Considerations for the optimization of in vitro models of chloropicrin toxicity.

Chloropicrin (CP) is a common agricultural fumigant historically used as a chemical warfare agent and is a concern for potential use in warfare and terrorist applications. Our inability to effectively treat CP-induced injuries makes it essential to better understand CP toxicity. We set out to elucidate variables that must be understood to achieve optimal exposure conditions for in vitro investigations given that such models are important for the study of CP injury and potential therapeutics. To this end, we evaluated the effects of volatility, cell seeding density, and serum concentration of cell culture medium on CP toxicity in an immortalized human corneal epithelial cell line. We found that even with very dilute solutions, CP remained highly volatile, so much so that a 0.0019% CP solution resulted in 90% cell death at time 0, but was nearly nontoxic 45 min later. Not surprisingly, the CP-induced IL-8 response was shown to vary with cell viability in this experiment. After exposure with 0.00115% CP, cells that were 12% confluent experienced over 40% more cell death than cells exposed at 87% confluency. Exposure with the same CP dose in medium containing concentrations of fetal bovine serum (FBS) ranging from 0.1% to 15% exhibited a 17% difference in cell viability. Given that chemical toxicity can be significantly influenced by volatility, cell density, and serum content of cell culture medium, these phenomena should be explored during the development and optimization of toxicant exposure models.

Behavioural adjustment of children with intellectual disability and their sibling is associated with their sibling relationship quality.

BACKGROUND: Understanding sibling relationship quality is important, as it is associated with mental health outcomes in both childhood and adulthood. Arguably, these relationships are even more important for individuals with intellectual disability, as siblings can be important sources of care, support, advocacy and friendship for one another. The intellectual disability field, however, has a tendency to assume that the relationship lacks reciprocity, and that it is the sibling with intellectual disability who affects the sibling, and that this effect is somehow 'negative'. METHODS: We examined whether the behaviour problems and prosocial behaviour of 500 child sibling pairs, where one child has an intellectual disability, were associated with their sibling relationship quality. Measures included the Strengths and Difficulties Questionnaires and the Sibling Relationship Questionnaire. Family poverty, the gender of both children, birth order and whether the child with intellectual disability had autism or Down syndrome were also included in the analyses. RESULTS: Confirmatory factor analysis indicated an adequate model fit for the latent variables measuring sibling relationships. The final structural model found that the prosocial behaviour and internalising problems of the children with intellectual disability, their typically developing siblings' prosocial behaviours and sibling birth order were associated with intimacy-companionship in the sibling relationship. The internalising, externalising and prosocial behaviours of the children with intellectual disability, their siblings' externalising behaviours and sibling birth order were associated with antagonism-quarrelling in the sibling relationship. CONCLUSIONS: We found that the behaviours of both the child with intellectual disability and their sibling were associated with both 'positive' and 'negative' dimensions of their sibling relationship. This indicates a bidirectional and reciprocal effect.

Types and correlates of school absenteeism among students with intellectual disability.

BACKGROUND: It appears that students with intellectual disability (ID) are more frequently absent from school compared with students without ID. The objective of the current study was to estimate the frequency of absence among students with ID and the reasons for absence. Potential reasons included the attendance problems referred to as school refusal, where absence is related to emotional distress; truancy, where absence is concealed from parents; school exclusion, where absence is instigated by the school; and school withdrawal, where absence is initiated by parents. METHODS: Study participants were 629 parents (84.6% mothers) of Australian school students (Mage  = 11.18 years; 1.8% Aboriginal and/or Torres Strait Islander) with an ID. Participants completed a questionnaire battery that included the School Non-Attendance ChecKlist via which parents indicated the reason their child was absent for each day or half-day absence their child had over the past 20 school days. The absence data presented to parents had been retrieved from school records. RESULTS: Across all students, absence occurred on 7.9% of the past 20 school days. In terms of school attendance problems as defined in existing literature, school withdrawal accounted for 11.1% of absences and school refusal for 5.3% of absences. Students were also absent for other reasons, most commonly illness (32.0%) and appointments (24.2%). Of students with more than one absence (n = 217; 34.5%), about half were absent for more than one reason. Students attending mainstream schools had lower attendance than those attending special schools. CONCLUSIONS: Students with ID were absent for a range of reasons and often for multiple reasons. There were elevated rates of school withdrawal and school refusal. Understanding the reasons for absenteeism can inform targeted prevention and intervention supports.

siRNA high throughput screening identifies regulators of chloropicrin and hydrogen fluoride injury in human corneal epithelial cell models.

Corneal injuries induced by various toxicants result in similar clinical presentations such as corneal opacity and neovascularization. Many studies suggest that several weeks post-exposure a convergence of the molecular mechanisms drives these progressive pathologies. However, chemical agents vary in toxicological properties, and early molecular responses are anticipated to be somewhat dissimilar for different toxicants. We chose 3120 targets from the Dharmacon Human Druggable genome to screen for chloropicrin (CP) and hydrogen fluoride (HF) corneal injury as we hypothesized that targets identified in vitro may be effective as therapeutic targets in future studies. Human immortalized corneal epithelial cells (SV40-HCEC) were used for screening. Cell viability and IL-8 were analyzed to down-select hits into validation studies, where multiplex cytokine analysis and high content analysis were performed to understand toxicant effect and target function. Some endpoints were also evaluated in a second human immortalized corneal epithelial cell line, TCEpi. Over 20 targets entered validation studies for CP and HF; of these, only three targets were shared: NR3C1, RELA, and KMT5A. These findings suggest that early molecular responses to different toxicants may be somewhat distinctive and present dissimilar targets for possible early intervention.

Effects of exercise on vasomotor symptoms in menopausal women: a systematic review and meta-analysis.

The frequency and severity of menopausal vasomotor symptoms negatively impact quality of life. This systematic review evaluates the potential of exercise to relieve the subjective frequency and severity of vasomotor symptoms. We searched four databases to identify randomized controlled trials (RCTs) that evaluated the effect of structured exercise (e.g. aerobic training) on the severity and/or frequency of vasomotor symptoms in menopausal women. Two reviewers independently screened records for eligibility, extracted data and assessed risks of bias and evidence certainty using the Cochrane tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE). When suitable, data were pooled using random-effect meta-analyses. We appraised 21 RCTs involving 2884 participants. Compared to no-treatment control, exercise significantly improved severity of vasomotor symptoms (10 studies, standardized mean difference [SMD] = 0.25; 95% confidence interval [CI]: 0.04 to 0.47, p = 0.02, very low certainty of evidence); the effect size was attenuated when studies with a high risk of bias were excluded (SMD = 0.11, 95% CI: -0.03 to 0.26, p = 0.13). No significant changes in vasomotor frequency were found between exercise and control (SMD = 0.14, 95% CI: -0.03 to 0.31, p = 0.12, high certainty of evidence). In conclusion, exercise might improve vasomotor symptom severity. Future rigorous RCTs addressing the limitations of current review are warranted to explore the optimal exercise prescription principles to target the severity of vasomotor symptoms.

Improved Neutron Lifetime Measurement with UCNτ.

We report an improved measurement of the free neutron lifetime τ_{n} using the UCNτ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10^{6} surviving ultracold neutrons (UCNs) after storing in UCNτ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τ_{n} from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τ_{n} measurements and by performing a global likelihood fit to all data while self-consistently incorporating the ß-decay lifetime. Both techniques achieve consistent results and find a value τ_{n}=877.75±0.28_{stat}+0.22/-0.16_{syst} s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

COVID-19 impact on psychological outcomes of parents, siblings and children with intellectual disability: longitudinal before and during lockdown design.

BACKGROUND: Parents of children with intellectual disability (ID) report comparatively lower levels of well-being than parents of children without ID. Similarly, children with ID, and to a lesser extent their siblings, are reported to show comparatively higher levels of behaviour and emotional problems. Psychological problems may be accentuated by restrictions associated with the COVID-19 pandemic, due to increased social, caring and economic stressors and reduced social support. However, existing studies have not been able to examine the impact of COVID-19 restrictions accounting for pre-COVID levels of well-being in these families. In a naturalistic design, we examined outcomes for parents, siblings and children with ID in a two-wave longitudinal study where Wave 2 data were gathered for some families before and some during COVID-19 restrictions. METHODS: Parents of children with ID who took part in a Wave 2 survey pre-lockdown (n = 294) and during/post-lockdown (n = 103) completed a number of measures about their well-being and the behaviour and emotional problems of both their child with ID and their nearest-in-age sibling. These same measures had also been completed for all families 2-3 years previously in Wave 1 of the study. RESULTS: After accounting for covariates including family socio-economic circumstances, pre-lockdown and post-lockdown groups did not differ on Waves 1 to 2 change for measures of parental psychological distress, life satisfaction, the impact of caregiving on their lives or perceived positive gains; nor child or sibling internalising or externalising behaviour problems. CONCLUSIONS: Findings of the current study indicate that during and shortly after the COVID-19 lockdown in the United Kingdom, well-being in families of children with an ID (as reported by parents) was at similar levels compared with prior to the lockdown period.

Failure to replicate a robust Down syndrome advantage for maternal well-being.

BACKGROUND: Family members caring for children with intellectual disability (ID) routinely report heightened levels of psychological distress. However, families of children with Down syndrome typically report better outcomes (known as the Down syndrome advantage). We examined whether the Down syndrome advantage would be present for maternal psychological distress, impact of caregiving, life satisfaction and perceived positive impact of the child with ID when controlling for external variables. METHODS: Mothers of children with Down syndrome (n = 111) and mothers of children with ID of mixed aetiologies (n = 196) completed measures about their own mental health, perceived impact of caregiving, life satisfaction and perceived positive impact of their child on themselves and the family unit. RESULTS: A series of group comparisons revealed small to moderate differences supporting the presence of a putative Down syndrome advantage in relation to personal maternal well-being outcomes. However, when child-related characteristics and external variables were controlled, the Down syndrome advantage was no longer present, with reduced, small effect sizes observed for all maternal outcomes. CONCLUSIONS: Initial group differences in psychological distress and life satisfaction were largely associated with family poverty, indicating that the Down syndrome advantage may be less robust than previously thought. Future research should seek to move beyond examining the existence of the putative Down syndrome advantage and focus on how families of children with Down syndrome experience family life, including longitudinal research exploring responses to life cycle and transition challenges.

The willingness of UK adults with intellectual disabilities to take COVID-19 vaccines.

BACKGROUND: Given the much greater COVID-19 mortality risk experienced by people with intellectual disabilities (ID), understanding the willingness of people with ID to take a COVID-19 vaccine is a major public health issue. METHOD: In December 2020 to February 2021, across the United Kingdom, 621 adults with ID were interviewed remotely and 348 family carers or support workers of adults with ID with greater needs completed an online survey, including a question on willingness to take a COVID-19 vaccine if offered. RESULTS: Eighty-seven per cent of interviewees with ID were willing to take a COVID-19 vaccine, with willingness associated with white ethnicity, having already had a flu vaccine, gaining information about COVID-19 from television but not from social media, and knowing COVID-19 social restrictions rules. A percentage of 81.7% of surveyed carers of adults with ID with greater needs reported that the person would be willing to take a COVID-19 vaccine, with willingness associated with white ethnicity, having a health condition of concern in the context of COVID-19, having had a flu vaccine, being close to someone who had died due to COVID-19, and having shielded at some point during the pandemic. CONCLUSIONS: Reported willingness to take the COVID-19 vaccine is high among adults with ID in the United Kingdom, with factors associated with willingness having clear implications for public health policy and practice.

Infrared spectroscopy of serum as a potential diagnostic screening approach for naturally occurring canine osteoarthritis associated with cranial cruciate ligament rupture.

OBJECTIVE: To evaluate infrared (IR) spectroscopy of serum as a screening tool to differentiate dogs affected by naturally occurring osteoarthritis (OA) associated with cranial cruciate ligament rupture (CrCLR) and controls. METHOD: 104 adult dogs with CrCLR (affected group) and 50 adult control dogs were recruited for this prospective observational study. Serum samples were collected preoperatively from CrCLR dogs and from a subset of these dogs at 4-, and 12-week post-surgical intervention to stabilize the affected stifles. Serum was collected once from control dogs. Dry films were made from serum samples, and IR absorbance spectra acquired. Data preprocessing, principal component analysis and multivariate analysis of covariance were performed to separate samples from the two groups, and to evaluate temporal differences. Weighted logistic regression with L1 regularization method was used to develop a predictive model. Model performance based on an independent test set was evaluated. RESULTS: Spectral data analysis revealed significant separation between the sera of CrCLR and control dogs (P < 0.0001), but not amongst different time points in the OA group. The sensitivity, specificity, AUC and accuracy of the test set were 84.62%, 96.15%, 93.20% and 92.31% respectively. CONCLUSIONS: These findings confirm the potential of IR-spectroscopy of serum with chemometrics methods to differentiate controls from dogs with OA associated with CrCLR. This is the first step in development of an economic, and comparatively simple IR-based screening serum test for OA. Utility of this tool as a clinical screening and diagnostic test requires further investigation and validation.

Synthetic Designs and Structural Investigations of Biomimetic Ni-Fe Thiolates.

Described are the syntheses of several Ni(µ-SR)2Fe complexes, including hydride derivatives, in a search for improved models for the active site of [NiFe]-hydrogenases. The nickel(II) precursors include (i) nickel with tripodal ligands: Ni(PS3)- and Ni(NS3)- (PS33- = tris(phenyl-2-thiolato)phosphine, NS33- = tris(benzyl-2-thiolato)amine), (ii) traditional diphosphine-dithiolates, including chiral diphosphine R,R-DIPAMP, (iii) cationic Ni(phosphine-imine/amine) complexes, and (iv) organonickel precursors Ni( o-tolyl)Cl(tmeda) and Ni(C6F5)2. The following new nickel precursor complexes were characterized: PPh4[Ni(NS3)] and the dimeric imino/amino-phosphine complexes [NiCl2(PCH═NAn)]2 and [NiCl2(PCH2NHAn)]2 (P = Ph2PC6H4-2-). The iron(II) reagents include [CpFe(CO)2(thf)]BF4, [Cp*Fe(CO)(MeCN)2]BF4, FeI2(CO)4, FeCl2(diphos)(CO)2, and Fe(pdt)(CO)2(diphos) (diphos = chelating diphosphines). Reactions of the nickel and iron complexes gave the following new Ni-Fe compounds: Cp*Fe(CO)Ni(NS3), [Cp(CO)Fe(µ-pdt)Ni(dppbz)]BF4, [( R,R-DIPAMP)Ni(µ-pdt)(H)Fe(CO)3]BArF4, [(PCH═NAn)Ni(µ-pdt)(Cl)Fe(dppbz)(CO)]BF4, [(PCH2NHAn)Ni(µ-pdt)(Cl)Fe(dppbz)(CO)]BF4, [(PCH═NAn)Ni(µ-pdt)(H)Fe(dppbz)(CO)]BF4, [(dppv)(CO)Fe(µ-pdt)]2Ni, {H[(dppv)(CO)Fe(µ-pdt)]2Ni]}BF4, and (C6F5)2Ni(µ-pdt)Fe(CO)2(dppv) (DIPAMP = (CH2P(C6H4-2-OMe)2)2; BArF4- = [B(C6H3-3,5-(CF3)2]4-)) Within the context of Ni-(SR)2-Fe complexes, these new complexes feature new microenvironments for the nickel center: tetrahedral Ni, chirality, imine, and amine coligands, and Ni-C bonds. In the case of {H[(dppv)(CO)Fe(µ-pdt)]2Ni}+, four low-energy isomers are separated by ≤3 kcal/mol, one of which features a biomimetic HNi(SR)4 site, as supported by density functional theory calculations.

Total ankle replacement in patients with haemophilic arthropathy: primary arthroplasty and conversion of painful ankle arthrodesis to arthroplasty.

INTRODUCTION: There are two general surgical approaches for operative treatment of end-stage haemophilic ankle arthropathy: ankle arthrodesis and total ankle replacement (TAR). AIM: The aim of this study was to determine intraoperative and postoperative complications and evaluate the mid-term clinical and radiographic outcomes of TAR in patients with haemophilic arthropathy. METHODS: Fourteen patients with a mean age of 51.4 ± 10.2 years (range = 32.9-63.7) were treated for end-stage haemophilic ankle arthropathy. Nine procedures were primary arthroplasties, five procedures were conversions of painful ankle arthrodesis to TAR. The mean duration of follow-up was 5.8 ± 2.3 years (range = 2.0-9.2). Component stability and alignment was assessed with weight-bearing radiographs. Clinical assessment was performed. RESULTS: One patient sustained an intraoperative medial malleolar fracture. In two patients, delayed wound healing was observed. In one patient, open arthrolysis was performed due to painful arthrofibrosis. Both components were neutrally aligned. Visual analogue scale (VAS) significantly decreased from 8.5 ± 0.9 (range = 8-10) to 1.3 ± 1.6 (range = 0-6). Significant functional improvement including range of motion (ROM) and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score was observed. The summarized components of the SF-36 physical and mental outcomes score significantly improved at the latest follow-up. Complication rates and clinical/radiographic outcomes were comparable in patients with primary TAR and conversion of ankle arthrodesis to TAR. CONCLUSION: The mid-term results following TAR or a conversion procedure in patients with haemophilic arthropathy are encouraging. However, for postoperative success, access to an experienced, multidisciplinary team including a haematologist is mandatory.

Impact of diabetes duration on achieved reductions in glycated haemoglobin, fasting plasma glucose and body weight with liraglutide treatment for up to 28 weeks: a meta-analysis of seven phase III trials.

This meta-analysis of seven randomized, placebo-controlled studies (total 3222 patients) evaluated whether type 2 diabetes (T2D) duration affects the changes in blood glucose control and body weight that can be achieved with liraglutide and placebo. With liraglutide 1.2 mg, shorter diabetes duration was associated with a significantly greater, but clinically non-relevant, difference in glycated haemoglobin (HbA1c) reduction (p < 0.05), i.e. a 0.18% (1.96 mmol/mol) reduction in HbA1c per 10 years shorter diabetes duration. With liraglutide 1.8 mg, shorter diabetes duration was associated with a small but statistically significant trend for greater fasting plasma glucose (FPG) reduction (p < 0.05), i.e. a 0.38 mmol/l reduction in FPG per 10 years shorter diabetes duration. Neither the liraglutide 1.8 mg nor placebo results showed a significant association between HbA1c and diabetes duration and neither the liraglutide 1.2 mg nor placebo results showed a significant association between FPG and diabetes duration. Likewise, neither liraglutide nor placebo showed a significant association between change in weight and diabetes duration. These results suggest diabetes duration has a clinically negligible effect on achievable blood glucose control and weight outcomes with liraglutide and placebo in patients with T2D.

Efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-SWITCH): a randomized, double-blind, double-dummy, active-controlled 26-week trial.

AIMS: To confirm superiority on glycaemic control by switching from sitagliptin to liraglutide 1.8 mg/d versus continued sitagliptin. MATERIALS AND METHODS: A randomized, multicentre, double-blind, double-dummy, active-controlled trial across 86 office- or hospital-based sites in North America, Europe and Asia. Subjects with type 2 diabetes who had inadequate glycaemic control (glycated haemoglobin [HbA1c] 7.5-9.5% on sitagliptin (100 mg/d) and metformin (≥1500 mg daily) for ≥90 days were randomized to either switch to liraglutide (n = 203) or continue sitagliptin (n = 204), both with metformin. The primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a confirmatory secondary endpoint. RESULTS: Greater reduction in mean HbA1c was achieved with liraglutide than with continued sitagliptin [-1.14% vs. -0.54%; estimated mean treatment difference (ETD): -0.61% (95% CI -0.82 to -0.40; p < 0.0001)], confirming superiority of switching to liraglutide. Body weight was reduced more with liraglutide [-3.31 kg vs. -1.64 kg; ETD: -1.67 kg (95% CI -2.34 to -0.99; p < 0.0001)]. Nausea was more common with liraglutide [44 subjects (21.8%)] than with continued sitagliptin [16 (7.8%)]. Three subjects (1.5%) taking sitagliptin reported a confirmed hypoglycaemic episode. CONCLUSIONS: Subjects insufficiently controlled with sitagliptin who switch to liraglutide can obtain clinically relevant reductions in glycaemia and body weight, without compromising safety. A switch from sitagliptin to liraglutide provides an option for improved management of type 2 diabetes while still allowing patients to remain on dual therapy.

Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study).

AIM: To evaluate the efficacy and safety of adding insulin degludec (IDeg) to treatment in patients with type 2 diabetes receiving liraglutide and metformin and qualifying for treatment intensification because of inadequate glycaemic control. METHODS: In this 26-week, double-blind trial, patients who still had inadequate glycaemic control after a 15-week run-in period with initiation and dose escalation of liraglutide to 1.8 mg in combination with metformin (≥1500 mg) were randomized to addition of once-daily IDeg ('IDeg add-on to liraglutide' arm; n = 174) or placebo ('placebo add-on to liraglutide' arm; n = 172), with dosing of both IDeg and placebo based on titration guidelines. RESULTS: At 26 weeks, the mean change in glycated haemoglobin level was greater in the IDeg add-on to liraglutide arm (-1.04%) than in the placebo add-on to liraglutide arm (-0.16%; p < 0.0001). Similarly, the mean fasting plasma glucose reduction was greater, and self-measured plasma glucose values were lower at all eight time points, with IDeg add-on versus placebo add-on (both p < 0.0001). At 26 weeks, the IDeg dose was 51 U (0.54 U/kg). During the run-in period with liraglutide, body weight decreased by ∼3 kg in both groups. After 26 weeks, the mean change was +2.0 kg (IDeg add-on to liraglutide) and -1.3 kg (placebo add-on to liraglutide). Confirmed hypoglycaemia rates were low in both groups, although higher with IDeg than with placebo (0.57 vs. 0.12 episodes/patient-years of exposure; p = 0.0002). Nocturnal confirmed hypoglycaemia was infrequent in both groups, with no episodes of severe hypoglycaemia, and no marked differences in adverse events with either treatment approach. CONCLUSION: The addition of liraglutide and IDeg to patients sub-optimally treated with metformin and liraglutide and requiring treatment intensification was found to be effective and well-tolerated.

Basal insulin peglispro versus insulin glargine in insulin-naïve type 2 diabetes: IMAGINE 2 randomized trial.

AIMS: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. MATERIAL AND METHODS: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. RESULTS: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). CONCLUSIONS: Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

The Intersection of NO and H2S: Persulfides Generate NO from Nitrite through Polysulfide Formation.

Hydrogen sulfide (H2S) and nitric oxide (NO) are important biosignaling molecules, and their biochemistries are increasingly recognized to be intertwined. Persulfides are an oxidized product of biological H2S and have emerged as important species involved in the biological action of reactive sulfur species. Using isolated persulfides, we employed a combination of experimental and computational methods to investigate the contribution of persulfides to H2S/NO crosstalk. Our studies demonstrate that isolated persulfides react with nitrite to produce NO via polysulfide and perthionitrite intermediates. These results highlight the importance of persulfides, polysulfides, and perthionitrite as intertwined reactive nitrogen and sulfur species.

Sumatriptan improves postoperative quality of recovery and reduces postcraniotomy headache after cranial nerve decompression.

BACKGROUND: Microvascular decompression (MVD) is a surgical treatment for cranial nerve disorders via a small craniotomy. The postoperative pain of this procedure can be classified as surgical site somatic pain and postcraniotomy headache similar in nature to a migraine, including its association with photophobia, nausea, and vomiting. This headache can be difficult to treat and can impact on postoperative recovery. Sumatriptan is used to treat migraine-like headaches in various settings. This single-centre randomized controlled trial investigated whether postoperative administration of sumatriptan after MVD surgery impacts the quality of postoperative recovery. METHODS: Fifty patients who complained of postoperative headache after MVD were randomized to receive an s.c. injection of sumatriptan (6 mg) or saline. The primary outcome was quality of recovery as measured by the Quality of Recovery-40 (QoR-40) score at 24 h. RESULTS: The QoR-40 scores were significantly higher in the sumatriptan group (median 184; interquartile range 169-196) than in the placebo group (133; 119-155; P<0.01), suggesting higher quality of recovery. The sumatriptan group also had significantly lower headache scores at 4, 12, and 24 h. There were no significant differences in other secondary outcomes. CONCLUSIONS: Use of sumatriptan improved the quality of recovery as measured by the QoR-40 and reduction of headache at 24 h after surgery. Sumatriptan is a useful alternative treatment for postcraniotomy headache. The mechanism remains unknown but could be related to reduction in headache, mood modulation, or both, mediated by a serotonin effect. CLINICAL TRIAL REGISTRATION: NCT01632657.

Repeated Warm Water Immersion Induces Similar Cerebrovascular Adaptations to 8 Weeks of Moderate-Intensity Exercise Training in Females.

Exercise training has the potential to enhance cerebrovascular function. Warm water immersion has recently been shown to enhance vascular function including the cerebrovascular response to heating. We suggest that passive heating can be used alternatively to exercise. Our aim was to compare the effects of exercise with warm-water immersion training on cerebrovascular and thermoregulatory function. 18 females (25±5 y) performed 8 weeks of cycling (70% HRmax) or warm water immersion (42°C) for 30 min 3 times per week. Brachial artery flow-mediated dilation (FMD) and peak cardiorespiratory fitness (VO2peak) were measured prior to and following both interventions. A passive heat stress was employed to obtain temperature thresholds (Tb) and sensitivities for sweat rate (SR) and cutaneous vasodilation (CVC). Middle cerebral artery velocity (MCAv) was measured throughout. FMD and VO2peak improved following both interventions (p<0.05). MCAv and cerebrovascular conductance were higher at rest and during passive heating (p<0.001 and <0.001, respectively) following both interventions. SR occurred at a lower Tb following both interventions and SR sensitivity also increased, with a larger increase at the chest (p<0.001) following water immersion. CVC occurred at a lower Tb (p<0.001) following both interventions. Warm water immersion elicits similar cerebrovascular, conduit, and thermoregulatory adaptations compared to a period of moderate-intensity exercise training.

The interactions between municipal socioeconomic status and age on hip fracture risk.

SUMMARY: Age modifies the effect of area-level socioeconomic status (SES) in the risk of fragility hip fractures (HF). For older individuals, the risk of HF increases as SES increases. For younger individuals, risk of HF increases as SES decreases. Our study may help decision-makers to better direct the implementation of political decisions. INTRODUCTION: The effect of socioeconomic status (SES) on hip fracture (HF) incidence remains unclear. The objective of this study is to evaluate the association between HF incidence and municipality-level SES as well as interactions between age and SES. METHODS: From the Portuguese Hospital Discharge Database, we selected hospitalizations (2000-2010) of patients aged 50+, with HF diagnosis (codes 820.x, ICD9-CM), caused by traumas of low/moderate energy, excluding bone cancer cases and readmissions for aftercare. Municipalities were classified according to SES (deprived to affluent) using 2001 Census data. A spatial Bayesian hierarchical regression model (controlling for data heterogeneity and spatial autocorrelation), using the Poisson distribution, was used to quantify the relative risk (RR) of HF, 95% credible interval (95%CrI), and analyze the interaction between age and SES after adjusting for rural conditions. RESULTS: There were 96,905 HF, 77.3% of which were on women who, on average, were older than men (mean age 81.2±8.5 vs 78.2±10.1 years) at admission (p<0.001). In women, there was a lower risk associated with better SES: RR=0.83 (95%CrI 0.65-1.00) for affluent versus deprived. There was an inverse association between SES and HF incidence rate in the youngest and a direct association in the oldest, for both sexes, but significant only between deprived and affluent in older ages (≥75 years). CONCLUSIONS: Interaction between SES and age may be due to inequalities in lifestyles, access to health systems, and preventive actions. These results may help decision-makers to better understand the epidemiology of hip fractures and to better direct the available funding.