Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

EELS: Autonomous snake-like robot with task and motion planning capabilities for ice world exploration.

Ice worlds are at the forefront of astrobiological interest because of the evidence of subsurface oceans. Enceladus in particular is unique among the icy moons because there are known vent systems that are likely connected to a subsurface ocean, through which the ocean water is ejected to space. An existing study has shown that sending small robots into the vents and directly sampling the ocean water is likely possible. To enable such a mission, NASA's Jet Propulsion Laboratory is developing a snake-like robot called Exobiology Extant Life Surveyor (EELS) that can navigate Enceladus' extreme surface and descend an erupting vent to capture unaltered liquid samples and potentially reach the ocean. However, navigating to and through Enceladus' environment is challenging: Because of the limitations of existing orbital reconnaissance, there is substantial uncertainty with respect to its geometry and the physical properties of the surface/vents; communication is limited, which requires highly autonomous robots to execute the mission with limited human supervision. Here, we provide an overview of the EELS project and its development effort to create a risk-aware autonomous robot to navigate these extreme ice terrains/environments. We describe the robot's architecture and the technical challenges to navigate and sense the icy environment safely and effectively. We focus on the challenges related to surface mobility, task and motion planning under uncertainty, and risk quantification. We provide initial results on mobility and risk-aware task and motion planning from field tests and simulated scenarios.

Teaching conflict management: An approach to increasing students' value, confidence, and ability.

INTRODUCTION: The primary aim was to explore how to effectively teach conflict management. We focused on three aspects of conflict management: (1) the value students place on conflict management, (2) their confidence in their ability to manage conflict, and (3) their skill in navigating conflict scenarios. METHODS: This approach to teaching conflict management included a consistent educational approach applied by three different instructors at two universities. The class session, provided to second-year student pharmacists, was designed to address ACPE Standards focused on students' conflict management skills. A Likert-style survey, administered pre- and post-classroom intervention, assessed three aspects of conflict management: value, confidence, and ability. The survey also included open-ended questions to explore students' perceptions of conflict management. RESULTS: Analysis of pre- and post-intervention surveys found that 76 out of 83 students completed both surveys (91.5% response rate). Cronbach's alphas of the value, confidence, and ability scales were 0.82, 0.86, and 0.78, respectively, at pretest and 0.93, 0.86, and 0.90, respectively, at posttest. CONCLUSIONS: Changes in student beliefs regarding the value of conflict management, as well as their confidence in and ability to engage in a crucial conversation, were statistically significant after one classroom session.

Individual differences in social intelligence and perception of emotion expression of masked and unmasked faces.

Facial expressions provide key information for successful social interactions. Recent research finds that accurate perception of emotion expressions decreases when faces are presented with face masks. What is unknown is how individual differences in social intelligence may influence perception of masked emotion expressions. In this study, participants (n = 224) completed an emotion perception task of face stimuli presented with and without face masks and completed two measures of social intelligence: the Reading the Mind in the Eyes Test (RMET) and the Tromsø Social Intelligence Scale (TSIS). Face masks were found to significantly decrease the accurate identification of emotion expressions, impacting the perception of disgust and sad expressions the most. Further, the type of emotion misattributed to facial expressions varied across expressions. Performance on the RMET test did predict perception accuracy, while scores on the TSIS did not. As face masks continue to be common globally, we must be aware that they cause interference with our social interactions and perceptions. Further, some individuals may be more negatively impacted by these effects than others. As such, it is important that we find ways to ensure that we are effectively communicating with one another and have patience when perception mistakes arise.

Is photosynthetic enhancement sustained through three years of elevated CO2 exposure in 175-year-old Quercus robur?

Current carbon cycle models attribute rising atmospheric CO2 as the major driver of the increased terrestrial carbon sink, but with substantial uncertainties. The photosynthetic response of trees to elevated atmospheric CO2 is a necessary step, but not the only one, for sustaining the terrestrial carbon uptake, but can vary diurnally, seasonally and with duration of CO2 exposure. Hence, we sought to quantify the photosynthetic response of the canopy-dominant species, Quercus robur, in a mature deciduous forest to elevated CO2 (eCO2) (+150 µmol mol-1 CO2) over the first 3 years of a long-term free air CO2 enrichment facility at the Birmingham Institute of Forest Research in central England (BIFoR FACE). Over 3000 measurements of leaf gas exchange and related biochemical parameters were conducted in the upper canopy to assess the diurnal and seasonal responses of photosynthesis during the 2nd and 3rd year of eCO2 exposure. Measurements of photosynthetic capacity via biochemical parameters, derived from CO2 response curves, (Vcmax and Jmax) together with leaf nitrogen concentrations from the pre-treatment year to the 3rd year of eCO2 exposure, were examined. We hypothesized an initial enhancement in light-saturated net photosynthetic rates (Asat) with CO2 enrichment of ≈37% based on theory but also expected photosynthetic capacity would fall over the duration of the study. Over the 3-year period, Asat of upper-canopy leaves was 33 ± 8% higher (mean and standard error) in trees grown in eCO2 compared with ambient CO2 (aCO2), and photosynthetic enhancement decreased with decreasing light. There were no significant effects of CO2 treatment on Vcmax or Jmax, nor leaf nitrogen. Our results suggest that mature Q. robur may exhibit a sustained, positive response to eCO2 without photosynthetic downregulation, suggesting that, with adequate nutrients, there will be sustained enhancement in C assimilated by these mature trees. Further research will be required to understand the location and role of the additionally assimilated carbon.

Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Diel niche variation in mammals associated with expanded trait space.

Mammalian life shows huge diversity, but most groups remain nocturnal in their activity pattern. A key unresolved question is whether mammal species that have diversified into different diel niches occupy unique regions of functional trait space. For 5,104 extant mammals we show here that daytime-active species (cathemeral or diurnal) evolved trait combinations along different gradients from those of nocturnal and crepuscular species. Hypervolumes of five major functional traits (body mass, litter size, diet, foraging strata, habitat breadth) reveal that 30% of diurnal trait space is unique, compared to 55% of nocturnal trait space. Almost half of trait space (44%) of species with apparently obligate diel niches is shared with those that can switch, suggesting that more species than currently realised may be somewhat flexible in their activity patterns. Increasingly, conservation measures have focused on protecting functionally unique species; for mammals, protecting functional distinctiveness requires a focus across diel niches.

Intermittent compression induces transitory hypoxic stimuli, upstream vasodilation and enhanced perfusion of skin capillaries, independent of age and diabetes.

The benefit of enhanced shear stress to the vascular endothelium has been well-documented in conduit arteries but is less understood in skin microcirculation. The aim of this study was to provide physiological evidence of the vascular changes in skin microcirculation induced by intermittent pneumatic compression (IPC) of 1 s cuff inflation (130 mmHg) every 20 s to the palm of the hand for 30 min. The oxygenation and hemodynamics of dorsal mid-phalangeal finger skin microcirculation were assessed by laser Doppler fluximetry and reflectance spectroscopy before, during, and after IPC in 15 young (18-39 years old) and 39 older (40-80 years old) controls and 32 older subjects with type 2 diabetes mellitus. Each individual cuff inflation induced: 1) brief surge in flux immediately after cuff deflation followed by 2) transitory reduction in blood oxygen for ∼4 s, and 3) a second increase in perfusion and oxygenation of the microcirculation peaking ∼11 s after cuff deflation in all subject groups. With no significant change in blood volume observed by reflectance spectroscopy, despite the increased shear stress at the observed site, this second peak in flux and blood oxygen suggests a delayed vasoactive response upstream inducing increased arterial influx in the microcirculation that was higher in older controls and subjects with diabetes compared to young controls (P < 0.001, P < 0.001, respectively) and achieving maximum capillary recruitment in all subject groups. Transitory hypoxic stimuli with conducted vasodilation may be a mechanism through which IPC enhances capillary perfusion in skin microcirculation independent of age and type 2 diabetes mellitus.NEW & NOTEWORTHY This study demonstrates that hand intermittent pneumatic compression evokes transitory hypoxic stimuli in distal finger skin microcirculation inducing vasodilation of arterial inflow vessels, enhanced perfusion, and maximum capillary recruitment in young and older subjects and older subjects with type 2 diabetes mellitus. Enhanced shear stress in the microcirculation did not appear to induce local skin vasodilation.

Intraoral Microbial Metabolism and Association with Host Taste Perception.

Metabolomics has been identified as a means of functionally assessing the net biological activity of a particular microbial community. Considering the oral microbiome, such an approach remains largely underused. While the current knowledge of the oral microbiome is constantly expanding, there are several deficits in knowledge particularly relating to their interactions with their host. This work uses nuclear magnetic resonance spectroscopy to investigate metabolic differences between oral microbial metabolism of endogenous (i.e., salivary protein) and exogenous (i.e., dietary carbohydrates) substrates. It also investigated whether microbial generation of different metabolites may be associated with host taste perception. This work found that in the absence of exogenous substrate, oral bacteria readily catabolize salivary protein and generate metabolic profiles similar to those seen in vivo. Important metabolites such as acetate, butyrate, and propionate are generated at relatively high concentrations. Higher concentrations of metabolites were generated by tongue biofilm compared to planktonic salivary bacteria. Thus, as has been postulated, metabolite production in proximity to taste receptors could reach relatively high concentrations. In the presence of 0.25 M exogenous sucrose, increased catabolism was observed with increased concentrations of a range of metabolites relating to glycolysis (lactate, pyruvate, succinate). Additional pyruvate-derived molecules such as acetoin and alanine were also increased. Furthermore, there was evidence that individual taste sensitivity to sucrose was related to differences in the metabolic fate of sucrose in the mouth. High-sensitivity perceivers appeared more inclined toward continual citric acid cycle activity postsucrose, whereas low-sensitivity perceivers had a more efficient conversion of pyruvate to lactate. This work collectively indicates that the oral microbiome exists in a complex balance with the host, with fluctuating metabolic activity depending on nutrient availability. There is preliminary evidence of an association between host behavior (sweet taste perception) and oral catabolism of sugar.

Mesoscope: A Web-based Tool for Mesoscale Data Integration and Curation.

Interest is growing for 3D models of the biological mesoscale, the intermediate scale between the nanometer scale of molecular structure and micrometer scale of cellular biology. However, it is currently difficult to gather, curate and integrate all the data required to define such models. To address this challenge we developed Mesoscope (mesoscope.scripps.edu/beta), a web-based data integration and curation tool. Mesoscope allows users to begin with a listing of molecules (such as data from proteomics), and to use resources at UniProt and the PDB to identify, prepare and validate appropriate structures and representations for each molecule, ultimately producing a portable output file used by CellPACK and other modeling tools for generation of 3D models of the biological mesoscale. The availability of this tool has proven essential in several exploratory applications, given the high complexity of mesoscale models and the heterogeneity of the available data sources.

Improving advanced pharmacy practice experiences with an intention/reflection practice.

BACKGROUND AND PURPOSE: Experiential learning in pharmacy has the potential to offer transformative experiences for students. Advanced pharmacy practice experiences (APPEs) can be improved if students are encouraged and able to (1) identify and track individual learning gains and interests, and (2) develop self-awareness and intrinsic motivation. EDUCATIONAL ACTIVITY AND SETTING: The intention/reflection (I/R) practice was developed to address these educational concepts and help facilitate meaningful experiences during APPEs. The I/R tool is a simple, nontechnical, resource-light activity consisting of a set of three to five questions at the beginning, midpoint, and end of an APPE. The questions were designed to help students identify how they can attain meaningful gains from each APPE. Preceptors across three universities designed, implemented, and evaluated the impact of an I/R practice within the context of a variety of APPEs. The APPEs varied between 4, 5, 6, and 10 weeks and were focused on patient care and academia. FINDINGS: Three of the I/R questions were selected for thematic analysis, one at each point of the rotation. These questions were strategically selected because they demonstrate the value resulting from the progressive nature of the I/R tool. The answers to the three questions were descriptively coded to capture the main thought(s) of each student's response. A quarter of students indicated I/R helped them achieve their goals. SUMMARY: A retrospective pre-post survey demonstrated statistically significant improvements in all survey items, including (1) ability to identify learning outcomes, (2) focus and motivation, and (3) self-awareness and metacognition.

Drivers of Mercury Cycling in the Rapidly Changing Glacierized Watershed of the High Arctic's Largest Lake by Volume (Lake Hazen, Nunavut, Canada).

Across the Arctic, glaciers are melting and permafrost is thawing at unprecedented rates, releasing not only water to downstream aquatic systems, but also contaminants like mercury, archived in ice over centuries. Using concentrations from samples collected over 4 years and calibrated modeled hydrology, we calculated methylmercury (MeHg) and total mercury (THg) mass balances for Lake Hazen, the world's largest High Arctic lake by volume, for 2015 and 2016. Glacial rivers were the most important source of MeHg and THg to Lake Hazen, accounting for up to 53% and 94% of the inputs, respectively. However, due to the MeHg and THg being primarily particle-bound, Lake Hazen was an annual MeHg and THg sink. Exports of MeHg and THg out the Ruggles River outflow were consequently very low, but erosion and permafrost slumping downstream of the lake increased river MeHg and THg concentrations significantly before entering coastal waters in Chandler Fjord. Since 2001, glacial MeHg and THg inputs to Lake Hazen have increased by 0.01 and 0.400 kg yr-1, respectively, in step with dramatic increases in glacial melt. This study highlights the potential for increases in mercury inputs to arctic ecosystems downstream of glaciers despite recent reductions in global mercury emissions.

Long-term clinical, radiological, and histological follow-up after complex ventral incisional hernia repair using urinary bladder matrix graft reinforcement: a retrospective cohort study.

BACKGROUND: Complex ventral incisional hernia repair represents a challenging clinical condition in which biologically derived graft reinforcement is often utilized, but little long-term data inform that decision. Urinary bladder matrix (UBM) has shown effectiveness in diverse clinical settings as durable reinforcement graft material, but it has not been studied over a long term in ventral incisional hernia repair. This study evaluates the clinical, radiographic, and histological outcome of complex incisional hernia repair using UBM reinforcement with 12-70 months of follow-up. METHODS: A single-arm, retrospective observational study of all ventral incisional hernia repairs utilizing UBM reinforcement over a 6-year time frame by a single surgeon was performed. Patients were assessed in long-term follow-up clinically and with the Carolina Comfort Scale. A subset of patients was assessed with abdominal wall ultrasound or CT scan. Three patients had abdominal wall fascial biopsies years after the incisional hernia repair with UBM graft, and the histology is analyzed. RESULTS: 64 patients underwent repair of complex incisional hernias with UBM graft reinforcement by a single surgeon. 42 patients had concomitant procedures including large or small bowel resection, excision of infected mesh, evacuation of abscess or hematoma, cholecystectomy, or panniculectomy with abdominoplasty. 16 patients had ostomies at the time of repair. Median follow-up time is 36 months, with a range of 12-70 months. Nine patients (14%) have required surgical repair of a recurrent hernia, and a tenth patient has a recurrence that is managed non-surgically, for a total recurrence rate of 15.6% over the entire time frame. Median time to recurrence was 32 months, and a Kaplan-Meier freedom from recurrence curve is depicted. 28 patients have undergone ultrasound or CT assessments of the abdominal wall which demonstrate radiographic fascial integrity 12-70 months after repair. Three patients have been re-explored for unrelated reasons in the years following ventral incisional hernia repair with UBM, and full thickness fascial biopsies demonstrate a robust remodeling response histologically similar to native myofascial tissue. No patients have developed graft infection, fistulization to the graft, or required graft explantation. Carolina Comfort Scale assessment of 45 patients 3 years after the repair averaged 16 out of a possible 115. CONCLUSION: In 64 patients undergoing complex ventral incisional hernia repair with UBM reinforcement, all have experienced successful resolution of complex clinical conditions and 15.6% of these repairs have recurred at a median follow-up of 3 years. Three full-thickness biopsies of the repaired fascia years later shed light on a promising remodeling response which may signal strength and durability comparable to native fascia.

Inclusive fitness for in-laws.

Cooperation among kin is common across the natural world and can be explained in terms of inclusive fitness theory, which holds that individuals can derive indirect fitness benefits from aiding genetically related individuals. However, human kinship includes not only genetic kin but also kin by marriage: our affines (in-laws) and spouses. Can cooperation between these genetically unrelated kin be reconciled with inclusive fitness theory? Here, we argue that although affinal kin and spouses do not necessarily share genetic ancestry, they may have shared genetic interests in future reproduction and, as such, can derive indirect fitness benefits though cooperating. We use standard inclusive fitness theory to derive a coefficient of shared reproductive interest (s) that predicts altruistic investment both in genetic kin and in spouses and affines. Specifically, a behaviour that reduces the fitness of the actor by c and increases the fitness of the recipient by b will be favoured by natural selection when sb > c We suggest that the coefficient of shared reproductive interest may provide a valuable tool for understanding not only the evolution of human kinship but also cooperation and conflict across the natural world more generally.

Telephone follow-up after treatment for endometrial cancer: A qualitative study of patients' and clinical nurse specialists' experiences in the ENDCAT trial.

PURPOSE: Endometrial cancer is the sixth most common female cancer worldwide. There is little evidence that routine hospital surveillance increases survival or decreases morbidity following treatment. Gynaecology Oncology clinical nurse specialists (CNSs) are ideally placed to provide the care, information and support to enable women with a gynaecological cancer to self-manage and live well. A multi-centre randomised controlled trial (RCT) compared hospital follow-up (HFU) with telephone follow-up (TFU) by CNSs. The structured telephone intervention focused on information provision to meet patients psychosocial and information needs. This study aimed to explore the views of women who had received TFU and the CNS's who had delivered the service. METHOD: A qualitative study to complement the RCT using semi-structured interviews was conducted. Twenty-five patients were randomly selected from participants in the TFU arm stratified by study site. Seven CNSs were interviewed. RESULTS: Patient and CNS regarded TFU positively; Three themes emerged from the patient interviews; Convenient Care, Discrete Personalised Care, Confidence and Reassurance. Themes arising from the CNS interviews were Patient Centred Care, Holistic Care and, Confidence and Skills. Patients found that TFU with CNS's was convenient and enabled discussion of issues and information provision at time-points relevant to them. The CNS's found the structured format of TFU enabled them to utilise their skills and knowledge to identify and meet patients holistic needs. CONCLUSIONS: Alternative models of care such as TFU provided by CNSs provides the care, information and support to enable women treated for endometrial cancer to self-manage and live well.

Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

The use of magnetically controlled growing rods in paediatric Osteogenesis Imperfecta with early onset, progressive scoliosis.

Osteogenesis Imperfecta (OI) is a condition of bone fragility and can present with early onset scoliosis that can cause respiratory complications in later life. The fear of instrumenting the spine in OI is the possibility of fracture either on primary insertion or subsequent lengthening. Magnetically controlled growing rods were inserted to control a scoliosis in a 6-year old with OI type IV. Fixation was obtained using pedicle screws proximally and distally with sublaminar bands around the ribs proximally. These rods have been remotely lengthened on multiple occasions over a 2-year period. This has controlled the scoliosis whilst also allowing the spine to grow. There are no complications to report. This case reports the use of magnetically controlled growth rods used to manage early onset scoliosis in OI. Frequent lengthening, achieving small increases in length on every occasion protects against the risk of fracture during the lengthening procedure.

Benefits of pre-emptive analgesia by local infiltration at day-case general anaesthetic open inguinal hernioplasty.

Introduction The open prosthetic repair of inguinal hernias under local anaesthesia (LA) is well established, with the concept of intraoperative 'pre-emptive analgesia' evolving so that patients are as comfortable as possible. We used a peri-incisional LA solution in patients undergoing day-case inguinal hernioplasty under general anaesthesia (GA) and recorded use of analgesia in the immediate postoperative period. Methods In this observational cohort study, 100 consecutive unselected men underwent open inguinal hernia repair as a day case. Of these, 75 underwent repair under GA and 25 with peri-incisional LA solution (equal mixture of 0.5% bupivacaine and 1% lignocaine with 1:200,000 adrenaline). Analgesia prescribed at induction, for maintenance and after cessation of anaesthesia was scored in accordance with the World Health Organization (WHO) analgesic ladder. Results The median age in the GA group was 59 years (range: 25-89 years) and in the GA+LA group, it was 62 years (range: 27-88 years). Of the 100 patients, 82 underwent a mesh plug repair by seven surgeons whereas 18 underwent a flat (Lichtenstein) mesh repair by two surgeons. WHO analgesic induction and postoperative scores were significantly lower in the GA+LA group (p=0.034 and p<0.001 respectively). There was also a significant difference in use of postoperative antiemetics (23% vs 0% in the GA only and GA+LA cohorts respectively, p=0.020). Six patients (8%) in the GA group failed day-case discharge criteria. Conclusions Patients undergoing contemporary day-case GA inguinal hernioplasty with pre-emptive LA solution infiltration require lower levels of postoperative opioid analgesia and antiemetics. These cases are less likely to fail discharge criteria for planned day surgery.

Moving to human trials for argon neuroprotection in neurological injury: a narrative review.

Despite the global burden of brain injury, neuroprotective agents remain elusive. There are no clinically effective therapies which reduce mortality or improve long-term cognitive outcome. Ventilation could be an easily modifiable variable in resuscitation; gases are relatively simple to administer. Xenon is the prototypic agent of a new generation of experimental treatments which show promise. However, use is hindered by its prohibitive cost and anaesthetic properties. Argon is an attractive option, being cheaper, easy to transport, non-sedating, and mechanistically distinct from xenon. In vitro and in vivo models provide evidence of argon reducing brain injury, with improvements in neurocognitive, histological, and biomarker metrics, as well as improved survival. Current data suggest that the effect of argon is mediated via the toll-like receptors 2 and 4, the extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3 kinase (PI-3K)-AKT pathways. Ventilation with argon appears to be safe in pigs and preliminary human trials. Given recent evidence that arterial hyperoxia may be harmful, the supplementation of high-concentration argon may not necessitate changes to clinical practice. Given the logistic benefits, and the evidence for argon neuroprotection summarized in this manuscript, we believe that the time has come to consider developing Phase II clinical trials to assess its benefit in acute neurological injury.