The impact of COVID-19 on the well-being of Victorian children born with cleft lip and/or palate.

BACKGROUND: A longitudinal cohort study was established to investigate the well-being of children born with cleft lip and/or palate (CL/P) during the COVID-19 pandemic, in Victoria, Australia. MATERIALS AND METHODS: The Royal Children's Hospital cleft service database was used to identify children aged between 4 and 17 years old born with an isolated CL/P. Families of eligible children who consented to participate were asked to complete the Strengths and Difficulties Questionnaire (SDQ) between October and December 2020 and again 6-month later. SDQ results from typically developing Australian children during the COVID-19 pandemic were utilized from a previously published study. RESULTS: 63 parents completed the baseline questionnaire, with 44 completing the 6-month follow-up. For participants at baseline, the mean age was 8.9 years, with 55% male. All outcome domains of the SDQ improved between baseline and timepoint 2, with the difference in total difficulties scores being statistically significant, indicating a reduction in total difficulties at timepoint 2, associated with the easing of COVID-19 restrictions. When compared with the Australian population during the COVID-19 pandemic, Victorian children born with CL/P had lower SDQ scores for all difficulties outcome domains, with statistically significant results for conduct problems, hyperactivity, peer problems and total difficulties, indicating fewer difficulties for children born with CL/P. CONCLUSIONS: Children born with CL/P experienced fewer difficulties when compared with the typically developing Australian population during the COVID-19 pandemic. The level of restrictions imposed because of the pandemic also had little influence on the well-being of these children.

PACK syndrome: A case series and review.

A rare overlap syndrome between CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and primary biliary cholangitis (PBC) is described as PACK syndrome, an acronym for primary biliary cholangitis, anticentromere antibodies, CREST syndrome, and keratoconjunctivitis sicca. In this retrospective cohort analysis and review, we present fourteen patients who meet diagnostic criteria for PACK syndrome in one of the largest case series of this group. All patients were female, 86% of whom were White with an average age of 66.7 years (range 39-78 years). The prevalence was 5.08% in our PBC cohort (n=256) similar to previous findings. CREST syndrome was diagnosed prior to PBC in 58% of our patients and limited pulmonary and renal involvement were observed. This syndrome is rare, but given its insidious development, clinicians should be aware of this potential overlap in CREST-only and PBC-only patients.

Modernising physician resource planning: a national interactive web platform for Canadian medical trainees.

BACKGROUND: Healthcare systems rely heavily upon human resources to ensure high-quality access to care for the general population. With significant health worker shortages predicted worldwide in the coming decades, maximizing the current workforce by means of a physician resource planning (PRP) strategy that ensures the right number, mix, and distribution of physicians to meet population needs is warranted. In Canada, there is an insufficient number of primary care providers, and disproportionately low numbers of specialist physicians in rural compared to urban regions. Currently, Canadian medical students are not effectively included in PRP strategy and lack the required information for career orientation to help rebalance the population's workforce needs. This paper present the Health Human Resource (HHR) Platform, a comprehensive web tool that includes relevant workforce data to empower medical students in choosing a discipline based on both personal interests and social accountability. RESULTS: Physician workforce data, comments from Canadian residency program directors, and career planning resources were collected by the Canadian Federation of Medical Student's (CFMS) HHR Task Force. This information was consolidated to create a national interactive platform that uses a map, comparison table, and trend graphs to illustrate over 500,000 unique data points from 37 datasets, including specific information and resources spanning 62 medical specialties from 2015 onwards. There was a 24.6% response rate for program director comments. During the first 4 months of the HHR Platform launch, there were 2434 different users, of which 985 were returning, with an average of 20.0 users per day spending on average 3 min on the platform. CONCLUSIONS: The HHR Platform constitutes a national approach to PRP informing medical students on the mix and distribution of physicians needed to meet the future healthcare demands of the Canadian population.

Surgeon-performed intubation in awake patients utilising an anterior commissure laryngoscope with bougie: a retrospective case series.

OBJECTIVE: This retrospective case series examined the outcomes of surgeon-performed intubation using the anterior commissure rigid laryngoscope and bougie in adults with a difficult airway, including awake patients. METHODS: This study comprised a series of adult patients who underwent surgeon-performed intubation over a 10-year period. They were identified by a records search for the Current Procedural Terminology ('CPT') code 31500 - 'intubation by surgeon'. RESULTS: Forty-nine intubations performed in the operating theatre were reviewed. Intubation performed by the surgeon using the rigid anterior commissure laryngoscope was successful in 47 of the cases (96 per cent). Over half of the patients had experienced failed intubation attempts with other methods by other providers prior to the surgeon performing direct laryngoscopy. Twenty intubations were performed without paralytics and with the patient awake. CONCLUSION: In properly selected adults who need an urgent, secure airway in the operating theatre, surgeon-performed anterior commissure laryngoscopic intubation using a bougie should be considered a safe, reliable procedure. In most cases, this procedure can be performed in selected patients whilst awake, with sedation.

Systematic review of the methods used in economic evaluations of targeted physical activity and sedentary behaviour interventions.

The burden of noncommunicable diseases (NCD) on health systems worldwide is substantial. Physical inactivity and sedentary behaviour are major risk factors for NCD. Previous attempts to understand the value for money of preventative interventions targeting physically inactive individuals have proved to be challenging due to key methodological challenges associated with the conduct of economic evaluations in public health. A systematic review was carried out across six databases (Medline, SPORTSDiscus, EconLit, PsychINFO, NHS EED, HTA) along with supplementary searches. The review examines how economic evaluations published between 2009-March 2017 have addressed methodological challenges with the aim of bringing to light examples of good practice for future studies. Fifteen economic evaluations from four high-income countries were retrieved; there is a dearth of studies targeting sedentary behaviour as an independent risk factor from physical activity. Comparability of studies from the healthcare and societal perspectives were limited due to analysts' choice in cost categories, valuation technique and time horizon differing substantially. The scarcity of and inconsistencies across economic evaluations for these two behaviours have exposed a mismatch between calls for more preventative action to tackle NCD and the lack of information available on how resources may be optimally allocated in practice. Consequently, this paper offers a table of recommendations on how future studies can be improved.

A unified framework for land cover monitoring based on a discrete global sampling grid (GSG).

Environmental monitoring and assessment of the extent and change of land uses and their renewable natural resources over time is a key element in many international processes and one crucial basis for sustainable management. Remote sensing plays an increasingly important role in these monitoring systems, especially if the interest is in large areas. Integration of remote sensing requires comprehensive and careful preprocessing and a high level of expertise which is not always at hand in all applications. However, easy-to-implement sampling techniques based on visual interpretation are an alternative approach for utilizing remote sensing imagery, including the evolving archives of georeferenced and preprocessed data provided by virtual globes like Google Earth, Bing, and others. The goal of this paper is to propose a simple unified framework that may be used in the context of sampling studies and environmental monitoring from local to global scale. Besides the definition of a sampling design, the observation or plot design, i.e., defining how observations are to be made and recorded, has a strong influence on the precision of estimates as well as the overall efficiency of a sampling exercise. As an example, we present a simulation study focusing on the estimation of forest cover in artificial landscapes with different coverage and degree of fragmentation. The sampling units we compare are point clusters with different configuration and spatial extent.

Development and Validation of an Analytical Method to Quantitate Tris(chloroisopropyl)phosphate in Rat and Mouse Plasma using Gas Chromatography with Flame Photometric Detection.

Tris(chloropropyl)phosphate (TCPP) is an organophosphorus flame retardant (OPFR) and plasticizer increasingly used in consumer products and as a replacement for brominated flame retardants. Commercially available TCPP is a mixture of four structural isomers the most abundant of which is tris(1-chloro-2-propyl)phosphate (TCPP-1). Although there is a widespread use of TCPP and potential for human exposure, there is limited data on the safety or toxicity of TCPP. The National Toxicology Program is conducting long-term studies to examine the toxicity of the TCPP in rats after lifetime exposure, including perinatal oral exposure. Quantitative estimates of internal dose are essential to interpret toxicological findings in rodents. To aid in this, a method was fully validated to quantitate the most abundant isomer, TCPP-1, in female Harlan Sprague Dawley (HSD) rat and B6C3F1 mouse plasma with partial validation in male rat plasma, and male and female mouse plasma. The method used protein precipitation using trichloroacetic acid followed by the extraction with toluene, and analysis by gas chromatography with flame photometric detection. The performance of the method was evaluated over 5-70 ng TCPP-1/mL plasma. The method was linear (r ≥ 0.99), accurate (inter-day relative error: ≤ ± -7.2) and precise (inter-batch relative standard deviation: ≤27.5%). The validated method has lower limits of quantitation and detection of ~5 and 0.9 ng/mL, respectively, in female HSD rat plasma and can be used on samples as small as 50 µL demonstrating the applicability to plasma samples from toxicology studies.

Contact X-ray Brachytherapy as an Adjunct to a Watch and Wait Approach is an Affordable Alternative to Standard Surgical Management of Rectal Cancer for Patients with a Partial Clinical Response to Chemoradiotherapy.

AIMS: Emerging evidence suggests that contact X-ray brachytherapy (CXB) may increase the clinical complete response rate and durability when administered after standard chemoradiotherapy in patients with rectal cancer. The addition of CXB in partial responders is therefore probably cost-effective. The affordability of widening access to CXB in the UK, however, has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling with Monte Carlo simulation was used to evaluate long-term costs for the management of patients with rectal cancers who were given a CXB boost when a clinical complete response was not initially achieved following chemoradiotherapy in order to facilitate a watch and wait approach. A third-party payer (National Health Service) perspective was adopted, probabilistic sensitivity analysis was carried out and a scenario analysis was performed to investigate the effect of the number of referral centres and number of patients treated with CXB. RESULTS: We estimate that 818 (95% confidence interval 628-1021) patients per year are eligible for CXB as an adjunct to a watch and wait approach in England and Wales. As this management is less costly than surgical management for each individual patient, the more patients treated, the more affordable the technology. Even if as few as 125 patients are treated nationally in 15 centres, the cost of implementing this technology would be less than £4 million. If the average number of patients treated in each centre is 30, this technology would be cost saving within 5 years. CONCLUSIONS: The cost of CXB is not prohibitive according to the National Institute for Health and Care Excellence threshold for implementation of new technology and may even be cost saving within 5 years compared with standard surgical management, depending on the uptake of the technology and the number of referral centres.

Early barriers to neonatal porcine islet engraftment in a dual transplant model.

Porcine islet xenografts have the potential to provide an inexhaustible source of islets for ß cell replacement. Proof-of-concept has been established in nonhuman primates. However, significant barriers to xenoislet transplantation remain, including the poorly understood instant blood-mediated inflammatory reaction and a thorough understanding of early xeno-specific immune responses. A paucity of data exist comparing xeno-specific immune responses with alloislet (AI) responses in primates. We recently developed a dual islet transplant model, which enables direct histologic comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared with rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL [terminal deoxynucleotidyl transferase dUTP nick end labeling])-positive cells) of NPIs compared with AIs. Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI (wild-type) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (α1,3-galactosyltransferase knockout) compared with AIs. These findings demonstrate an augmented macrophage and antibody response toward xenografts compared with allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment.

A Cost-Effectiveness Analysis of Contact X-ray Brachytherapy for the Treatment of Patients with Rectal Cancer Following a Partial Response to Chemoradiotherapy.

AIMS: Following chemoradiotherapy in patients with rectal cancer, the addition of contact X-ray brachytherapy (CXB) in partial responders might increase the proportion of patients with a clinical complete response (cCR) and who are thus suitable for watch and wait management. However, the long-term cost-effectiveness of this approach has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling and a Markov simulation were used to compare long-term costs, quality-adjusted life years (QALYs) and cost-effectiveness from a third-party payer (National Health Service) perspective for treatment strategies after chemoradiotherapy; watch and wait with CXB when a cCR was not initially achieved after external beam radiotherapy (EBRT) (WWCXB), watch and wait with EBRT alone (WWEBRT) and radical surgery for all patients. The effect of uncertainty in model parameters and patient demographics was investigated. RESULTS: WWCXB had a higher QALY payoff than both radical surgery and WWEBRT and was less costly in most scenarios and demographic cohorts. In all plausible scenarios, WWCXB was the most cost-effective, at a threshold of £20 000/QALY. This finding was insensitive to uncertainty associated with model parameters. CONCLUSIONS: WWCXB is likely to be cost-effective compared with both WWEBRT alone and radical surgery. These findings support the use of CXB boost as an adjunct to a watch and wait strategy.

Fatal SV40-associated pneumonia and nephropathy following renal allotransplantation in rhesus macaque.

Recrudescence of latent and dormant viruses may lead to overwhelming viremia in immunosuppressed hosts. In immunocompromised hosts, Simian virus 40 (SV40) reactivation is known to cause nephritis and demyelinating central nervous system disease. Here, we report SV40 viremia leading to fatal interstitial pneumonia in an immunosuppressed host following renal allotransplantation.

Whole body physiologically based modelling of ß-blockers in the rat: events in tissues and plasma following an i.v. bolus dose.

BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Previous PBPK model development of enantiomers of a series of seven racemic ß-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design. KEY RESULTS: Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments. CONCLUSIONS AND IMPLICATIONS: PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.

SNX27 links DGKζ to the control of transcriptional and metabolic programs in T lymphocytes.

Sorting nexin 27 (SNX27) recycles PSD-95, Dlg1, ZO-1 (PDZ) domain-interacting membrane proteins and is essential to sustain adequate brain functions. Here we define a fundamental SNX27 function in T lymphocytes controlling antigen-induced transcriptional activation and metabolic reprogramming. SNX27 limits the activation of diacylglycerol (DAG)-based signals through its high affinity PDZ-interacting cargo DAG kinase ζ (DGKζ). SNX27 silencing in human T cells enhanced T cell receptor (TCR)-stimulated activator protein 1 (AP-1)- and nuclear factor κB (NF-κB)-mediated transcription. Transcription did not increase upon DGKζ silencing, suggesting that DGKζ function is dependent on SNX27. The enhanced transcriptional activation in SNX27-silenced cells contrasted with defective activation of the mammalian target of rapamycin (mTOR) pathway. The analysis of Snx27 -/- mice supported a role for SNX27 in the control of T cell growth. This study broadens our understanding of SNX27 as an integrator of lipid-based signals with the control of transcription and metabolic pathways.

Dynamic control over catalytic function using responsive bisthiourea catalysts.

Two novel bisthiourea molecular motor-based catalysts were designed and their dynamic control of activity and stereoselectivity in the Henry reaction using heat and light as external stimuli was investigated. Enantioselective organocatalysis studies established that a basic functional group is not required within the catalyst core to effect efficient dual stereocontrol, illustrating novel stimuli responsive organocatalysts.

Current practice of continence advisors in managing faecal incontinence in the United Kingdom: results of an online survey.

AIM: To investigate the current practice of continence advisors in the United Kingdom. METHOD: Continence advisors were contacted by email or letter to participate in a survey. The survey contained 27 questions which addressed the practice of each continence advisor, their knowledge of continence management and the adequacy of their training. RESULTS: Two hundred and twenty-six out of a total of 448 continence advisors (50.4%), responded. One hundred and seventy (76.9%) advisors treated both faecal and urinary incontinence, 51 (23.1%) treated urinary incontinence. Thirty-six advisors (16.1%) were lone workers and 130 (58.6%) had more than 10 years' experience. The majority of the advisors (75.6%) performed a digital rectal examination as part of their assessment. Regarding the management of faecal incontinence, 148 prescribed suppositories, 127 offered enemas and 147 advised on rectal irrigation. Most of the advisors taught pelvic floor exercises (n = 207) and urge resistance techniques (n = 188). One hundred and fifty-nine (87.4%) prescribed the Peristeen Coloplast® anal plug and 78 (47.6%) prescribed the Renew® anal insert. Eighty-nine advisors (42.6%) felt they had not been adequately trained to provide a bowel continence service. CONCLUSION: The majority of continence advisors in the UK manage faecal incontinence. They are able to initiate a broad range of conservative treatment options; however, almost half of the advisors who answered the survey felt inadequately trained and may be better supported by further training.

Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection.

Promoting health and reducing costs: a role for reform of self-monitoring of blood glucose provision within the National Health Service.

AIM: To determine the cost-effectiveness of all options for the self-monitoring of blood glucose funded by the National Health Service, providing guidance for disinvestment and testing the hypothesis that advanced meter features may justify higher prices. METHODS: Using data from the Health and Social Care Information Centre concerning all 8 340 700 self-monitoring of blood glucose-related prescriptions during 2013/2014, we conducted a cost-minimization analysis, considering both strip and lancet costs, including all clinically equivalent technologies for self-monitoring of blood glucose, as determined by the ability to meet ISO-15197:2013 guidelines for meter accuracy. RESULTS: A total of 56 glucose monitor, test strip and lancet combinations were identified, of which 38 met the required accuracy standards. Of these, the mean (range) net ingredient costs for test strips and lancets were £0.27 (£0.14-£0.32) and £0.04 (£0.02-£0.05), respectively, resulting in a weighted average of £0.28 (£0.18-£0.37) per test. Systems providing four or more advanced features were priced equal to those providing just one feature. A total of £12 m was invested in providing 42 million self-monitoring of blood glucose tests with systems that fail to meet acceptable accuracy standards, and efficiency savings of £23.2 m per annum are achievable if the National Health Service were to disinvest from technologies providing lesser functionality than available alternatives, but at a much higher price. CONCLUSION: The study uncovered considerable variation in the price paid by the National Health Service for self-monitoring of blood glucose, which could not be explained by the availability of advanced meter features. A standardized approach to self-monitoring of blood glucose prescribing could achieve significant efficiency savings for the National Health Service, whilst increasing overall utilisation and improving safety for those currently using systems that fail to meet acceptable standards for measurement accuracy.

Bilateral transcutaneous tibial nerve stimulation for chronic constipation.

AIM: Chronic constipation is difficult to treat when symptoms are intractable. Colonic propulsion may be altered by distal neuromodulation but this is conventionally delivered percutaneously. Transcutaneous tibial nerve stimulation is noninvasive and cheap: this study aimed to assess its efficacy in chronic constipation. METHOD: Eighteen patients (median age 46 years, 12 female) with chronic constipation were recruited consecutively. Conservative and behavioural therapy had failed to improve symptoms in all 18. Thirty minutes of daily bilateral transcutaneous tibial nerve stimulation was administered by each patient at home for 6 weeks. The primary outcome measure was a change in the Patient Assessment of Constipation Quality of Life (PAC-QoL) score. Change in Patient Assessment of Constipation Symptoms (PAC-SYM), weekly bowel frequency and visual analogue scale (VAS) score were also measured. RESULTS: Fifteen patients (12 female) completed the trial. The PAC-QoL score improved significantly with treatment [pretreatment, median 2.95, interquartile range (IQR) 1.18; posttreatment, median 2.50, IQR 0.70; P = 0.047]. There was no change in PAC-SYM score (pretreatment, median 2.36, IQR 1.59; posttreatment, median 2.08, IQR 0.92; P = 0.53). Weekly stool frequency improved as did VAS score, but these did not reach statistical significance (P = 0.229 and 0.161). The PAC-QoL and PAC-SYM scores both improved in four (26%) patients. Two patients reported complete cure. There were no adverse events reported. CONCLUSION: Bilateral transcutaneous tibial nerve stimulation appears to be effective in a quarter of patients with chronic constipation. Carefully selected patients with less severe disease may benefit more. This requires further study.

Geomorphic and geologic controls of geohazards induced by Nepal's 2015 Gorkha earthquake.

The Gorkha earthquake (magnitude 7.8) on 25 April 2015 and later aftershocks struck South Asia, killing ~9000 people and damaging a large region. Supported by a large campaign of responsive satellite data acquisitions over the earthquake disaster zone, our team undertook a satellite image survey of the earthquakes' induced geohazards in Nepal and China and an assessment of the geomorphic, tectonic, and lithologic controls on quake-induced landslides. Timely analysis and communication aided response and recovery and informed decision-makers. We mapped 4312 coseismic and postseismic landslides. We also surveyed 491 glacier lakes for earthquake damage but found only nine landslide-impacted lakes and no visible satellite evidence of outbursts. Landslide densities correlate with slope, peak ground acceleration, surface downdrop, and specific metamorphic lithologies and large plutonic intrusions.