Carbon dioxide contributes to the beneficial effect of pressurization in a portable hyperbaric chamber at high altitude

Regional cerebral oxygenation (rSO2) and peripheral oxygen saturation (SpO2) have been studied in subjects inside a portable hyperbaric chamber at altitude during pressurization. The effects of the accumulation of carbon dioxide within the chamber on rSO2 and SpO2 have also been investigated. Three studies of cerebral regional oxygenation were undertaken, using near-IR spectroscopy, in subjects who had ascended to 3475 m in the Alps, 4680 m in the Andes or 5005 m in the Himalayas. At 3475 m and 5005 m the effects of the removal of inspired carbon dioxide by a soda lime scavenger were also studied. On pressurization of the chamber to 19.95 kPa, inspired carbon dioxide rose within the chamber from 0.03% (0.06 kPa) ambient to over 1% (1.3 kPa). At 5005 m, SpO2 rose from a baseline of 79.5% (S.D. 4.5%) to 95.9% (2.0%) (P<0.0001), and cerebral rSO2 rose from 64.6% (3.4%) to 69.4% (3.6%) (P<0.0001). The introduction of a soda lime CO2 scavenger into the breathing circuit resulted in a drop in SpO2 from 95.9% (2.03%) to 93.6% (2.07%) (P<0.001) and a fall in rSO2 from 69.4% (3.64%) to 68.5% (3.5%) (P<0.01). Chamber pressure was maintained throughout at 19.95 kPa. Similar changes were seen at the other altitudes. Cerebral rSO2 increased rapidly following pressurization at all three altitudes. Scavenging of inspired carbon dioxide was associated with a significant fall in cerebral rSO2 and SpO2, and we estimate that the contribution of carbon dioxide may account for up to one-third of the beneficial effect of the portable hyperbaric chamber.     

The anterior bias in visual art: The case of images of animals

Composition is an important topic in visual art. The literature suggests a bias for objects on the right side (Levy, 1976) and two additional biases with respect to positioning of objects within a rectangular frame: a Centre bias and an Inward bias (Palmer, Gardner, & Wickens, 2008). We analysed images of animals from three datasets of works of art: two datasets were from artists well known for their portraits of animals (Bewick, Stubbs) and the third was a medieval bestiary. There was no overall displacement of the subject to the right or to the left of the picture. However, we found a bias consisting of more space in front compared to behind the animal, consistent with Palmer at al.'s findings and with their definition of an Inward bias. Because our animals never face towards the centre we use the term Anterior bias. In addition, we found a modulation of this bias on the basis of the facing direction of the animal, consisting of a stronger Anterior bias for left-facing animals. This asymmetry may originate from a combination of an Anterior bias and a Right bias. Finally, with respect to size we found that the size of the animals predicted the proportion of the picture occupied, an effect known as “canonical size”.     

The role of Tenonplasty in the management of limbal and scleral ischemia due to acute ocular chemical burns

Of the various manifestations of ocular chemical burns (OCBs), ischemia of the limbus and the peri-limbal sclera indicates poor prognosis and in severe cases threaten the integrity of the globe. Tenonplasty is a surgical procedure which involves advancing the Tenon’s capsule over the ischemic areas to provide a vascular supply and to enable migration of the conjunctival epithelium. This review aims to provide an overview of the diagnosis of limbal ischemia and its management with Tenonplasty. A literature review was conducted using the keywords “Tenonplasty,” “Tenon’s capsule,” “ocular chemical injury,” “ocular thermal injury,” “Tenon advancement,” “scleral ischemia,” and “limbal ischemia,” and outcomes were studied from seven selected articles. In addition to clinical evaluation, in vivo imaging techniques such as anterior segment optical coherence tomography angiography can provide an objective method of measuring and monitoring the ischemia and re-perfusion of the peri-limbal vasculature. Tenonplasty can be performed in eyes with acute OCBs with scleral or limbal ischemia by dissecting the Tenon’s layer from the orbit and securing it to the limbus. The indications, mechanism of action, peri-operative considerations, surgical technique, and post-operative care of Tenonplasty are discussed in detail. The average time for post-operative re-epithelization ranges from 1 to 6 months with the formation of a symblepharon being the most common complication. In conclusion, Tenonplasty is a globe-salvaging procedure in cases with severe limbal and scleral ischemia because of OCBs and has good anatomical outcomes priming the globe for subsequent re-constructive and vision-restoring surgeries.     

Assessment of Rapid MinION Nanopore DNA Virus Meta-Genomics Using Calves Experimentally Infected with Bovine Herpes Virus-1

Bovine respiratory disease (BRD), which is the leading cause of morbidity and mortality in cattle, is caused by numerous known and unknown viruses and is responsible for the widespread use of broad-spectrum antibiotics despite the use of polymicrobial BRD vaccines. Viral metagenomics sequencing on the portable, inexpensive Oxford Nanopore Technologies MinION sequencer and sequence analysis with its associated user-friendly point-and-click Epi2ME cloud-based pathogen identification software has the potential for point-of-care/same-day/sample-to-result metagenomic sequence diagnostics of known and unknown BRD pathogens to inform a rapid response and vaccine design. We assessed this potential using in vitro viral cell cultures and nasal swabs taken from calves that were experimentally challenged with a single known BRD-associated DNA virus, namely, bovine herpes virus 1. Extensive optimisation of the standard Oxford Nanopore library preparation protocols, particularly a reduction in the PCR bias of library amplification, was required before BoHV-1 could be identified as the main virus in the in vitro cell cultures and nasal swab samples within approximately 7 h from sample to result. In addition, we observed incorrect assignment of the bovine sequence to bacterial and viral taxa due to the presence of poor-quality bacterial and viral genome assemblies in the RefSeq database used by the EpiME Fastq WIMP pathogen identification software.     

Design details for overdose education and take‐home naloxone kits: Codesign with family medicine,emergency department,addictions medicine and community

IntroductionOverdose education and naloxone distribution (OEND) programmes equip and train people who are likely to witness an opioid overdose to respond with effective first aid interventions. Despite OEND expansion across North America, overdose rates are increasing, raising questions about how to improve OEND programmes. We conducted an iterative series of codesign stakeholder workshops to develop a prototype for take‐home naloxone (THN)‐kit (i.e., two doses of intranasal naloxone and training on how to administer it).MethodsWe recruited people who use opioids, frontline healthcare providers and public health representatives to participate in codesign workshops covering questions related to THN‐kit prototypes, training on how to use it, and implementation, including refinement of design artefacts using personas and journey maps. Completed over 9 months, the workshops were audio‐recorded and transcribed with visible results of the workshops (i.e., sticky notes, sketches) archived. We used thematic analyses of these materials to identify design requirements for THN‐kits and training.ResultsWe facilitated 13 codesign workshops to identify and address gaps in existing opioid overdose education training and THN‐kits and emphasize timely response and stigma in future THN‐kit design. Using an iterative process, we created 15 prototypes, 3 candidate prototypes and a final prototype THN‐kit from the synthesis of the codesign workshops.ConclusionThe final prototype is available for a variety of implementation and evaluation processes. The THN‐kit offers an integrated solution combining ultra‐brief training animation and physical packaging of nasal naloxone to be distributed in family practice clinics, emergency departments, addiction medicine clinics and community settings.Patient or Public ContributionThe codesign process was deliberately structured to involve community members (the public), with multiple opportunities for public contribution. In addition, patient/public participation was a principle for the management and structuring of the research team.     

Participants' experiences of the management of screen‐detected complex polyps within a structured bowel cancer screening programme

BackgroundThe Bowel Screening Wales complex polyp removal service was introduced to address variations in surgery rates for screen‐detected complex benign colorectal polyps, to improve the quality of the screening service and to make management of these polyps more equitable across Wales. Little is known about patient experiences and the potential impact on quality of life when undergoing complex polyp removal. This study is part of a wider research programme evaluating the decision‐making, pathways and outcomes from complex polyp removal.ObjectiveThis study aimed to understand experiences of having a complex polyp removed and how this may influence quality of life.DesignSemi‐structured telephone interviews were conducted, and a thematic approach was used for data analysis.Setting and ParticipantsAll participants had a complex polyp removed after a positive stool test and review by Bowel Screening Wales'' Network Multi‐Disciplinary Team.ResultsTwenty‐one participants were interviewed. Most participants had their complex polyps removed endoscopically and reported no or minor problems or negative outcomes following their procedure. For a small minority, worse problems (e.g., pain, bowel dysfunction) and negative outcomes (e.g., cancer) followed their procedures. Most participants felt supported and reassured throughout their procedures. Any physical and emotional changes to quality of life were mainly linked to procedure outcomes.DiscussionExperiences of complex polyp removal were generally positive, with minimal changes in quality of life.ConclusionsWhile most people had a positive experience of having a complex polyp removed, support initiatives, such as counselling or signposting to coping strategies, may be helpful to reduce any potential negative effects of procedures on quality of life.Patient or Public ContributionFour patient and public involvement partners provided feedback on participant materials.     

Using the Hierarchies of Evidence Applied to Lifestyle Medicine (HEALM) Approach to Assess the Strength of Evidence on Associations between Dietary Patterns and All-Cause Mortality

Dietary guidelines should be underpinned by high-quality evidence. Quality assessment methods that reflect traditional evidence hierarchies prioritise evidence from randomised controlled trials (RCTs). The Hierarchies of Evidence Applied to Lifestyle Medicine (HEALM) approach is an alternative quality assessment method for research questions that for practical and/or ethical reasons, cannot be answered using RCTs. The aim of this study was to investigate how the HEALM approach could be used to assess the strength of evidence on associations between dietary patterns and all-cause mortality (a research question that is difficult to answer using RCTs). Two data sources were used: an existing systematic review of dietary patterns and all-cause mortality that synthesised evidence from observational studies; and an overview of reviews that was conducted to summarise relevant evidence from mechanistic and intervention studies. A set of four criteria were developed and used in the application of HEALM. Using different datasets in combination, the strength of evidence was rated as ‘Grade B: moderate/suggestive’ or ‘Grade C: insufficient/inconclusive’. HEALM is a novel approach for integrating and assessing the strength of evidence from mechanistic, intervention, and observational studies. Further research is needed to address the practical challenges that were identified in the application of HEALM.     

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA)

Background Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor.Methods NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity.Results In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype.Conclusions NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT03494816","term_id":"NCT03494816"}}NCT03494816.Subject terms: Surgical oncology, Renal cell carcinoma, Predictive markers     

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala. Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01257-0.     

Environment Symmetry Drives a Multidirectional Code in Rat Retrosplenial Cortex

We investigated how environment symmetry shapes the neural processing of direction by recording directionally tuned retrosplenial neurons in male Lister hooded rats exploring multicompartment environments that had different levels of global rotational symmetry. Our hypothesis built on prior observations of twofold symmetry in the directional tuning curves of rats in a globally twofold-symmetric environment. To test whether environment symmetry was the relevant factor shaping the directional responses, here we deployed the same apparatus (two connected rectangular boxes) plus one with fourfold symmetry (a 2 × 2 array of connected square boxes) and one with onefold symmetry (a circular open-field arena). Consistent with our hypothesis we found many neurons with tuning curve symmetries that mirrored these environment symmetries, having twofold, fourfold, or onefold symmetric tuning, respectively. Some cells expressed this pattern only globally (across the whole environment), maintaining singular tuning curves in each subcompartment. However, others also expressed it locally within each subcompartment. Because multidirectionality has not been reported in naive rats in single environmental compartments, this suggests an experience-dependent effect of global environment symmetry on local firing symmetry. An intermingled population of directional neurons were classic head direction cells with globally referenced directional tuning. These cells were electrophysiologically distinct, with narrower tuning curves and a burstier firing pattern. Thus, retrosplenial directional neurons can simultaneously encode overall head direction and local head direction (relative to compartment layout). Furthermore, they can learn about global environment symmetry and express this locally. This may be important for the encoding of environment structure beyond immediate perceptual reach.SIGNIFICANCE STATEMENT We investigated how environment symmetry shapes the neural code for space by recording directionally tuned neurons from the retrosplenial cortex of rats exploring single- or multicompartment environments having onefold, twofold, or fourfold rotational symmetry. We found that many cells expressed a symmetry in their head direction tuning curves that matched the corresponding global environment symmetry, indicating plasticity of their directional tuning. They were also electrophysiologically distinct from canonical head directional cells. Notably, following exploration of the global space, many multidirectionally tuned neurons encoded global environment symmetry, even in local subcompartments. Our results suggest that multidirectional head direction codes contribute to the cognitive mapping of the complex structure of multicompartmented spaces.