Low-Dose Azathioprine in Combination with Allopurinol: The Past, Present and Future of This Useful Duo.

The inflammatory bowel diseases (IBD) are complex immune-mediated inflammatory diseases that are associated with significant morbidity around the world. As our understanding of IBD, and other immune-mediated inflammatory diseases, advances the number of therapeutic targets has increased which has rapidly driven the development and introduction of new therapies. While these new therapies have shown promise they come with the significant drawback of high costs. For many IBD patients around the world the cost of newer therapies is prohibitive which means treating clinicians often need to turn to optimising simpler, older, and inexpensive medications. The concept of optimising well established cheaper medications is not unique to the management of IBD as health systems all over the world look to reduce costs while simultaneously improving patient outcomes. Despite thiopurines being used in the management IBD for over 60 years, many clinicians are still hesitant to use them due to perceptions around limited efficacy and poor tolerance. One method identified to potentially increase utilisation of thiopurines involves the coadministration of allopurinol. In this review we will explore the history, pharmacology, recent studies and give recommendations for the utilisation of the usual duo of azathioprine combined with allopurinol.

Prolonged endoscopic retrograde cholangiopancreatography results in higher rates of pancreatitis and unplanned hospitalisation.

BACKGROUND AND AIM: Although complications from endoscopic retrograde cholangiopancreatography (ERCP) are well described, procedure duration has received scant attention. The relationship between ERCP duration and patient demographics, indications, results and complications were examined. METHODS: A contemporaneously recorded database of 2572 consecutive ERCPs performed between 2008 and 2018 by a single endoscopist was analysed. Those taking under 40 min were compared with those taking over 40 min. RESULTS: Of 2572 cases, 2213 took under 40 min and 359 took over 40 min. Emergency cases (relative risk 2.10), older age (66.6 vs 61.6 years p value < 0.01) and no previous sphincterotomy (relative risk 1.94) were factors which resulted in prolonged procedures. The indication of change or removal of stent for benign conditions resulted in fewer prolonged procedures (relative risk 0.37). Indications of pancreatitis, cholangitis and positive intraoperative cholangiogram were not associated with procedure length. Findings of biliary stricture(s) (relative risk 2.02) and failure to cannulate desired duct (relative risk 3.69) were associated with prolonged procedures. Choledocholithiasis (relative risk 0.62), dilated bile duct without stricture/stone (relative risk 0.46) and normal ductal anatomy (relative risk 0.50) resulted in fewer prolonged procedures. Procedures taking over 40 min had increased risks of complications resulting in unplanned or prolongation of hospitalisation (relative risk 1.41) and pancreatitis (relative risk 1.74). CONCLUSIONS: Prolonged procedures had increased rates of pancreatitis and unplanned/prolonged hospitalisation. Failed access to desired duct, advanced age, biliary strictures, no previous sphincterotomy and unplanned emergency cases were associated with prolonged procedures.

Laboratory Validation of Instrumented Mouthguard for Use in Sport.

Concussion is an inherent risk of participating in contact, combat, or collision sports, within which head impacts are numerous. Kinematic parameters such as peak linear and rotational acceleration represent primary measures of concussive head impacts. The ability to accurately measure and categorise such impact parameters in real time is important in health and sports performance contexts. The purpose of this study was to assess the accuracy of the latest HitIQ Nexus A9 instrumented mouthguard (HitIQ Pty. Ltd. Melbourne Australia) against reference sensors in an aluminium headform. The headform underwent drop testing at various impact intensities across the NOCSAE-defined impact locations, comparing the peak linear and rotational acceleration (PLA and PRA) as well as the shapes of the acceleration time-series traces for each impact. Mouthguard PLA and PRA measurements strongly correlated with (R2 = 0.996 and 0.994 respectively), and strongly agreed with (LCCC = 0.997) the reference sensors. The root mean square error between the measurement devices was 1 ± 0.6g for linear acceleration and 47.4 ± 35 rad/s2 for rotational acceleration. A Bland-Altman analysis found a systematic bias of 1% for PRA, with no significant bias for PLA. The instrumented mouthguard displayed high accuracy when measuring head impact kinematics in a laboratory setting.

Potential of Soft-Shelled Rugby Headgear to Lower Regional Brain Strain Metrics During Standard Drop Tests.

BACKGROUND: The growing concern for player safety in rugby has led to an increased focus on head impacts. Previous laboratory studies have shown that rugby headgear significantly reduces peak linear and rotational accelerations compared to no headgear. However, these metrics may have limited relevance in assessing the effectiveness of headgear in preventing strain-based brain injuries like concussions. This study used an instantaneous deep-learning brain injury model to quantify regional brain strain mitigation of rugby headgear during drop tests. Tests were conducted on flat and angled impact surfaces across different heights, using a Hybrid III headform and neck. RESULTS: Headgear presence generally reduced the peak rotational velocities, with some headgear outperforming others. However, the effect on peak regional brain strains was less consistent. Of the 5 headgear tested, only the newer models that use open cell foams at densities above 45 kg/m3 consistently reduced the peak strain in the cerebrum, corpus callosum, and brainstem. The 3 conventional headgear that use closed cell foams at or below 45 kg/m3 showed no consistent reduction in the peak strain in the cerebrum, corpus callosum, and brainstem. CONCLUSIONS: The presence of rugby headgear may be able to reduce the severity of head impact exposure during rugby. However, to understand how these findings relate to brain strain mitigation in the field, further investigation into the relationship between the impact conditions in this study and those encountered during actual gameplay is necessary.

The Impact of Drop Test Conditions on Brain Strain Location and Severity: A Novel Approach Using a Deep Learning Model.

In contact sports such as rugby, players are at risk of sustaining traumatic brain injuries (TBI) due to high-intensity head impacts that generate high linear and rotational accelerations of the head. Previous studies have established a clear link between high-intensity head impacts and brain strains that result in concussions. This study presents a novel approach to investigating the effect of a range of laboratory controlled drop test parameters on regional peak and mean maximum principal strain (MPS) predictions within the brain using a trained convolutional neural network (CNN). The CNN is publicly available at https://github.com/Jilab-biomechanics/CNN-brain-strains . The results of this study corroborate previous findings that impacts to the side of the head result in significantly higher regional MPS than forehead impacts. Forehead impacts tend to result in the lowest region-averaged MPS values for impacts where the surface angle was at 0° and 45°, while side impacts tend to result in higher regional peak and mean MPS. The absence of a neck in drop tests resulted in lower regional peak and mean MPS values. The results indicated that the relationship between drop test parameters and resulting regional peak and mean MPS predictions is complex. The study's findings offer valuable insights into how deep learning models can be used to provide more detailed insights into how drop test conditions impact regional MPS. The novel approach used in this paper to predict brain strains can be applied in the development of better methods to reduce the brain strain resulting from head accelerations such as protective sports headgear.

Management of Newly Diagnosed Multiple Myeloma Today, and in the Future.

Treatment options have expanded rapidly and widely in the past two decades for patients with multiple myeloma. Triplet novel agent-based induction regimens have been accepted as the standard practice wordwide over the last decade both for transplant-eligible and non-eligible patients. The addition of anti-CD38 monoclonal antibodies as part of quadruplet regimens has led to even deeper and longer-lasting responses. The impressive results shown by the quadruplets havebeen practice-changing where accessible in recent years. Chimeric antigen receptor T cell therapy and bispecific antibodies are being tested in the upfront setting and have the potential to once again shift the paradigm of treatment of newly diagnosed MM.

A multi-taxon analysis of European Red Lists reveals major threats to biodiversity.

Biodiversity loss is a major global challenge and minimizing extinction rates is the goal of several multilateral environmental agreements. Policy decisions require comprehensive, spatially explicit information on species' distributions and threats. We present an analysis of the conservation status of 14,669 European terrestrial, freshwater and marine species (ca. 10% of the continental fauna and flora), including all vertebrates and selected groups of invertebrates and plants. Our results reveal that 19% of European species are threatened with extinction, with higher extinction risks for plants (27%) and invertebrates (24%) compared to vertebrates (18%). These numbers exceed recent IPBES (Intergovernmental Platform on Biodiversity and Ecosystem Services) assumptions of extinction risk. Changes in agricultural practices and associated habitat loss, overharvesting, pollution and development are major threats to biodiversity. Maintaining and restoring sustainable land and water use practices is crucial to minimize future biodiversity declines.

An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib.

Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1-3 prior therapies, including at least one bortezomib-based regimen, received carfilzomib 20 mg/m(2) in a twice-weekly, consecutive-day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents.

Survey of injury sources for a trampoline with equipment hazards designed out.

AIM: In Australia, trampolines contribute approximately one-quarter of all childhood play-equipment injuries. The purpose of this study was to gather and evaluate injury data from a nontraditional, 'soft-edged', consumer trampoline in which the equipment injury sources have been designed out. METHODS: A survey was undertaken in Queensland and New South Wales. The manufacturer of the nontraditional trampoline provided the University of Technology, Sydney, with their Australian customer database. Injury data were gathered in a pilot study by phone interview, then in a full study through an email survey. Results from 3817 respondents were compared with earlier Australian and US data from traditional trampolines gathered from emergency departments. RESULTS: A significantly lower proportion of the injuries caused by falling off or striking the equipment was found for this new design when compared with traditional trampolines both in Australia and in the USA. The age of children being injured on trampolines in Australia was found to be markedly lower than in North America. CONCLUSIONS: This research indicates that with appropriate design the more severe injuries on traditional trampolines can be significantly reduced.

Potential of Soft-Shell Rugby Headgear to Mitigate Linear and Rotational Peak Accelerations.

Rugby union is a popular sport played across the world. The physical contact inherent in the game means that players are at increased risk of concussive injury. In 2019, World Rugby created a new category of permitted headgear under Law 4 as a medical device. This established a pathway for headgear designed to reduce peak accelerations to be worn in matches. Investigations of the potential of soft-shelled protective headgear to reduce head impact accelerations have been mostly limited to the analysis of linear kinematics. However rotational head impact accelerations have long been implicated as far more injurious. The aim of this study, therefore, was to assess the linear and rotational acceleration reduction brought about by soft-shelled rugby headgear. A Hybrid III headform and neck were dropped onto a modular elastomer programmer impact surface, impacting at four different velocities (1.7-3.4 m/s) in five different impact orientations. Impact surface angles were 0°, 30°, and 45°. Peak linear and rotational accelerations, PLA and PRA respectively, were recorded. All headgear significantly reduced PLAs and PRAs when compared to a no headgear scenario. The new generation, headgear reduced all measures significantly more than the older generation of headgear. Impact locations offset from the center of mass of the headform resulted in the highest PRAs measured. As the impact surface angle increased, both PLAs and PRAs decreased. The study demonstrated that headgear tested lowered PLAs by up to 50%, and PRAs by up to 60% compared to the bare headform. Our data suggest that new generation headgear could make a difference on the field in reducing injurious impact accelerations in a collision.

Drop Test Kinematics Using Varied Impact Surfaces and Head/Neck Configurations for Rugby Headgear Testing.

World Rugby employs a specific drop test method to evaluate headgear performance, but almost all researchers use a different variation of this method. The aim of this study was, therefore, to quantify the differences between variations of the drop testing method using a Hybrid III headform and neck in the following impact setups: (1) headform only, with a flat steel impact surface, approximating the World Rugby method, (2 and 3) headform with and without a neck, respectively, onto a flat MEP pad impact surface, and (4) headform and neck, dropped onto an angled MEP pad impact surface. Each variation was subject to drop heights of 75-600 mm across three orientations (forehead, side, and rear boss). Comparisons were limited to the linear and rotational acceleration and rotational velocity for simplicity. Substantial differences in kinematic profile shape manifested between all drop test variations. Peak accelerations varied highly between variations, but the peak rotational velocities did not. Drop test variation also significantly changed the ratios of the peak kinematics to each other. This information can be compared to kinematic data from field head impacts and could inform more realistic impact testing methods for assessing headgear.

Potential of Soft-Shelled Rugby Headgear to Reduce Linear Impact Accelerations.

The purpose of this study was to examine the potential of soft-shelled rugby headgear to reduce linear impact accelerations. A hybrid III head form instrumented with a 3-axis accelerometer was used to assess headgear performance on a drop test rig. Six headgear units were examined in this study: Canterbury Clothing Company (CCC) Ventilator, Kukri, 2nd Skull, N-Pro, and two Gamebreaker headgear units of different sizes (headgears 1-6, respectively). Drop heights were 238, 300, 610, and 912 mm with 5 orientations at each height (forehead, front boss, rear, rear boss, and side). Impact severity was quantified using peak linear acceleration (PLA) and head injury criterion (HIC). All headgear was tested in comparison to a no headgear condition (for all heights). Compared to the no headgear condition, all headgear significantly reduced PLA and HIC at 238 mm (16.2-45.3% PLA and 29.2-62.7% HIC reduction; P < 0.0005, η p 2 = 0.987-0.991). Headgear impact attenuation lowered significantly as the drop height increased (32.4-5.6% PLA and 50.9-11.7% HIC reduction at 912 mm). There were no significant differences in PLA or HIC reduction between headgear units 1-3. Post hoc testing indicated that headgear units 4-6 significantly outperformed headgear units 1-3 and additionally headgear units 5 and 6 significantly outperformed headgear 4 (P < 0.05). The lowest reduction PLA and HIC was for impacts rear orientation for headgear units 1-4 (3.3 ± 3.6%-11 ± 5.8%). In contrast, headgear units 5 and 6 significantly outperformed all other headgear in this orientation (P < 0.0005, η p 2 = 0.982-0.990). Side impacts showed the greatest reduction in PLA and HIC for all headgear. All headgear units tested demonstrated some degree of reduction in PLA and HIC from a linear impact; however, units 4-6 performed significantly better than headgear units 1-3.

Developing a mathematical model to predict energy expenditure while bouncing on a trampoline.

Trampolining has become a popular recreational activity, but currently no method exists by which energy expenditure can be indirectly measured while bouncing. Therefore, the aim of this study was to produce a model to measure energy expenditure while bouncing on a trampoline. To achieve this, the study was completed in two stages. First, a model was developed which calculated the energy absorbed by the trampoline for a known weight. This was achieved using drop tests on a trampoline. Second, the efficiency of energy conversion while trampolining was measured. This involved healthy adults bouncing on a trampoline while energy expenditure was recorded using a gas analyser. The combined datasets from the two parts allowed the formation of a model which can predict energy expenditure while bouncing on a trampoline using only the user's weight as an input. This model can now be used with an on-trampoline measurement method to track energy expenditure while jumping, thereby facilitating the use of trampolines for health and fitness.

Investigating the effect of bouncing type on the physiological demands of trampolining.

Purpose: The aim of this study was to investigate whether altering the bounce style affects the physiological demands of trampolining. Methods: Twenty-eight healthy adults completed five, three-minute exercise bouts on a trampoline where; heart rate (HR), V ˙ O 2 (mL/min) and rate of EE (kJ/min) were collected for five different bouncing variations. Results: A one-way repeated measures MANOVA was then used to assess whether significant differences existed between the different bounce types for HR V ˙ O 2 and EE. A significant difference was found ( F 12 , 280 = 20.886, p = 0.0005), so a series of one-way repeated measures ANOVAs were used to identify the degree of significance. For V ˙ O 2 ( F 2.421 , 27 = 64.079, p = 0.0005, ηp 2 = 0.7) and EE ( F 2.989 , 27 = 44.979, p = 0.0005, ηp 2 = 0.6). Post-hoc tests found that for both V ˙ O 2 and EE a significant difference existed between the conventional bounce and each of the bounce variates (p = 0.0005). Conclusion: The results from this study indicated altering the bounce style does have a significant effect on the physiological demands of trampolining. The energy expenditure (EE) equation for trampolining can now be updated to more accurately reflect the rate of EE while performing different bounce styles.

Effectiveness of pads and enclosures as safety interventions on consumer trampolines.

BACKGROUND: Trampolines continue to be a major source of childhood injury. OBJECTIVE: To examine available data on trampoline injuries in order to determine the effectiveness of padding and enclosures. DESIGN: Trampoline injuries from the NEISS database from 2002 to 2007 were reclassified into five cause-categories, to examine evidence for injury trends. SETTING: The ASTM trampoline standard recommendations for safety padding were upgraded in 1999 and enclosures were introduced in 1997. This is the first study to examine the impact of these changes. PATIENTS: The sampling frame comprises patients with NEISS product code 'consumer trampolines' (1233). A systematic sample of 360 patients each year is taken. INTERVENTIONS: The prominent interventions recommended by the ASTM are netting enclosures to prevent falling off and safety padding to cover frames and springs. MAIN OUTCOME MEASURES: Proportion of injuries within each cause-category and trend estimates. RESULTS: There was no evidence for a decline within the injury cause-categories that should be prevented by these interventions from 2002 to 2007. CONCLUSIONS: If these interventions were effective the associated injury causes would be in decline. Instead they remain close to half of all trampoline injuries with no significant change over the period of the study. Follow-up studies are proposed to determine the reasons. Given the number of injuries involved it is recommended that steps be taken to ensure these safety interventions or their equivalents are in place, work properly and remain effective for the life of consumer trampolines.

Physiological Demands of Trampolining at Different Intensities.

Purpose: The aim of this study was to examine the physiological demands of trampolining, in comparison with treadmill running, using a larger sample size and a wider range of physiological measures, than had been reported in the previous research. Method: Twenty-three healthy adults completed three, three-minute exercise bouts on both a trampoline and treadmill at different intensities. Heart rate (HR), oxygen consumption ([Formula: see text]), energy expenditure (EE) and blood lactate (BL) were collected for each bout. Results: Results of a two-way repeated measures MANOVA indicated that there was a significant difference between the modalities ([Formula: see text] = 9.3, p <.0005, [Formula: see text] = 0.39). A follow up two-way repeated measures ANOVA then identified that significant differences existed between the modalities for each of the variables; [Formula: see text] ([Formula: see text] = 159, p <.0005, [Formula: see text] = 0.88), EE (= 136, p <.0005, [Formula: see text] = 0.86) and BL ([Formula: see text] = 171, p <.0005, [Formula: see text] = 0.89). Subsequent post hoc testing found [Formula: see text] to differ significantly between the medium intensities (p =.01 d =0.6). EE to differ significantly for the medium (p =.003, d =-0.7) and high intensities (p =.02, d =-0.5). BL to differ significantly for the low (p =.04, d =0.4), medium (p =.03, d =0.5) and high (p =.001 d =1.4) intensities. Conclusions: The results from our study indicated that while significant differences do occur between running and trampolining for a given intensity, the trendline associated with each of the variables is similar. Therefore, monitoring the intensity of the session based the percentage of the participant's maximum heart rate, which is commonly used in running, may also be applied to trampolining.

High-resolution genomic analysis in Waldenström's macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas.

Cytogenetic analyses have been historically limited in Waldenström's macroglobulinemia (WM) by the difficulty to obtain tumor metaphases. Thus, few recurrent karyotypic abnormalities have been reported and the molecular consequences of these imbalances are largely unknown. We used an array-based comparative genomic hybridization approach to better characterize the recurrent chromosome abnormalities associated with WM pathogenesis and to compare them with the publicly available findings in other B-cell neoplasias. The majority of the recurrent chromosome abnormalities identified in WM were shared with marginal zone lymphomas (MZL), as deletions of 6q23 and 13q14 and gains of 3q13-q28, 6p and 18q. On the other hand, gains of 4q and 8q were recurrently identified in WM but have not been described as being common abnormalities in MZL. The genetic consequences of these specific abnormalities remain elusive and further studies are critical to refine the search and to precise the molecular pathways affected by these abnormalities.

Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses.

Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.

Annual estimates of occupancy for bryophytes, lichens and invertebrates in the UK, 1970-2015.

Here, we determine annual estimates of occupancy and species trends for 5,293 UK bryophytes, lichens, and invertebrates, providing national scale information on UK biodiversity change for 31 taxonomic groups for the time period 1970 to 2015. The dataset was produced through the application of a Bayesian occupancy modelling framework to species occurrence records supplied by 29 national recording schemes or societies (n = 24,118,549 records). In the UK, annual measures of species status from fine scale data (e.g. 1 × 1 km) had previously been limited to a few taxa for which structured monitoring data are available, mainly birds, butterflies, bats and a subset of moth species. By using an occupancy modelling framework designed for use with relatively low recording intensity data, we have been able to estimate species trends and generate annual estimates of occupancy for taxa where annual trend estimates and status were previously limited or unknown at this scale. These data broaden our knowledge of UK biodiversity and can be used to investigate variation in and drivers of biodiversity change.

Protocol for M3P: A Comprehensive and Clinical Oriented Targeted Sequencing Panel for Routine Molecular Analysis in Multiple Myeloma.

Over the past 10 years next generation sequencing (NGS) approaches deciphered a large number of genomes from a wide variety of tumor types. However, despite most relevant findings, this technology has not yet been implemented into standard diagnostic workflows. Broad access to NGS technology is still limited, sequencing/analysis times exceed clinically relevant timeframes and despite huge cuts, costs remain significant. We proposed a custom-tailored gene panel, which focuses on a selected number of relevant genes and developed a clinically oriented NGS targeted sequencing approach for the molecular characterization of Multiple Myeloma (MM) tumors, allowing the description of the tumor genetic heterogeneity and its changes under selective pressure of antitumor therapy, in a more cost effective and faster turnaround timeframe.