Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease.

BACKGROUND: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer's disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation. OBJECTIVES: The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD. DESIGN, SETTING, PARTICIPANTS: This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care. MEASUREMENTS AND RESULTS: The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation. CONCLUSION: Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.

Considering community care in public health responses: A national study regarding palliative care during a prolonged coronavirus disease 2019 lockdown.

OBJECTIVE: To describe changes in palliative care characteristics, utilisation and outcomes in Victoria during a period of enhanced public health management and a prolonged lockdown due to coronavirus disease 2019. METHODS: A national retrospective cohort study with palliative care service setting comparisons in Victoria and other mainland states was conducted. RESULTS: Analysis of 48 non-Victorian services (n=53,428 patients) and 20 Victorian services (n=31,125 patients) showed that for community services, patient volume, average length of stay, functional dependency and the proportion of admissions in a deteriorating phase increased during the lockdown in Victoria, yet little changed in comparator states. Regarding inpatient services, the management of family/carer problems remained constant in comparator states, yet substantial fluctuations in outcomes in Victoria were observed. CONCLUSIONS: As health systems adapt to changing circumstances during the pandemic, the ability to upscale community services is critical. Addressing the implications of shifting inpatient care to the community needs attention. IMPLICATIONS FOR PUBLIC HEALTH: Our study highlights the need to ensure community care providers are adequately considered within public health management responses. 'Joined up' policy and implementation across care settings are essential, especially as major barriers to infection control and increased utilisation may be evident in the community during the coronavirus disease 2019 pandemic.

Magnetic resonance non-echo planar diffusion-weighted imaging accuracy in detecting cholesteatoma in comparison with clinical and surgical findings.

OBJECTIVE: Magnetic resonance imaging utilising non-echo planar diffusion-weighted imaging is known to have high sensitivity and specificity in detecting cholesteatoma. METHOD: Data was retrospectively collected from patients who had undergone non-echo planar diffusion-weighted imaging from 1 January 2010 to 31 December 2016. The ratio of average pixel grey-scale values between the middle-ear lesion, pons and temporal lobe was used to quantify the degree of restricted diffusion and assess the statistical significance to detect cholesteatoma. RESULTS: A total of 107 patients had non-echo planar diffusion-weighted imaging during the study period. Non-echo planar diffusion-weighted imaging shows good specificity and sensitivity with an excellent positive predictive value and accuracy. Analysis of the grey-scale pixel ratio for cholesteatoma detection showed statistically significant results. CONCLUSION: Non-echo planar diffusion-weighted magnetic resonance imaging is accurate for cholesteatoma assessment. When the middle-ear lesion non-echo planar diffusion-weighted imaging intensity is higher than the ipsilateral temporal lobe, it is highly suggestive of a cholesteatoma formation.

Necrotising otitis externa and how to reduce length of hospital stay: a complete audit cycle of 77 hospital admissions.

BACKGROUND: Necrotising otitis externa is a serious condition that requires hospital admission. Longer hospital stays are associated with increased complications. METHOD: This was a closed audit cycle in a tertiary ENT centre of patients presenting with necrotising otitis externa to the ENT department between 2015 and 2019. The aim was to audit the length of hospital stay in comparison to national figures as well as the time needed for investigations. RESULTS: The number of patients with necrotising otitis externa is increasing in England. Length of stay, however, appears to be more stable. A total of 66 admissions occurred over the study period for 48 patients in total, and mean length of stay was 12.4 days. After implementation of a new protocol, length of stay was reduced to 7.1 days. CONCLUSION: Patients with necrotising otitis externa require prompt diagnosis and management in order to shorten length of stay in hospital and avoid serious complications. Multi-disciplinary protocol development and implementation could help in reducing length of stay of necrotising otitis externa patients.

Outcomes of examination under anaesthesia of post-nasal space and grommet insertion in adults presenting with otitis media with effusion.

BACKGROUND: In adults, otitis media with effusion causes considerable morbidity and has poorly established outcomes. A small number of nasopharyngeal carcinoma patients present with isolated ear-related symptoms. The investigation of choice for these patients is a point of debate. METHODS: A retrospective cohort study was conducted using a local database of adult patients who underwent examination under anaesthesia of the post-nasal space with grommet insertion for otitis media with effusion between January 2014 and January 2016. RESULTS: Ninety-eight patients met the inclusion criteria. Follow-up duration ranged from 39 to 63 months. Complications of grommets were present in 36 out of 98 patients (36.73 per cent). The findings of examination under anaesthesia of the post-nasal space were documented as abnormal in three patients. No patient was diagnosed with nasopharyngeal carcinoma. CONCLUSION: Grommets in adults with otitis media with effusion as the sole presenting feature carry a high complication rate, especially in those with previously inserted grommets. Examination under anaesthesia of the post-nasal space offers a low yield. A magnetic resonance imaging scan of the post-nasal space may be a more sensitive alternative.

Acute mastoiditis in children: contemporary opportunities and challenges.

BACKGROUND: Mastoiditis is the most common intra-temporal complication of acute otitis media. Despite potentially lethal sequelae, optimal management remains poorly defined. METHOD: A retrospective case review was conducted of children diagnosed with mastoiditis at a tertiary referral centre, in North East England, between 2010 and 2017. RESULTS: Fifty-one cases were identified, 49 without cholesteatoma. Median patient age was 42 months (2 months to 18 years) and median hospital stay was 4 days (range, 0-27 days). There was no incidence trend over time. Imaging was conducted in 15 out of 49 cases. Surgery was performed in 29 out of 49 cases, most commonly mastoidectomy with (9 out of 29) or without (9 out of 29) grommets. Complications included sigmoid sinus thrombosis (3 out of 49) and extradural abscess (2 out of 51), amongst others; no fatalities occurred. CONCLUSION: A detailed contemporary description of paediatric mastoiditis presentation and management is presented. The findings broadly mirror those published by other UK centres, but suggest a higher rate of identified disease complications and surgical interventions.

Radiology of acute mastoiditis and its complications: a pictorial review and interpretation checklist.

BACKGROUND: Mastoiditis is an otological emergency, and cross-sectional imaging has a role in the diagnosis of complications and surgical planning. Advances in imaging technology are becoming increasingly sophisticated and, by the same token, the ability to accurately interpret findings is essential. METHODS: This paper reviews common and rare complications of mastoiditis using case-led examples. A radiologist-derived systematic checklist is proposed, to assist the ENT surgeon with interpreting cross-sectional imaging in emergency mastoiditis cases when the opinion of a head and neck radiologist may be difficult to obtain. RESULTS: A 16-point checklist (the 'mastoid 16') was used on a case-led basis to review the radiological features of both common and rare complications of mastoiditis; this is complemented with imaging examples. CONCLUSION: Acute mastoiditis has a range of serious complications that may be amenable to treatment, once diagnosed using appropriate imaging. The proposed checklist provides a systematic approach to identifying complications of mastoiditis.

Validation of a frailty index in older cancer patients with solid tumours.

BACKGROUND: Frailty is an indicator of physiological reserve in older people. In non-cancer settings, frailty indices are reliable predictors of adverse health outcomes. The aims of this study were to 1) derive and validate a frailty index (FI) from comprehensive geriatric assessment (CGA) data obtained in the solid tumour chemotherapy setting, and 2) to explore whether the FI-CGA could predict chemotherapy decisions and survival in older cancer patients with solid tumours. METHODS: Prospective cohort study of a consecutive series sample of 175 cancer patients aged 65 and older with solid tumours. A frailty index was calculated using an accumulated deficits model, coding items from the comprehensive geriatric assessment tool administered prior to chemotherapy decision-making. The domains of physical and cognitive functioning, nutrition, mood, basic and instrumental activities of daily living, and comorbidities were incorporated as deficits into the model. RESULTS: The FI-CGA had a right-skewed distribution, with median (interquartile range) of 0.27 (0.21-0.39). The 99% limit to deficit accumulation was below the theoretical maximum of 1.0, at 0.75. The FI-CGA was significantly related (p < 0.001) to vulnerability as assessed by the Vulnerable Elders Survey-13 and to medical oncologists' assessments of fitness or vulnerability to treatment. Baseline frailty as determined by the FI-CGA was also associated with treatment decisions (Treatment Terminated, Treatment Completed, No Planned Treatment) (p < 0.001), with the No Planned Treatment group significantly frailer than the other two groups. CONCLUSION: The FI-CGA is a potentially useful adjunct to cancer clinical decision-making that could predict chemotherapy outcomes in older patients with solid tumours.

Spatio-temporal dynamics in maturation and spawning of Patagonian toothfish Dissostichus eleginoides on the sub-Antarctic Kerguelen Plateau.

This study investigated maturation and spawning of Patagonian toothfish Dissostichus eleginoides in the Heard Island and McDonald Islands (HIMI) fishery on the Kerguelen Plateau in the Indian Sector of the Southern Ocean based on gonads and otoliths collected between 2004 and 2015 and using histological analyses and calibration of macroscopic staging criteria. Dissostichus eleginoides at HIMI spawn throughout the austral late autumn and winter months of May-August and spawning activity is concentrated on slopes along the west and south of the plateau around HIMI at depths of 1500-1900 m. Comparison between histological analyses and macroscopic gonad staging indicated that many fish that had spawned, as indicated by the presence of post-ovulatory follicles, returned to a resting stage which was macroscopically indistinguishable from maturing fish. Furthermore, the occurrence of females of all size classes with low gonado-somatic index and low macroscopic gonad stage during the spawning season suggested that a proportion of mature females did not spawn every year. Age-at-maturity estimates, based on the assumption that fish of macroscopic stages ≥2 were mature, decreased between the 2004-2009 and 2010-2015 periods for both sexes. The magnitude of this temporal variation in age at maturity, however, varied between gear types and fishing depths and variable sampling regimes probably influenced these variations. This study highlights the importance of correct interpretation of macroscopic gonad stages and understanding the influence of fishery operations on estimations of life-history parameters.

Mapping unmet supportive care needs, quality-of-life perceptions and current symptoms in cancer survivors across the Asia-Pacific region: results from the International STEP Study.

Background: To assess the supportive care needs, quality of life (QoL) and symptoms of patients with cancer after the end of first-line treatments and into survivorship in Asian countries using Australian data as benchmark. Patients and methods: A cross-sectional survey was carried out in Australia and eight high-income (HICs) and low-/middle-income (LMICs) Asian countries (China, Japan, Hong Kong SAR, South Korea, Myanmar, Thailand, India, Philippines) using validated scales (Cancer Survivors Unmet Needs scale), physical-symptom concerns (Cancer Survivors Survey of Needs subscale) and a single-item measure of global QoL perception. Results: Data were collected from 1873 patients. QoL was highest in Australia and all other countries had significantly lower QoL than Australia (all P < 0.001). One-quarter of the patients reported low QoL (scores 1-3/10). The most frequently reported symptoms were fatigue (66.6%), loss of strength (61.8%), pain (61.6%), sleep disturbance (60.1%), and weight changes (57.7%), with no difference in symptom experience between Australian data and all other countries, or between HICs and LMICs. Unmet needs of moderate/strong level were particularly high in all aspects assessed, particularly in the area of existential survivorship (psychosocial care) and receiving comprehensive cancer care. Australia and HICs were similar in terms of unmet needs (all low), but LMICs had a significantly higher number of needs both compared with Australia and HICs (all P < 0.001). Conclusion: Health care systems in Asian countries need to re-think and prioritize survivorship cancer care and put action plans in place to overcome some of the challenges surrounding the delivery of optimal supportive cancer care, use available resource-stratified guidelines for supportive care and test efficient and cost-effective models of survivorship care.

Optically efficient InAsSb nanowires for silicon-based mid-wavelength infrared optoelectronics.

InAsSb nanowires (NWs) with a high Sb content have potential in the fabrication of advanced silicon-based optoelectronics such as infrared photondetectors/emitters and highly sensitive phototransistors, as well as in the generation of renewable electricity. However, producing optically efficient InAsSb NWs with a high Sb content remains a challenge, and optical emission is limited to 4.0 µm due to the quality of the nanowires. Here, we report, for the first time, the success of high-quality and optically efficient InAsSb NWs enabling silicon-based optoelectronics operating in entirely mid-wavelength infrared. Pure zinc-blende InAsSb NWs were realized with efficient photoluminescence emission. We obtained room-temperature photoluminescence emission in InAs NWs and successfully extended the emission wavelength in InAsSb NWs to 5.1 µm. The realization of this optically efficient InAsSb NW material paves the way to realizing next-generation devices, combining advances in III-V semiconductors and silicon.

Development and evaluation of an online educational resource about cancer survivorship for cancer nurses: a mixed-methods sequential study.

Cancer survivorship is recognised globally as a key issue. In spite of the key role played by nurses in survivorship care, there is an identified gap in nurse's knowledge in this area. This study reports on the development and evaluation of an educational resource for nurses working with people affected by cancer. The resource was designed using adult learning principles and includes a variety of learning materials and point of care resources. A mixed-methods sequential exploratory design was used to undertake an evaluation of the programme. This included the use of online surveys and semi-structured interviews with pilot participants. A total of 21 participants completed an online survey and 11 participants completed a telephone interview. Overall, the participants found the Cancer Survivorship resource to be engaging, practical and intuitive. A major theme emerging from the survey and interview data was that the resource was applicable to practice and useful in developing survivorship care plans. Respondents requested additional information be included on the role of various health professionals working in survivorship as well as guidelines on when to make referrals. This study provides evidence that the Cancer Survivorship tool may be a promising vehicle for delivering evidence-based education on survivorship care.

Downstream effects of striatal-enriched protein tyrosine phosphatase reduction on RNA expression in vivo and in vitro.

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific tyrosine phosphatase that has been shown to de-phosphorylate several key neuronal signaling proteins, including kinases (extracellular signal-regulated kinase (ERK1/2), FYN, PYK2) and glutamate receptor subunits (N-methyl-d-aspartate receptor subtype 2B (NR2B), glutamate receptor 2 (GLUR2)). Step knock-out mice have increased phosphorylation of these substrates in the brain, with potential functional consequences in synaptic plasticity and cognitive tasks. It is therefore of interest to identify the molecular pathways and downstream transcriptional targets that are impacted by Step knockdown. In the present study, striatal RNA samples from Step wild-type, knock-out and heterozygous mice were hybridized to Affymetrix microarray chips and evaluated for transcriptional changes between genotypes. Pathway analysis highlighted Erk signaling and multiple pathways related to neurotrophin signaling, neuronal development and synaptic transmission. Potential genes of interest identified by microarray were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) in the cortex and hippocampus, which shared several transcriptional alterations with the striatum. In order to evaluate Step knockdown in an in vitro system, a panel of genes were evaluated using qRT-PCR in rat cortical neurons that were transduced with lentivirus expressing short hairpin RNA against Step or a non-targeting control. Our data suggest that Step has a role in the expression of immediate early genes relevant to synaptic plasticity, in both in vitro and in vivo systems.

The surgical anatomy of the piriformis tendon, with particular reference to total hip replacement: a cadaver study.

The piriformis muscle is an important landmark in the surgical anatomy of the hip, particularly the posterior approach for total hip replacement (THR). Standard orthopaedic teaching dictates that the tendon must be cut in to allow adequate access to the superior part of the acetabulum and the femoral medullary canal. However, in our experience a routine THR can be performed through a posterior approach without sacrificing this tendon. We dissected the proximal femora of 15 cadavers in order to clarify the morphological anatomy of the piriformis tendon. We confirmed that the tendon attaches on the crest of the greater trochanter, in a position superior to the trochanteric fossa, away from the entry point for broaching the intramedullary canal during THR. The tendon attachment site encompassed the summit and medial aspect of the greater trochanter as well as a variable attachment to the fibrous capsule of the hip joint. In addition we dissected seven cadavers resecting all posterior attachments except the piriformis muscle and tendon in order to study their relations to the hip joint, as the joint was flexed. At flexion of 90° the piriformis muscle lay directly posterior to the hip joint. The piriform fossa is a term used by orthopaedic surgeons to refer the trochanteric fossa and normally has no relation to the attachment site of the piriformis tendon. In hip flexion the piriformis lies directly behind the hip joint and might reasonably be considered to contribute to the stability of the joint. We conclude that the anatomy of the piriformis muscle is often inaccurately described in the current surgical literature and terms are used and interchanged inappropriately.

Actinomycosis of the middle ear.

OBJECTIVE: To present the first case of middle-ear actinomycosis in the UK in the last 60 years. The diagnosis and management of actinomycosis of the middle ear is also presented, as well as a review of the recent literature. CASE REPORT: This paper reports the case of a nine-year-old girl who presented with recurrent otorrhoea caused by actinomycosis. Mastoid exploration with clearance of the infected tissue, in conjunction with six months amoxicillin, resulted in long-term disease remission. Histology revealed Gram-positive, silver avid (on Grocott staining) and diastase-resistant periodic acid-Schiff negative staining of colonies; this profile was in keeping with the characteristic 'sulphur granules' of actinomycosis. CONCLUSION: Actinomycosis of the middle ear and mastoid is rare, with less than 45 cases presented in the worldwide literature. This case confirms that the disease should be treated with full surgical clearance and long-term antibiotics.

The 2012 ABC orthopaedic fellowship in North America: May 24 to July 2.

In May 2012, in airports across the globe, seven orthopaedic surgeons bravely said goodbye to their loved ones, and slowly turned towards their respective aircraft. Filled with expectation and mild trepidation they stepped into the unknown… the ABC fellowship of 2012.

Effect of hydrogen peroxide on human tendon allograft.

Bacterial contamination of tendon allografts at the completion of processing has historically been about 2 %, with tendons that are found to be culture positive being discarded. Treatment of tendon allograft with hydrogen peroxide at the beginning of tissue processing may reduce bacterial contamination, however, the potential side effects of hydrogen peroxide treatment include hydrolysis of the collagen and this may alter the mechanical properties of the graft. Pairs of human tendons were used. One was washed in 3 % hydrogen peroxide for 5 min and the untreated tendon was used as a control. The ultimate tensile strength of the tendons was determined using a material testing machine. A freeze clamp technique was used to hold the tendons securely at the high loads required to cause tendon failure. There was no statistical difference in the ultimate tensile strength between the treated and untreated tendons. Mean strength ranged from Extensor Hallucis Longus at 588 Newtons to Tibialis Posterior at 2,366 Newtons. Hydrogen peroxide washing may reduce bacterial contamination of tendon allograft and does not affect the strength of the tendon.