVID-19', (1.4); 'The online environment: the new normal' (2.1) 'Invisibility of male carers', (2.2) 'Carers supporting carers', (2.3) 'The only service you get is lip service: non-existent services', (2.4); 'Knowing your rights' (3.1) 'Emotional response to the caring role: Feeling devalued', (3.2) 'Emotional response to the caring role: Desperation of caring', (3.3) 'Multiple demands of the caring role.' CONCLUSIONS: The COVID-19 pandemic presented immense challenges to family carers of people with PMID but also provided some opportunities. Families had already struggled to receive many of the supports and services to which they were entitled to only to have these removed at the onset of the pandemic. The experiences of male carers have been largely absent from the literature with this research showing they want to be included in decision making and require tailored support services. Service providers should see the end of the COVID-19 pandemic as providing opportunity to re-examine current provision and design services with family carers. As the direct threat from COVID-19 diminishes and the experiences of those who lived through this period come to the fore, there is a need to re-examine current models and provision of support to family carers to better meet their needs.

Socio-economic and ethnic disparities in childhood cancer survival, Yorkshire, UK.

BACKGROUND: Establishing the existence of health inequalities remains a high research and policy agenda item in the United Kingdom. We describe ethnic and socio-economic differences in paediatric cancer survival, focusing specifically on the extent to which disparities have changed over a 20-year period. METHODS: Cancer registration data for 2674 children (0-14 years) in Yorkshire were analysed. Five-year survival estimates by ethnic group (south Asian/non-south Asian) and Townsend deprivation fifths (I-V) were compared over time (1997-2016) for leukaemia, lymphoma, central nervous system (CNS) and other solid tumours. Hazard ratios (HR: 95% CI) from adjusted Cox models quantified the joint effect of ethnicity and deprivation on mortality risk over time, framed through causal interpretation of the deprivation coefficient. RESULTS: Increasing deprivation was associated with significantly higher risk of death for children with leukaemia (1.11 (1.03-1.20)) and all cancers between 1997 and 2001. While we observed a trend towards reducing differences in survival over time in this group, a contrasting trend was observed for CNS tumours whereby sizeable variation in outcome remained for cases diagnosed until 2012. South Asian children with lymphoma had a 15% reduced chance of surviving at least 5 years compared to non-south Asian, across the study period. DISCUSSION: Even in the United Kingdom, with a universally accessible healthcare system, socio-economic and ethnic disparities in childhood cancer survival exist. Findings should inform where resources should be directed to provide all children with an equitable survival outcome following a cancer diagnosis.

Characterization of fennel germplasm for physiological persistence and drought recovery: Association with biochemical properties.

In the perennial medicinal plant fennel (Foeniculum vulgare), persistence over years, production stability, and successful post-drought recovery are as important as plant productivity. Characterization of productivity, post-drought recovery, persistency and their association with phytochemical properties has not yet been performed in fennel. In this study, 64 fennel genotypes (from 23 different countries) from four subspecies/varieties including F. vulgare ssp. piperitum, F. vulgare var. vulgare and F. vulgare var. dulce and F. vulgare var. azoricum were evaluated in the field over four years (2015-2018), then was assessed for post-drought recovery over the next two years (2019-2020). High genotypic variation was observed among genotypes and subspecies. Based on the GC-MS analysis, trans-anethole (22.4-90.6%), estragole (2.1-25.8%), fenchone (4.9-19.8%), and limonene (0.5-11.9%) are major components in the essential oils of the studied germplasm. The highest persistence and the lowest average post-drought recovery belonged to ssp. piperitum. This subspecies also had the highest amount of limonene, fenchone, and estragole and the lowest amount of trans-anethole compared to other subspecies. The highest essential oil content and stability was observed in var. dulce. Seed yield and persistence were found to be negatively associated, suggesting that selection for more productivity may indirectly promote less persistent genotypes. Post-drought recovery was negatively associated with two main phytochemical compounds of essential oil, fenchone and estragole, but positively associated with trans-anethole. Persistence had negative correlation with estragole content. Results indicated that indirect selection for post-drought recovery and persistence may be possible through selection for phytochemical properties. The negative correlation between some essential oil components may indicate that some are isomers, which can limit the ability to select for certain combinations. Superior genotypes identified in this study can be used to construct populations for future studies and as parents of crosses to develop new varieties.

Evaluating a novel approach to stimulate open science collaborations: a case series of "study-a-thon" events within the OHDSI and European IMI communities.

Objective: We introduce and review the concept of a study-a-thon as a catalyst for open science in medicine, utilizing harmonized real world, observation health data, tools, skills, and methods to conduct network studies, generating insights for those wishing to use study-a-thons for future research. Materials and Methods: A series of historical study-a-thons since 2017 to present were reviewed for thematic insights as to the opportunity to accelerate the research method to conduct studies across therapeutic areas. Review of publications and experience of the authors generated insights to illustrate the conduct of study-a-thons, key learning, and direction for those wishing to conduct future such study-a-thons. Results: A review of six study-a-thons have provided insights into their scientific impact, and 13 areas of insights for those wishing to conduct future study-a-thons. Defining aspects of the study-a-thon method for rapid, collaborative research through network studies reinforce the need to clear scientific rationale, tools, skills, and methods being collaboratively to conduct a focused study. Well-characterized preparatory, execution and postevent phases, coalescing skills, experience, data, clinical input (ensuring representative clinical context to the research query), and well-defined, logical steps in conducting research via the study-a-thon method are critical. Conclusions: A study-a-thon is a focused multiday research event generating reliable evidence on a specific medical topic across different countries and health systems. In a study-a-thon, a multidisciplinary team collaborate to create an accelerated contribution to scientific evidence and clinical practice. It critically accelerates the research process, without inhibiting the quality of the research output and evidence generation, through a reproducible process.

Impact of the COVID-19 pandemic on family carers of those with profound and multiple intellectual disabilities: perspectives from UK and Irish Non-Governmental Organisations.

BACKGROUND: Family carers of people with profound and multiple intellectual disabilities (PMID) experienced a reduction in healthcare services due to the COVID-19 pandemic. Many subsequently turned to Non-Governmental Organisations who worked to support families. However, little research has sought to capture the experiences of family carers or identify effective interventions which might support them. To address these concerns we explored the views of Non-Governmental sector workers across the UK and Ireland who supported families people with PMID during the COVID-19 pandemic. We also sought to explore their views on the characteristics of online support programmes for family carers.  METHODS: This study employed a qualitative design using focus groups with participants (n = 24) from five Non-Governmental Organisations across the UK and Ireland. A focus group guide included questions on challenges, supports, coping and resources which helped during lockdown restrictions. Focus groups were held online, were audio recorded and transcribed verbatim. The resulting transcripts were pseudonymised and subjected to thematic analysis. FINDINGS: Four themes were identified (i) 'mental and emotional health', (ii) 'they who shout the loudest' (fighting for services), (iii) 'lack of trust in statutory services' and (iv) 'creating an online support programme'. Mental and emotional health emerged as the most prominent theme and included three subthemes named as 'isolation', 'fear of COVID-19' and 'the exhaustion of caring'. CONCLUSIONS: The COVID-19 pandemic has increased the vulnerability of family carers who were already experiencing difficulties in accessing services and supports for their families. While Non-Governmental Organisations have been a crucial lifeline there is urgent need to design services, including online support programmes, in partnership with family carers which adequately address their needs.

Identification of a unique anti-Ro60 subset with restricted serological and molecular profiles.

Anti-Ro60 is one of the most common and clinically important serum autoantibodies that has a number of diagnostic and predictive capabilities. Most diagnostic laboratories report this simply as a qualitative positive/negative result. The objective of this study was to examine the clinical and serological relevance of a novel subset of anti-Ro60 in patients who display low levels of anti-Ro60 (anti-Ro60low ). We retrospectively identified anti-Ro60 sera during a 12-month period at a major immunopathology diagnostic laboratory in Australia. These all were anti-Ro60-precipitin-positive on the diagnostic gold standard counter-immuno-electrophoresis (CIEP). Lineblot immunoassay was used to stratify patients into either anti-Ro60low or anti-Ro60high subsets. We compared the medical and laboratory parameters associated with each group. Enzyme-linked immunosorbent assay (ELISA) and mass spectrometry techniques were used to analyse the serological and molecular basis behind the two subsets. Anti-Ro60low patients displayed less serological activity than anti-Ro60high patients with less intermolecular spreading, hypergammaglobulinaemia and less tendency to undergo anti-Ro60 isotype-switching than anti-Ro60high patients. Mass spectrometric typing of the anti-Ro60low subset showed restricted variable heavy chain subfamily usage and amino acid point mutations. This subset also displayed clinical relevance, being present in a number of patients with systemic autoimmune rheumatic diseases (SARD). We identify a novel anti-Ro60low patient subset that is distinct from anti-Ro60high patients serologically and molecularly. It is not clear whether they arise from common or separate origins; however, they probably have different developmental pathways to account for the stark difference in immunological maturity. We hence demonstrate significance to anti-Ro60low and justify accurate detection in the diagnostic laboratory.

Guidelines for Clinical Target Volume Definition for Perineural Spread of Major Salivary Gland Cancers.

AIMS: Postoperative radiotherapy is the standard of care for resected major salivary cancers that are at risk of locoregional recurrence. Of the various histological subtypes, perineural invasion is most common in adenoidcystic carcinomas of the three major salivary glands - parotid, submandibular and sublingual. The clinical target volume (CTV) for these cases must include the relevant cranial nerve pathways at risk. A contouring atlas was devised for delineation of the CTV of the nerves supplying the major salivary glands. MATERIALS AND METHODS: Using standard anatomy texts and e-anatomy sources the nerves supplying the major salivary glands were identified. Subsequently the pathways of the nerves were drawn on an archived patient's planning computed tomography scan. RESULTS: The innervation of the major salivary glands has been identified and studied. Both bone and soft tissue CTVs have been delineated. A full set of images and CTVs of all the relevant transverse computed tomography slices has been archived, a number of which are printed in this article. CONCLUSIONS: Variation in CTV delineation is a recognised problem in a variety of anatomic sites. Guidelines and atlases can standardise practice and may improve the safety and efficacy of therapy. An atlas has been generated to guide clinicians in delineating the CTVs for perineural spread in major salivary gland cancers.

Revisiting classic MRI findings of venous malformations: Changes in protocols may lead to potential misdiagnosis.

Introduction Magnetic resonance imaging (MRI) is most sensitive and specific for characterizing venous malformations (VMs). VMs typically demonstrate central enhancement on delayed-contrast imaging. Fluid-fluid levels (FFLs) are uncommon in VMs and common in lymphatic malformations (LMs). Technology has advanced since the initial description of these findings. Rates of detection of these MRI findings in VMs may have changed as MRI technology and techniques have evolved. Methods and methods A prospectively maintained database from a multidisciplinary vascular anomalies clinic was reviewed to identify patients with final diagnosis of VM or LM. Patients with reviewable contrast-enhanced MRIs were selected, reviewing the oldest MRI studies in the database against the newest MRI studies to identify equal numbers of patients from the temporal extremes. Imaging was reviewed to assess for presence of FFLs. Enhancement was quantified by measuring signal in the same location of the lesion both on pre- and postcontrast sequences Results Forty patients were identified for analysis. Twenty studies with sufficient archived imaging for review were performed between 1995 and 2006; 20 such studies were performed between 2011 and 2012. The new imaging cohort had higher rates of FFL visualization ( p = 0.001). Correlation was found between time to imaging following contrast and degree of enhancement ( p < 0.001). Inverse correlation was found between scan date and time to contrast ( p = 0.001) and scan date and enhancement ( p = 0.021). Conclusion FFLs should no longer be considered exclusionary for the diagnosis of VMs. Timing following contrast administration should be maximized to increase degree of enhancement to confirm the diagnosis of VMs.

Palladium(II)-Catalysed Aminocarbonylation of Terminal Alkynes for the Synthesis of 2-Ynamides: Addressing the Challenges of Solvents and Gas Mixtures.

2-Ynamides can be synthesised through PdII catalysed oxidative carbonylation, utilising low catalyst loadings. A variety of alkynes and amines can be used to afford 2-ynamides in high yields, whilst overcoming the drawbacks associated with previous oxidative methods, which rely on dangerous solvents and gas mixtures. The use of [NBu4 ]I allows the utilisation of the industrially recommended solvent ethyl acetate. O2 can be used as the terminal oxidant, and the catalyst can operate under safer conditions with low O2 concentrations.

Synthesis of 2-Alkynoates by Palladium(II)-Catalyzed Oxidative Carbonylation of Terminal Alkynes and Alcohols.

A homogeneous Pd(II) catalyst, utilizing a simple and inexpensive amine ligand (TMEDA), allows 2-alkynoates to be prepared in high yields by an oxidative carbonylation of terminal alkynes and alcohols. The catalyst system overcomes many of the limitations of previous palladium carbonylation catalysts. It has an increased substrate scope, avoids large excesses of alcohol substrate and uses a desirable solvent. The catalyst employs oxygen as the terminal oxidant and can be operated under safer gas mixtures.

Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression.

BACKGROUND: Little is known regarding patient characteristics that influence the speed of reflux oesophagitis (RO) healing. AIM: To investigate patient characteristics that may influence RO healing rates. METHODS: A post hoc analysis of clinical trial data for potent acid suppression treatment of RO (esomeprazole or AZD0865) was conducted. Group A underwent endoscopy at baseline, week 2 and 4, and group B at baseline, week 4 and 8. Group A patients were sub-grouped as 'rapid' (healed at 2 weeks) or unhealed at 2 weeks. Group B patients were sub-grouped as 'slow' (healed at 8 weeks, not at 4 weeks) or 'refractory' (not healed at 8 weeks). Logistic regression analysis was performed only for comparisons within group A. RESULTS: At 2, 4 and 8 weeks, RO had healed in 68%, 65% and 61% of patients unhealed at previous endoscopy, respectively. Low-grade [vs. high-grade (C or D)] RO was the only independent predictor of rapid healing in group A after logistic regression analysis. Significantly more rapid healers had low grade RO (A or B) at baseline than patients with refractory RO (84% vs. 49%; P < 0.001), and significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63%; P = 0.039). CONCLUSIONS: Low- (vs. high-) grade RO determines the most rapid benefit from acid suppression. Roughly two-thirds of patients healed with each time increment of potent acid suppression therapy. This suggests that some unhealed patients may still heal with continued therapy and that truly refractory RO is rare. (ClinicalTrials.gov: NCT00206245).

Misrepresentation of UK homicide characteristics in popular culture.

The homicide statistics of a popular UK television fictional crime series and the former Lothian & Borders police force region, Scotland were compared. This comparison was used to consider the implications for public attitudes which may influence the adoption of public health interventions to reduce homicide. 217 homicides were identified by 105 perpetrators in the television series 'Midsomer Murders' between 1997 and 2011; these were compared to 55 homicides by 53 perpetrators in the regional sample between 2006 and 2011. The numbers of serial killings (p < 0.0001), planned homicides, female perpetrators (p < 0.0001), shootings (p = 0.0456) and poisonings (p = 0.0289) were higher in the fictional sample. Lothian & Borders cases were almost all single killings, mostly unplanned, with a far greater rate of homicide by kitchen knives (p < 0.0001) and hitting/kicking (p = 0.0005) by intoxicated perpetrators. Control of access to pointed kitchen knives by members of certain groups may reduce homicide rates. If the popular perception of UK homicides is influenced by popular culture, the importance of such a public health intervention may not be apparent.

Aerobic oxidation catalysis with stable radicals.

Selective oxidation reactions are challenging when carried out on an industrial scale. Many traditional methods are undesirable from an environmental or safety point of view. There is a need to develop sustainable catalytic approaches that use molecular oxygen as the terminal oxidant. This review will discuss the use of stable radicals (primarily nitroxyl radicals) in aerobic oxidation catalysis. We will discuss the important advances that have occurred in recent years, highlighting the catalytic performance, mechanistic insights and the expanding synthetic utility of these catalytic systems.

Kitchen knives and homicide: a systematic study of people charged with murder in the Lothian and Borders region of Scotland.

A recent English study demonstrated high rates of kitchen knife use in homicides by mentally disordered offenders subject to independent inquiries. Everyone accused of homicide in Scotland undergoes psychiatric examination; all such evaluations in a Scottish region between 2006 and 2011 were systematically analysed to identify homicide characteristics. It was hypothesised that kitchen knives would be the commonest sharp instruments used, and would be associated with unplanned domestic homicide against known victims, with no independent association with mental disorder. Kitchen knives were used in 32 of 55 homicides: 94% of 34 sharp object homicides (p < 0.05). No independent association was found between kitchen knife use and planning, location, relationship, intoxication or mental disorder. Kitchen knife use in homicide appears to be a significant public health issue, and not only in the mentally disordered population. Research is recommended into kitchen knife use in non-fatal violence, and weapon control in populations at increased risk of knife violence.

Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors.

BACKGROUND AND PURPOSE: Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti-cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs). EXPERIMENTAL APPROACH: The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), the hypoxia-activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions. KEY RESULTS: Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia-induced changes in Raf/MEK/ERK signalling. CONCLUSIONS AND IMPLICATIONS: Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia-targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.