The impact of COVID-19 on epilepsy care: Perspectives from UK healthcare workers.

The COVID-19 pandemic has created an immense pressure on healthcare providers, resulting in a shift to remote consultations and the redeployment of healthcare workers (HCWs). We present survey data from the United Kingdom (UK) HCWs to outline how changes in healthcare provision impact clinicians' wellbeing and ability to provide adequate care. We designed an online survey to gather the experiences of HCWs providing care to people with epilepsy. We received seventy-nine responses from UK-based HCWs, of whom 43% reported an impact on their mental health. Changes to service delivery have resulted in 71% of clinicians performing > 75% of their consultations remotely. Diagnosing and treating epilepsy has changed, with a fifth of respondents being significantly less confident in diagnosing epilepsy. Ultimately, these results show that COVID-19 has had an overall negative impact on HCWs and their ability to provide epilepsy care. These results must be considered when reorganizing health services to ensure optimal outcomes for people with epilepsy.

Isomer-selected ion-molecule reactions of acetylene cations with propyne and allene.

One of the fundamental goals of chemistry is to determine how molecular structure influences interactions and leads to different reaction products. Studies of isomer-selected and resolved chemical reactions can shed light directly on how form leads to function. In the following, we present the results of gas-phase reactions between acetylene cations (C2D2+) with two different isomers of C3H4: propyne (DC3D3) and allene (H2C3H2). Our highly controlled, trapped-ion environment allows for precise determination of reaction products and kinetics. From these results, we can infer details of the underlying reaction dynamics of C2H2+ + C3H4. Through the synergy of experimental results and high-level quantum chemical potential energy surface calculations, we are able to identify distinct reaction mechanisms for the two isomers. We find long-range charge exchange with no complex formation is favored for allene, whereas charge exchange leads to an intermediate reaction complex for propyne and thus, different products. Therefore, this reaction displays a pronounced isomer-selective bi-molecular reactive process.

Multi-axis heterodyne interferometry at MHz frequencies: a short-arm measurement demonstration for LISA with off-the-shelf hardware.

We report the design, construction, and operation of a multi-axis heterodyne interferometry (MAHI) system operating at MHz heterodyne frequencies, which provides a testbed for technologies to be used in the Laser Interferometer Space Antenna (LISA) space-based gravitational wave mission. The system was calibrated for measurement of the piston, pitch, and yaw of a three-axis piezo-actuated mirror, giving measured calibration values that closely match those predicted by a simulation based on Gaussian beam tracing. The piston sensitivity of the MAHI system in the LISA band was measured to be below 10 pm Hz-1/2 for frequencies above 4 mHz and below 1 pm Hz-1/2 for frequencies above 35 mHz. The sensitivity is limited above 2 Hz by the mechanical vibrations of the apparatus and below 1 mHz by dimensional changes caused by temperature fluctuations. Evidence points towards scattered light as the limiting noise source at intermediate frequencies. The angular sensitivity of the MAHI system was measured to be close to or below 10 nrad Hz-1/2 for frequencies above 4 mHz and below 1 nrad Hz-1/2 for frequencies above 100 mHz. Noise budgets for both length and angle were determined, indicating the areas in which improvements must be made in order to reach increased sensitivity. The current operating sensitivity already provides a useful testbed for LISA technologies and a potential blueprint for future ground segment equipment.

Lobectomy vs. segmentectomy. A propensity score matched comparison of outcomes.

BACKGROUND: Segmentectomy has emerged as a lung parenchymal sparring alternative to the gold standard lobectomy in non-small cell lung cancer (NSCLC) patients. We hypothesized that there is parity between functional, local recurrence and survival outcomes. PATIENTS AND METHODS: Parenchymal sparring procedures including anatomical segmentectomies were propensity score matched 1:1 with lobectomies (n = 64). The primary outcomes included survival, functional and oncological outcomes. The oncological outcomes were: post-operative histology, clear margins and local recurrence rates. Kaplan Meier survival curves were used to compare the survival. Oncological and functional variables were assessed by Fischer exact test and t-test. RESULTS: The pre-operative performance status, ASA grade, lung function, risk factors, surgical approach and tumour histology were similar between the groups. The tumour size was significantly higher for lobectomies (32.4 ±â€¯17 vs. 24.6 ±â€¯12 mm, p = 0.01). The tumour staging in the segmentectomy group was similar to the lobectomy group (Ia; 50 vs. 34%; Ib: 29 vs. 37%; IIa 11 vs. 9.3%; IIb 5 vs. 14%; IIIa 5 vs. 4.6%, p = 0.83). The loco-regional recurrence was lower in the segmentectomy group (1.5 vs. 3.1%, p = 0.69). The up-staging and down-staging post-surgery was similar in both groups, while neo-adjuvant therapy was used in 5 lobectomy and 3 segmentectomy cases. The survival was similar at 1 year between the groups (88 vs. 92%, p = 0.65). Between 4 and 5 years, the survival reduced in the parenchymal sparing group to 39% vs. 68% in the lobectomy group (p = 0.04). CONCLUSION: Surgical selection bias could be an important confounder in the selection of patients undergoing segmentectomy. Similar up and down staging were demonstrated in the two groups. This is one of the first studies to investigate the results of segmentectomy versus lobectomy in stage II/IIIa NSCLC tumours. No significant differences were found in functional outcomes, but the survival decreased after 4 years in the segmentectomy group, which could be explained by lower survival in the stage II/IIIa tumours treated with segmentectomy.

Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults.

WHAT IS KNOWN AND OBJECTIVE: There are few studies examining both drug-drug and drug-disease interactions in older adults. Therefore, the objective of this study was to describe the prevalence of potential drug-drug and drug-disease interactions and associated factors in community-dwelling older adults. METHODS: This cross-sectional study included 3055 adults aged 70-79 without mobility limitations at their baseline visit in the Health Aging and Body Composition Study conducted in the communities of Pittsburgh PA and Memphis TN, USA. The outcome factors were potential drug-drug and drug-disease interactions as per the application of explicit criteria drawn from a number of sources to self-reported prescription and non-prescription medication use. RESULTS: Over one-third of participants had at least one type of interaction. Approximately one quarter (25·1%) had evidence of had one or more drug-drug interactions. Nearly 10·7% of the participants had a drug-drug interaction that involved a non-prescription medication. % The most common drug-drug interaction was non-steroidal anti-inflammatory drugs (NSAIDs) affecting antihypertensives. Additionally, 16·0% had a potential drug-disease interaction with 3·7% participants having one involving non-prescription medications. The most common drug-disease interaction was aspirin/NSAID use in those with history of peptic ulcer disease without gastroprotection. Over one-third (34·0%) had at least one type of drug interaction. Each prescription medication increased the odds of having at least one type of drug interaction by 35-40% [drug-drug interaction adjusted odds ratio (AOR) = 1·35, 95% confidence interval (CI) = 1·27-1·42; drug-disease interaction AOR = 1·30; CI = 1·21-1·40; and both AOR = 1·45; CI = 1·34-1·57]. A prior hospitalization increased the odds of having at least one type of drug interaction by 49-84% compared with those not hospitalized (drug-drug interaction AOR = 1·49, 95% CI = 1·11-2·01; drug-disease interaction AOR = 1·69, CI = 1·15-2·49; and both AOR = 1·84, CI = 1·20-2·84). WHAT IS NEW AND CONCLUSION: Drug interactions are common among community-dwelling older adults and are associated with the number of medications and hospitalization in the previous year. Longitudinal studies are needed to evaluate the impact of drug interactions on health-related outcomes.

An observational study of the success and complications of 2546 external cephalic versions in low-risk pregnant women performed by trained midwives.

OBJECTIVE: To evaluate the success of an external cephalic version (ECV) training programme, and to determine the rates of successful ECV, complications, and caesarean birth in a low-risk population. DESIGN: Prospective observational study. SETTING: Primary health care and hospital settings throughout the Netherlands (January 2008-September 2011). POPULATION: Low-risk women with a singleton fetus in breech presentation, without contraindications to ECV, were offered ECV at approximately 36 weeks of gestation. METHODS: Data were collected for all ECVs performed by midwives, and were entered into a national online database. MAIN MEASURES: Successful ECV was defined as the fetus having a cephalic presentation immediately following the procedure and at birth. Complications were observed at ≤ 30 minutes and between 30 minutes and 48 hours after the ECV procedure. All serious pregnancy outcomes that occurred after the ECV procedure until birth were reported. RESULTS: A total of 47% had a successful ECv and a cephalic at the time of birth: 34% of nulliparous and 66% of multiparous women. After ECV, 57% of women gave birth vaginally: 45% of nulliparous women and 76% of multiparous women. Within 30 minutes after ECV, and between 30 minutes and 48 hours after ECV, the proportion of women experiencing a complication or serious pregnancy outcome was 0.9% and 1.8%, respectively. Serious pregnancy outcome at any time following ECV until birth was experienced by 58 (2.5%) of the women. CONCLUSIONS: The success rate of ECVs performed by trained midwives in primary health care or hospital settings is comparable with that of other providers, and the procedure is safe for low-risk women.

Circulating and urinary adrenal corticosterone, progesterone, and estradiol in response to acute stress in female mice (Mus musculus).

In studies of stress, it can be difficult to obtain blood rapidly enough to avoid confounding steroid measures. Noninvasive urinary steroid measures may provide an alternative insofar as they reflect systemic steroids. In Experiment 1, we profiled urinary corticosterone, progesterone, and estradiol in ovariectomized female mice following 1 h on an elevated platform. This increased urinary corticosterone for 3 h and progesterone for 4 h. In Experiment 2, blood and urine samples were obtained at 0-6 h following stressor offset. Females showed increased serum corticosterone and progesterone immediately after stressor offset. Urinary corticosterone was increased at both 0 and 2 h post-stress, while an increase in progesterone 2-6 h after stressor offset was not significant. Estradiol was not influenced by this mild stressor. In Experiment 3, mice were exposed to a more severe 1 h stressor, a rat across a wire-mesh grid. In serum, both corticosterone and progesterone were elevated immediately after stressor offset and returned to baseline within 2 h. In urine, this severe stressor elevated corticosterone immediately and 2 h after stressor offset, and in progesterone 2 h after stressor offset. Estradiol in serum was not dynamic, but it was significantly elevated in urine 4 h after stressor offset. Urinary measures generally reflected systemic measures; however, with a different time course resulting in a longer return to baseline. We suggest that the relative value of serum or urinary steroid measures in mice depends upon the experimental design, and that estradiol may only respond when the stressor is severe.

Re-evaluation of pectoralis major height as an anatomic reference for humeral height in fracture hemiarthroplasty.

BACKGROUND: Shoulder replacement may be indicated for complex proximal humeral fractures. The primary reason for disappointing results is the nonanatomic position of the prosthesis because the normal anatomic landmarks are disrupted when fractured. An anatomic reference outside of the zone of injury may facilitate proper positioning of fracture arthroplasty reconstructions. It is unknown whether the measurement from the top of the pectoralis major tendon (PMT) to the top of the humeral head is related to patient height. MATERIALS AND METHODS: PMT measurements were performed on 21 pairs of cadaveric shoulders. A second group of PMT measurements was performed on 107 patients receiving a shoulder magnetic resonance imaging scan. A third PMT comparison group was included using historical measurements from 20 pairs of cadaveric shoulders. All heights, sexes, and ages were known. Statistical analysis used mixed-effects linear regression models. RESULTS: A consistent association between patient height and PMT was found, with a mean distance from the top of the PMT to the top of the humeral head of 58.9 mm in men and 55.2 mm in women. For every 10-mm increase in patient height over 1.7 m, there is a 1.7-mm increase in PMT (P = .01). Age was not associated with PMT distance (P > .5). CONCLUSIONS: A predictable measurement from the upper portion of the PMT to the top of the humeral head exists to guide implant height in fracture hemiarthroplasty and may be approximated by use of patient height and sex.

What really happens to tuberculosis patients classified as lost to follow-up in West Yorkshire?

Tuberculosis (TB) patients who do not complete treatment pose a potential public health risk. In West Yorkshire, local clinicians suspected that this risk was overestimated by the national Enhanced Tuberculosis Surveillance system. We audited patients who failed to complete treatment and were categorised as lost-to-follow-up (LTFU) between 2004 and 2008, using a combination of hand searching existing records and obtaining additional information from clinicians. In the study period 2,031 TB cases with reported outcome were notified in West Yorkshire, 23% (n=474) did not complete treatment, and 199 (42%) of those were categorised as LTFU 12 months after notification. Of these 199, 49% (n=98) remained LTFU after the audit, 51% (n=101) were re-classified to the following categories: 24% (n=47) transferred abroad, 16% (n=31) recommenced and completed treatment, 6% (n=13) transferred to another clinic in the United Kingdom (UK), and 5% (n=10) died. These patients therefore no-longer posed a public health risk. Further training for clinicians to improve accuracy of outcome reporting has been initiated. Nationally, the collection of treatment outcome data needs to be strengthened and extending the follow-up for treatment outcome monitoring should be considered.

Comparison of atom interferometers and light interferometers as space-based gravitational wave detectors.

We consider a class of proposed gravitational-wave detectors based on multiple atomic interferometers separated by large baselines and referenced by common laser systems. We compute the sensitivity limits of these detectors due to intrinsic phase noise of the light sources, noninertial motion of the light sources, and atomic shot noise and compare them to sensitivity limits for traditional light interferometers. We find that atom interferometers and light interferometers are limited in a nearly identical way by intrinsic phase noise and that both require similar mitigation strategies (e.g., multiple-arm instruments) to reach interesting sensitivities. The sensitivity limit from motion of the light sources is slightly different and, in principle, favors the atom interferometers in the low-frequency limit, although the limit in both cases is severe.

Circadian rhythm and response to an acute stressor of urinary corticosterone, testosterone, and creatinine in adult male mice.

In small laboratory species, steroid measures can be obtained more frequently and less invasively from urine than blood. Insofar as urinary levels reflect systemic levels, they could provide advantages particularly for measurement of glucocorticoids, whose blood levels react rapidly to handling and stress. In Experiment 1, urinary samples were collected from male mice every second hour over a 14:10 h light:dark cycle. Samples were analyzed via enzyme immunoassay for corticosterone, testosterone, and creatinine. Corticosterone had peak concentrations 1 h after light offset and a trough 1 h after light onset. Testosterone showed peak concentrations 5-7 h after light onset and lowest concentrations during the dark phase of the cycle. Creatinine showed some variation over the light-dark cycle, but steroid measures showed similar trends with and without adjustment for creatinine. In Experiment 2, mice were stressed via an injection at times close to the determined peak and trough levels of corticosterone. In urinary samples taken 90 min after injection, corticosterone was significantly higher in injected animals at both times relative to levels in control animals, but testosterone was unaffected by injection stress. In Experiment 3, serum and urine samples were collected from mice every sixth hour across the diurnal cycle. Corticosterone peaked in urine and serum immediately after light offset, and urinary measures predicted those in serum. These data indicate that urinary corticosterone reflects systemic levels in mice, document circadian variation in urinary testosterone, and indicate that circadian variation in creatinine is minimal, but potentially relevant in stressed animals.

Hypoxia triggers a HIF-mediated differentiation of peripheral blood mononuclear cells into osteoclasts.

BACKGROUND: The source and mechanisms leading to osteoclast (OC) generation during tooth movement are not clearly understood. We hypothesized that during tooth movement, OC differentiate from peripheral blood mononuclear cells (PBMNC) downstream of the global hypoxia-inducible transcription factor hypoxia-inducible factor (HIF)-1α. OBJECTIVE: The objective of this study was to demonstrate up-regulation of OC growth factors from osteoblasts (OB) and subsequent conversion of PBMNC into functional OC under hypoxic stress. MATERIAL AND METHODS: Human primary PBMNC were cocultured with/without OB and subjected to either hypoxia (2.5% O2) or normoxia (21% O2) over 14 days. Levels of HIF, vascular endothelial growth factor (VEGF) and receptor activator for nuclear factor kappa-ß ligand (RANKL) were measured. Conversion of PBMNC into OC was measured using resorption and TRAP assays. RESULTS: Functional OC were only observed in response to hypoxia during coculture of PBMNC and OB and only after up-regulation of HIF, VEGF and RANKL in the hypoxic conditions. YC-1, a HIF inhibitor, reduced OC formation in response to hypoxia. CONCLUSION: Hypoxia triggers the differentiation of PBMNC into functional OC in the presence of OB in a HIF-dependent manner as would occur during orthodontic loading of the periodontal ligament space.

Immunology of Diabetes Society T-Cell Workshop: HLA class I tetramer-directed epitope validation initiative T-Cell Workshop Report-HLA Class I Tetramer Validation Initiative.

BACKGROUND: Identification of T-cell reactivity to ß-cell antigen epitopes is an important goal for studying pathogenesis and for designing and monitoring of immunotherapeutic interventions in type 1 diabetes (T1D). METHODS: We performed a multicentre validation of known human leukocyte antigen (HLA) class I CD8+ T-cell epitopes. To this end, peripheral blood T-cell responses were measured in 35 recently (<2 years) diagnosed HLA-A*02:01+ T1D patients using blind-coded HLA-A2 tetramers (TMrs) and pentamers (PMrs), encompassing two epitopes of preproinsulin (PPI; PPIA12-20 and PPIB10-18) and two epitopes of glutamic acid decarboxylase (GAD; GAD114-122 and GAD536-545). We also compared the readout of TMrs and PMrs with a CD8+ T-cell interferon-γ enzyme-linked immunospot assay. RESULTS: Despite the minute frequencies of autoreactive cells detected by TMrs/PMrs, most (73-77%) T1D patients had responses to one or more of the epitopes used. All four epitopes were recognized by T1D patients, with a prevalence ranging from 5 to 25%. TMrs and PMrs detected more positive responses to the ß-cell epitopes than CD8+ T-cell interferon-γ enzyme-linked immunospot. However, concordance between positive responses to TMrs and PMrs was limited. CONCLUSIONS: Using a multicentre blind-coded setup and three different T-cell assays, we have validated PPI and GAD epitopes as commonly recognized CD8+ T-cell targets in recently diagnosed T1D patients. Both TMrs and PMrs showed higher detection sensitivity than the CD8+ T-cell interferon-γ enzyme-linked immunospot assay. However, there are some important methodological issues that need to be addressed in using these sensitive techniques for detecting low frequency responses.

Immunology of Diabetes Society T-Cell Workshop: HLA class II tetramer-directed epitope validation initiative.

BACKGROUND: Islet-antigen-specific CD4+ T cells are known to promote auto-immune destruction in T1D. Measuring T-cell number and function provides an important biomarker. In response to this need, we evaluated responses to proinsulin and GAD epitopes in a multicentre study. METHODS: A tetramer-based assay was used in five participating centres to measure T-cell reactivities to DR0401-restricted epitopes. Three participating centres concurrently performed ELISPOT or immunoblot assays. Each centre used blind-coded, centrally distributed peptide and tetramer reagents. RESULTS: All participating centres detected responses to auto-antigens and the positive control antigen, and in some cases cloned the corresponding T cells. However, response rates varied among centres. In total, 74% of patients were positive for at least one islet epitope. The most commonly recognized epitope was GAD270-285. Only a minority of the patients tested by tetramer and ELISPOT were concordant for both assays. CONCLUSIONS: This study successfully detected GAD and proinsulin responses using centrally distributed blind-coded reagents. Centres with little previous experience using class II tetramer reagents implemented the assay. The variability in response rates observed for different centres suggests technical difficulties and/or heterogeneity within the local patient populations tested. Dual analysis by tetramer and ELISPOT or immunoblot assays was frequently discordant, suggesting that these assays detect distinct cell populations. Future efforts should investigate shared blood samples to evaluate assay reproducibility and longitudinal samples to identify changes in T-cell phenotype that correlate with changes in disease course.

Effect of acute hyperglycaemia, long-term glycaemic control and insulin on endothelial dysfunction and inflammation in Type 1 diabetic patients with different characteristics.

OBJECTIVE: To investigate the possibility of reversing endothelial dysfunction and inflammation by glucose normalization, antioxidants and insulin per se, in different subgroups of Type 1 diabetic patients. METHODS: Three subgroups of Type 1 diabetic patients were studied: patients within 1 month of diagnosis (subgroup 1); patients with approximately 5 years' disease duration and with glycated haemoglobin (HbA(1c)) 7.0% since diagnosis (subgroup 3). Participants underwent four procedures: 2-h hyperglycaemic clamp followed by: (A) 12 h near-normalization of blood glucose, with the addition of vitamin C during the last 6 h; (B) 12-h vitamin C and near-normalization of blood glucose for the last 6 h; (C) both vitamin C and near-normalization of blood glucose for 12 h; (D) hyperglycaemic-hyperinsulinaemic clamp for 12 h, with the addition of vitamin C during the last 6 h. RESULTS: After 2 h of hyperglycaemia, markers of endothelial dysfunction, nitrotyrosine, 8-iso prostaglandin F2alpha, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, interleukin (IL)-6 and IL-18 were increased in all the subgroups. Levels were normalized, at all time points, by treatments A, B and C in the subgroups 1 and 2. In the third subgroup, levels were normalized only by the simultaneous normalization of blood glucose and vitamin C treatment. During treatment D, the levels were improved at 6 h in all the subgroups, but normalized at 12 h only after vitamin C in subgroups 1 and 2, but not in subgroup 3. CONCLUSIONS: This study suggests that different subgroups of Type 1 diabetic patients react identically to acute hyperglycaemia and insulin, but differently to glucose normalization.

Photofrin PDT for early stage oesophageal cancer: long term results in 40 patients and literature review.

BACKGROUND: Yorkshire Laser Centre experience of PDT in early oesophageal cancer (EOCa) to determine long survival at 3 and 5 years (absolute) and factors which might influence outcome. MATERIAL/METHOD: The records of patients who had PDT (1997-2009) for oesophageal cancer were reviewed and those with EOCa were studied and analysed. All patients had standard work up and staging. PDT was carried out using Photofrin 2 mg/kw bw, iv followed 24-72 h later by endoscopic illumination with 630 nm laser light. Results were assessed based on pathological response to treatment and survival at 3 and 5 years post-PDT. RESULTS: There were 40 patients with EOCa amongst 144 who had PDT for oesophageal cancer. 30 male and 10 female (mean age 77, range 48-84). 35 had adenocarcinoma and 5 squamous cell carcinoma. 20 of the former had Barrett's mucosa. There was no operative or 30-day mortality and no serious complications. Adverse effects were noted in 10 patients including 2 with skin photosensitivity and 3 with mild stricture requiring one dilatation. The median follow up was 76.1 (range 36-150 months). In this period 24 patients have died between 2 and 150 months (median 41 months). 16 patients are alive in between 36 and 110 months. 3 and >or=5 years or more survival (absolute) were 72.5% and 53.8%, respectively. CONCLUSION: Endoscopic PDT should be considered as the treatment of choice in patients with EOCa who are ineligible for surgical resection. We suggest that a carefully designed study of a cohort of patients with EOCa comparing surgical resection with endoscopic PDT is warranted.

Complications and follow-up after pancreas-preserving total duodenectomy for duodenal polyps.

BACKGROUND: Patients with duodenal polyps are at risk of duodenal cancer. Pancreas-preserving total duodenectomy (PPTD) is an alternative to partial pancreatoduodenectomy. METHODS: Twelve patients (seven men and five women) with a median age of 59 (interquartile range (i.q.r.) 50-67) years underwent PPTD for large (over 20 mm) solitary polyps or multiple (more than three) duodenal polyps confined to the muscularis propria on endoscopic ultrasonography. RESULTS: Median hospital stay was 21 (i.q.r. 10-36) days with no deaths and no blood transfusion. Six patients developed postoperative complications, one requiring reoperation. Histology demonstrated gastrointestinal stromal tumour in three patients, low-grade dysplasia in one, moderate-grade dysplasia in eight and duodenal intramucosal adenocarcinoma in one. During a median follow-up of 20 (i.q.r. 8-41) months one patient experienced recurrent acute pancreatitis (due to hypertriglyceridaemia) and one developed a jejunal adenocarcinoma in the neoduodenum. CONCLUSION: The morbidity of PPTD is similar to that of partial pancreatoduodenectomy, but PPTD preserves the whole pancreas and reduces the number of anastomoses.