Simultaneous co-axial multi-modal inspection using a laser driven x-ray and neutron source.

Laser-plasma interactions have been demonstrated to produce bright sources of energetic radiation including ions, electrons, photons across the electro-magnetic spectrum, and neutrons. Combinations of species can significantly increase information from non-destructive imaging. Here we demonstrate single-shot co-axial radiography with both x-ray and fast-neutron radiation from a laser-driven source using a pair of gated microchannel plate photomultiplier tube channels and a fast scintillator medium. The outlined system demonstrates recovery full-width-half-maximum of (18 ± 3) ns, which is sufficient to isolate x-rays from neutrons up to (72 ± 20) MeV and could be isolated only a short distance (2 m) from the target.

Online learning: an effective option for teaching ENT to medical students?

OBJECTIVE: ENT is underrepresented in the curriculum, and this has been compounded by coronavirus disease 2019. Recent restructures have removed ENT placements from the curriculum. This lack of exposure needs to be addressed, and increased use of online learning represents an opportunity to facilitate this. This study aimed to evaluate whether online learning can effectively deliver undergraduate ENT teaching. METHODS: An online ENT module was created; content was structured on the Sheffield Medical School curriculum. Pre- and post-module tests and 5-point Likert scales were used to assess student knowledge and confidence, respectively. RESULTS: A total of 115 participants were recruited. Test scores improved by 29 per cent (p < 0.001) and confidence by 66 per cent. Anatomy and ENT conditions demonstrated significant improvement in confidence, with a lower confidence score for examination. CONCLUSION: This study showed improved knowledge and confidence, whilst highlighting greater efficacy in content over practical skills teaching. Online learning is a validated educational tool; however, it should not be used as a replacement but as an adjunct to supplement learning.

Revision of Litoria rothii (Anura: Pelodryadidae) from northern Australia.

Litoria rothii is a widespread pelodryadid frog with a charismatic laughing advertisement call, distributed across the Australian Monsoon Tropics and southern New Guinea. Given its large distribution spanning well-known biogeographic barriers, variation in male advertisement calls and the prevalence of unresolved species complexes in the Australian frog fauna, we examine the genetic, morphological and acoustic diversity in the species from across its range. Our analyses reveal the presence of a previously unrecognised species in western parts of the range of L. rothii sensu lato, which we describe herein as a new species. Litoria ridibunda sp. nov. is distinguished from L. rothii on the basis of paraphyly of nuclear gene trees with L. everetti from Indonesia, colour patterns on the posterior thigh and male advertisement calls. Compared to L. rothii, the new species has a less contrasting pattern on the posterior thigh and a male advertisement call with a greater number of notes per call and a greater call duration. In particular, the magnitude of call differences between the species is highest where the ranges of the two species are in proximity in north-western Queensland. Our study further emphasises the undiagnosed diversity that remains in Australian frogs, even in relatively large, charismatic, frequently encountered species that often share human dwellings.

A mixed method study into obstetric sonographer-led-discharge and other forms of sonographer role extension.

Introduction: Sonographer-led-discharge was proposed in a maternity unit to provide a holistic service, cut waiting times, ease staffing pressures and increase job satisfaction. This study explored sonographers' experiences and perspectives of this new extended role and other areas of non-obstetric role extension. Understanding these will inform future practice and the success of the proposed obstetric sonographer-led-discharge and career structure. Methods: A mixed methodology, cross-sectional study was performed, with a purposive, non-probability sample using an online data collection tool. The data were analysed using descriptive statistics and thematic analysis. Results: In total, 93 sonographers participated in the study. Of these, 25% of sonographers currently practising obstetric ultrasound said they would not undertake the proposed obstetric sonographer-led-discharge role extension although 90% of the participants said role extension provides job satisfaction. Several themes emerged from the data, including job satisfaction, benefits to the hospital, improved patient pathway, time, personal factors, litigation and intra- and interprofessional resistance. A total of 54% of staff currently performing a role extension have experienced either inter- or intraprofessional conflict and only 48.5% said their workload was manageable. Conclusions: The data collected suggested that, with training and support, the proposed obstetric sonographer-led-discharge role is an appropriate role extension for sonographers. These findings support the premise of the proposed sonographic career structure, although the inter- and intraprofessional resistance identified in the study could form a significant barrier if it is not appropriately considered and managed.

Antimicrobial stewardship in companion animal practice: an implementation trial in 135 general practice veterinary clinics.

BACKGROUND: Antimicrobial stewardship programmes (ASPs) have been widely implemented in medical practice to improve antimicrobial prescribing and reduce selection for multidrug-resistant pathogens. OBJECTIVES: To implement different antimicrobial stewardship intervention packages in 135 veterinary practices and assess their impact on antimicrobial prescribing. METHODS: In October 2018, general veterinary clinics were assigned to one of three levels of ASP, education only (CON), intermediate (AMS1) or intensive (AMS2). De-identified prescribing data (1 October 2016 to 31 October 2020), sourced from VetCompass Australia, were analysed and a Poisson regression model fitted to identify the effect of the interventions on the incidence rates of antimicrobial prescribing. RESULTS: The overall incidence rate (IR) of antimicrobial prescribing for dogs and cats prior to the intervention was 3.7/100 consultations, which declined by 36% (2.4/100) in the implementation period, and by 50% (1.9/100) during the post-implementation period. Compared with CON, in AMS2 there was a 4% and 6% reduction in the overall IR of antimicrobial prescribing, and a 24% and 24% reduction in IR of high importance antimicrobial prescribing, attributable to the intervention in the implementation and post-implementation periods, respectively. A greater mean difference in the IR of antimicrobial prescribing was seen in high-prescribing clinics. CONCLUSIONS: These AMS interventions had a positive impact in a large group of general veterinary practices, resulting in a decline in overall antimicrobial use and a shift towards use of antimicrobials rated as low importance, with the greatest impact in high-prescribing clinics.

Vitamin E and beta-carotene status of dairy cows: a survey of plasma levels and supplementation practices.

Culling rate in dairy cattle has increased considerably, thereby reducing cows longevity and raising sustainability concerns worldwide. In the last decades, feeding systems have changed towards larger inclusion of preserved forages and reduced fresh herbage, which may limit vitamin E and beta-carotene dietary supply to dairy cows. Because of higher oxidative stress, engendered by greater milk production of modern genetics, the requirement for these nutrients is increased. Therefore, this study aimed to assess the current status of vitamin E and beta-carotene of commercial dairy cows. Blood vitamin E and beta-carotene concentrations were measured in 2 467 dairy cows from 127 farms in Belgium, Germany, Iberia and The Netherlands, that were visited once. Five cows were randomly selected per lactation stage per farm: Dry (between 30 and 1 day(s) before calving), Very-early (from calving until 15 days in milk (DIM)), Early (between 16 and 119 DIM), and Mid-late (from 120 DIM onwards). In addition, a survey was conducted to retrieve data on vitamin E and beta-carotene supplementation and feeding practices. Vitamin E and beta-carotene blood concentrations dropped considerably around calving. Among all surveyed cows, more than 75 and 44% were deficient in vitamin E and beta-carotene (i.e., blood concentration below 3.0 and 3.5 mg/l, respectively). Of the Very-early group, more than 97 and 78% of the cows were deficient in vitamin E and beta-carotene, respectively, with respective blood concentrations of 1.15 and 2.71 mg/l, which was significantly lower than the other lactation stages. Vitamin E and beta-carotene blood concentrations, as well as their supplementation levels, significantly varied among countries. Vitamin E and beta-carotene blood concentrations were positively related to the total estimated daily intakes of vitamin E and beta-carotene. Therefore, blood concentrations of vitamin E and beta-carotene depend on their respective level of intake, which is generally below recommendations and varies greatly between countries. Supplementation could contribute to provide cows with adequate amounts of vitamin E and beta-carotene all along the lactation, to ensure their lifetime performance and improve their fertility.

Staff and participant perceptions of optimal recruitment and retention strategies for biomedical cohort studies in the Caribbean.

PURPOSE: To identify staff and participants perspectives of best practices that facilitate achieving enrollment and retention targets in biomedical cohort studies in Caribbean populations. METHODS: Eight focus group discussions (FGDs) were held with research stakeholders including research (i) nurses/study supervisors, (ii) field staff/data collectors, and (iii) rural and urban participants of the Third Jamaica Health and Lifestyle Survey (a national NCD risk factor survey with biospecimen collection) to capture qualitative data on experiences with recruitment, training, retention challenges and potential solutions or strategies for strengthening future efforts. RESULTS: Our findings indicate that trained, experienced study staff with good interpersonal communication skills enhanced the proficiency of field operations and attracted study participants. Targeted community and stakeholder engagement alongside strong support from the coordinating center increased the reach and efficiency of the data collectors. Timely participant feedback, gender-appropriate approaches, and socioeconomic balance enhanced equitable enrollment and retention of participants of cohort studies particularly the hard to reach groups. CONCLUSION: Well-functioning research teams using traditional and social media promotion, applying gender-appropriate and personalized approaches together with strategies for reaching the less accessible socioeconomic groups, are effective for recruiting and retaining members of a Caribbean cohort. These strategies may also enhance the recruitment of other Black populations in the Diaspora including the US and Caribbean into biomedical studies including cancer research.

Tonsillitis, tonsillectomy, and deep neck space infections in England: the case for a new guideline for surgical and non-surgical management.

INTRODUCTION: Tonsillectomy is a common surgical procedure performed chiefly for recurrent tonsillitis. The Scottish Intercollegiate Guidance Network (SIGN) introduced guidelines in 1998 to improve patient selection for tonsillectomy and reduce the potential harm to patients from surgical complications such as haemorrhage. Since the introduction of the guidance, the number of admissions for tonsillitis and its complications has increased. National Hospital Episode Statistics over a 20-year period were analysed to assess the trends in tonsillectomy, post-tonsillectomy haemorrhage, tonsillitis and its complications with reference to the guidance, procedures of limited clinical value and the associated costs and benefits. MATERIALS AND METHODS: A literature search was conducted via PubMed and the Cochrane Library to identify relevant research. Hospital Episode Statistics data were interrogated and relevant data compared over time to assess trends related to the implementation of national guidance. RESULTS: Over the period analysed, the incidence of deep neck space infections has increased almost five-fold, mediastinitis ten-fold and peritonsillar abscess by 1.7-fold compared with prior to SIGN guidance. Following procedures of limited clinical value implementation, the incidence of deep neck space infections has increased 2.4-fold, mediastinitis 4.1-fold and peritonsillar abscess 1.4-fold compared with immediately prior to clinical commissioning group rationing. The rate of tonsillectomy and associated haemorrhage (1-2%) has remained relatively constant at 46,299 (1999) compared with 49,447 (2009) and 49,141 (2016), despite an increase in the population of England by seven million over the 20-year period. DISCUSSION: The rise in admissions for tonsillitis and its complications appears to correspond closely to the date of SIGN guidance and clinical commissioning group rationing of tonsillectomy and is on the background of a rise in the population of the UK. The move towards daycase tonsillectomy has reduced bed occupancy after surgery but this has been counteracted by an increase in admissions for tonsillitis and deep neck space infections, sometimes requiring lengthy intensive care stays and a protracted course of rehabilitation. The total cost of treating the complications of tonsillitis in England in 2017 is estimated to be around £73 million. The cost of tonsillectomy and treating post-tonsillectomy haemorrhage is £56 million by comparison. The total cost per annum for tonsillectomy prior to the introduction of SIGN guidance was estimated at £71 million with tonsillitis and its complications accounting for a further £8 million.

Evaluation of environmental and comfort improvements on affective welfare in heifer calves on smallholder dairy farms.

A controlled trial on zero-grazed smallholder dairy farms was conducted to determine the effect of environmental and comfort improvements on sucking and lying behaviours in heifer calves on Kenyan smallholder dairy farms. The study involved 187 heifer calves from 150 farms in two Kenyan counties, 75 farms per county. Farms in one county received animal welfare training and improvements in the calf pen that included: 1) placement of rubber mats on the lying area; 2) fixing gaps/holes in the flooring and roofing; and 3) attaching a rubber nipple on the wall of the calf pen. During the 16-month data collection period, bimonthly farm visits were used to collect data on lying time (using accelerometers) and other animal- and farm-level factors. Multilevel mixed-effects linear regression was used to model daily lying times and frequency of lying bouts, with the animal as a random effect. Over the visits, daily lying times and lying bout durations averaged 12.6-86.7 min/bout, respectively, while the median for the frequency of lying bouts was between 30-46/day. Provision of rubber nipples for non-nutritive sucking lowered proportions of cross-sucking, self-sucking and object-sucking behaviours slightly but not significantly. In a final daily lying time model, superficial lymph node enlargement, body condition score and use of wood shaving/ sawdust/ crop waste as beddings had positive associations. In contrast, group housing and rubber mat use had negative associations with daily lying time. In an interaction term, lying time was significantly higher for calves on clean versus dirty floors if the age was <190 days but this difference diminished significantly in older animals. In a second interaction term, lying time was lower for calves with leaking versus non-leaking roofs, regardless of the pen floor level, but lying time was higher on elevated than non-elevated floors if the roof was intact. In the final model of the frequency of lying bouts, the use of a rubber mat, the years of experience in dairy farming, and calf body weight had negative associations. In contrast, body condition score had a positive association. In an interaction, the frequency of daily lying bouts was lower on clean floors than dirty floors, irrespective of tethering status, but when the floor was dirty, the lying bouts were higher for animals not tethered than the ones sometimes tethered. We conclude that the comfort improvements enhanced the welfare and lying experience of heifer calves on smallholder dairy farms.

The Role of 18F-FDG PET/CT in Suspected Intraocular Sarcoidosis and Tuberculosis.

Purpose: To determine the utility of fluorine-18 fluorodeoxyglucose Positron Emission Tomography Computed Tomography (FDG PET/CT) in patients with suspected ocular sarcoidosis (OS) or intraocular tuberculosis (IOTB) in a resource-constrained, TB endemic area.Methods: Independent review of the FDG PET/CTs, Computed Tomography (CT) scans and chest radiographs (CXRs) of patients with suspected OS or IOTB and inconclusive conventional workup.Results: Twenty-nine PET/CTs and CXRs were reviewed, with 38% of PET/CTs and CTs demonstrating evidence of TB or sarcoidosis, compared to 21% of CXRs. The sensitivity, specificity, positive and negative predictive values for PET/CT and CT were similar - 85.7%, 95.5%, 85.7% and 95.5% for OS, and 33.3%, 100%, 100% and 68% for IOTB respectively and for CXR, 57.1%, 100%, 100% and 88% for OS, and 16.7%, 100%, 100% and 63% for IOTB.Conclusion: PET/CT added no significant additional benefit over Chest CT in patients with suspected OS or IOTB.

The management of adult appendicitis during the COVID-19 pandemic: an interim analysis of a UK cohort study.

BACKGROUND: Acute appendicitis (AA) is the most common general surgical emergency. Early laparoscopic appendicectomy is the gold-standard management. SARS-CoV-2 (COVID-19) brought concerns of increased perioperative mortality and spread of infection during aerosol generating procedures: as a consequence, conservative management was advised, and open appendicectomy recommended when surgery was unavoidable. This study describes the impact of the first weeks of the pandemic on the management of AA in the United Kingdom (UK). METHODS: Patients 18 years or older, diagnosed clinically and/or radiologically with AA were eligible for inclusion in this prospective, multicentre cohort study. Data was collected from 23rd March 2020 (beginning of the UK Government lockdown) to 1st May 2020 and included: patient demographics, COVID status; initial management (operative and conservative); length of stay; and 30-day complications. Analysis was performed on the first 500 cases with 30-day follow-up. RESULTS: The patient cohort consisted of 500 patients from 48 sites. The median age of this cohort was 35 [26-49.75] years and 233 (47%) of patients were female. Two hundred and seventy-one (54%) patients were initially treated conservatively; with only 26 (10%) cases progressing to an operation. Operative interventions were performed laparoscopically in 44% (93/211). Median length of hospital stay was significantly reduced in the conservatively managed group (2 [IQR 1-4] days vs. 3 [2-4], p < 0.001). At 30 days, complications were significantly higher in the operative group (p < 0.001), with no deaths in any group. Of the 159 (32%) patients tested for COVID-19 on admission, only 6 (4%) were positive. CONCLUSION: COVID-19 has changed the management of acute appendicitis in the UK, with non-operative management shown to be safe and effective in the short-term. Antibiotics should be considered as the first line during the pandemic and perhaps beyond.

Expansion of immature, nucleated red blood cells by transient low-dose methotrexate immune tolerance induction in mice.

Biological treatments such as enzyme-replacement therapies (ERT) can generate anti-drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low-dose methotrexate (TLD-MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long-lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD-MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high-risk, cross-reactive immunological material (CRIM)-negative infantile-onset Pompe disease (IOPD) patients. More recently, evaluation of TLD-MTX demonstrated benefit in CRIM-positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD-MTX, non-targeted transcriptional and proteomic screens were conducted and revealed up-regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter-119+ CD71+ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD-MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.

Developing immune-regulatory materials using immobilized monosaccharides with immune-instructive properties.

New strategies for immune modulation have shown real promise in regenerative medicine as well as the fight against autoimmune diseases, allergies, and cancer. Dendritic cells (DCs) are gatekeepers of the immune system and their ability in shaping the adaptive immune responses makes DCs ideal targets for immune modulation. Carbohydrates are abundant in different biological systems and are known to modulate DC phenotype and function. However, how simple monosaccharides instruct DC function is less well understood. In this study, we used a combinatorial array of immobilized monosaccharides to investigate how they modulate DC phenotype and function and crucially the impact of such changes on downstream adaptive immune responses. Our data show that a selection of monosaccharides significantly suppress lipopolysaccharide-induced DC activation as evidenced by a reduction in CD40 expression, IL-12 production, and indoleamine 2,3-dioxygenase activity, while inducing a significant increase in IL-10 production. These changes are indicative of the induction of an anti-inflammatory or regulatory phenotype in DCs, which was further confirmed in DC-T cell co-cultures where DCs cultured on the 'regulatory' monosaccharide-coated surfaces were shown to induce naïve T cell polarization toward regulatory phenotype. Our data also highlighted a selection of monosaccharides that are able to promote mixed Treg and Th17 cell differentiation, a T cell phenotype expected to be highly immune suppressive. These data show the potential immunomodulatory effects of immobilized monosaccharides in priming DCs and skewing T cell differentiation toward an immune-regulatory phenotype. The ability to fine-tune immune responses using these simple carbohydrate combinations (e.g. as coatings for existing materials) can be utilized as novel tools for immune modulation with potential applications in regenerative medicine, implantable medical devices, and wound healing where reduction of inflammatory responses and maintaining immune homeostasis are desirable.

Involving older people with multimorbidity in decision-making about their primary healthcare: A Cochrane systematic review of interventions (abridged).

OBJECTIVE: To assess the effects of interventions aimed at involving older people with multimorbidity in decision-making about their healthcare during primary care consultations. METHODS: Cochrane methodological procedures were applied. Searches covered all relevant trial registries and databases. Randomised controlled trials were identified where interventions had been compared with usual care/ control/ another intervention. A narrative synthesis is presented; meta-analysis was not appropriate. RESULTS: 8160 abstracts and 54 full-text articles were screened. Three studies were included, involving 1879 patient participants. Interventions utilised behaviour change theory; cognitive-behavioural therapy and motivational interviewing; multidisciplinary, holistic patient review and organisational changes. No studies reported the primary outcome 'patient involvement in decision-making about their healthcare'. Patient involvement was evident in the theory underpinning interventions. Certainty of evidence (assessed using GRADE) was limited by small studies and inconsistency in secondary outcomes measured. CONCLUSION: The evidence base is currently too limited to interpret with certainty. Transparency in design and consistency in evaluation, using validated measures, is required for future interventions involving older patients with multimorbidity in decisions about their healthcare. PRACTICE IMPLICATIONS: There is a large gap between clinical guidelines for multimorbidity and an evidence base for implementation of their recommendations during primary care consultations with older people.

Advanced radiological investigations and findings amongst community assault victims admitted to a tertiary South African hospital.

BACKGROUND: Community assault (CA) has been increasing in certain Cape Town suburbs over the past decade. There are limited CA-related imaging data. The aim of this study was to review CA-related advanced radiological investigations and findings at a Level 1 South African Trauma Centre. METHOD: A retrospective study at Tygerberg Hospital, Cape Town, from 1 January through 30 June 2013. All advanced radiological investigations performed on CA victims at the time of admission were retrieved and analysed by patient demographics, imaging investigations and radiological findings. RESULTS: Sixty-two patients (n=62) with a median age of 25 years were included; CT brain was acquired in 90% (n=56) and was abnormal in 68% (n=42). Craniofacial fractures were demonstrated in 60% (n=37), with involvement of the paranasal sinuses in 32% (n=20) and the base of skull in 19% (n=12). Almost half (n=28/62; 45%) had intracranial haemorrhage, which was intra-axial in 36% (n=22/62), extra-axial in 34% (n=21/62) and both intra- and extra-axial in 23% (n=14/62). Cerebral oedema was present in 29% (n=18/62), with herniation in 10% (n=6/62). Non-cranial CT was acquired in 52% (n=32/62), of whom 19 (n=19/32; 59%) also underwent CT brain. CT abdomen was acquired in approximately a quarter of the cohort (n=16/62, 26%), demonstrating abnormalities in 15 (24%). Fifteen cervical spine CTs were performed (n=15/62; 24%) demonstrating no acute bony injury. CONCLUSION: We recommend a high index of suspicion for severe intracranial injury in CA victims and urgent tertiary referral of those with a depressed level of consciousness. Prospective work is required to determine the long-term outlook for survivors.

Histologically confirmed tuberculosis-associated obstructive pulmonary disease.

Although chronic airflow limitation (CAL) is an important long-term consequence of tuberculosis (TB), little is known about the disease process. We present what we believe to be the first case of histologically confirmed residual TB-associated obstructive pulmonary disease (TOPD) in a 23-year-old non-smoking man who developed severe CAL after one episode of TB, with no other plausible risk factors. Lung biopsies identified residual post-TB pathology affecting the small airways and vessels throughout his lung; this has not been reported previously. These findings strengthen the argument that TOPD may be a phenotype of CAL distinct from both smoking-related chronic obstructive pulmonary disease and bronchiectasis.

Utility of routine chest radiography in ocular tuberculosis and sarcoidosis.

BACKGROUND: Tuberculosis (TB) and sarcoidosis commonly present with pulmonary and ocular involvement. Routine chest radiography (CXR) is recommended in the workup for suspected intraocular TB (IOTB) or intraocular sarcoidosis (IOS); however, data on the utility of CXR in this setting are lacking. METHODS: A post-hoc analysis was performed of a prospectively collected data set comprising 104 patients with uveitis of unknown cause. A pulmonologist and thoracic radiologist, blinded to the final diagnosis, independently reported these CXRs as being in keeping with TB or sarcoidosis. RESULTS: CXRs were reported as normal/indeterminate (n = 88), probable/previous TB (n = 9) or possible/probable sarcoidosis (n = 8), with a 96% inter-observer concordance. CXRs were more often abnormal in IOS than in IOTB (5/8 vs. 5/34, P = 0.01). CXR had a sensitivity of 14.7%, specificity of 94.3%, positive predictive value (PPV) of 55.6% and negative predictive value (NPV) of 69.5% for IOTB, compared with a sensitivity of 62.5%, specificity of 96.9%, PPV of 62.5% and NPV of 96.9% for IOS. Overall diagnostic accuracy was 54.5% (58.1% in human immunodeficiency virus [HIV] positive participants) in the case of IOTB and 79.9% for IOS. CONCLUSION: CXR had high specificity and NPV for IOS, and poor overall diagnostic accuracy for IOTB, including in the HIV-positive population.

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post-treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti-alemtuzumab antibodies, including inhibitory antibodies, during the 2-year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti-alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.

Percutaneous heel cord release for clubfoot: a retrospective, multicentre cost analysis.

PURPOSE: The Ponseti method of treatment is the standard of care for idiopathic clubfoot. Following serial casting, percutaneous tendo-Achilles tenotomy (TAT) is performed to correct residual equinus. This procedure can be performed in either the outpatient clinic or the operating room. The purpose of this study was to evaluate the expense of this procedure by examining hospital charges in both settings. METHODS: We retrospectively reviewed charts of 382 idiopathic clubfoot patients with a mean age of 2.4 months (0.6 to 26.6) treated with the Ponseti method at three institutions. Patients were divided into three groups depending on the setting for the TAT procedure: 140 patients in the outpatient clinic (CL), 219 in the operating room with discharge following the procedure (OR) and 23 in the operating room with admission to hospital for observation (OR+). Medical records were reviewed to analyze age, deformity, perioperative complications and specific time spent in each setting. Hospital charges for all three groups were standardized to one institution's charge structure. RESULTS: Charges among the three groups undergoing TAT (CL, OR, OR+) were found to be significantly different ($3840.60 versus $7962.30 versus $9110.00, respectively; p ≤ 0.001), and remained significant when separating unilateral and bilateral deformities (p < 0.001). There were nine total perioperative complications (six returns to the ER and three unexpected admissions to the hospital): five (2.3%) in the OR group, four (17.4%) in the OR+ group and none in the CL group. The OR+ group statistically had a higher rate of complications compared with the other two groups (p = 0.006). The total event time of the CL group was significantly shorter compared with the OR and OR+ groups (129.1, 171.7 and 1571.6 minutes respectively; p < 0.001). CONCLUSION: Hospital charges and total event time were significantly less when percutaneous TAT was performed in the outpatient clinic compared with the operating room. In addition, performing the procedure in clinic was associated with the lowest rate of complications. LEVEL OF EVIDENCE: Therapeutic, Level III.