Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes.

Background: There is an urgent need for pharmacological treatment for cocaine (COC) use disorder (CUD). Glutamatergic transmission in the prefrontal cortex is affected by addictive behaviors. Clavulanic acid (CLAV), a glutamate transporter GLT-1 (excitatory amino acid transporter) activator, is a clinical-stage medication that has potential for treating CUD. Methods: In a pilot study, nine participants with CUD received 500 mg CLAV with dose escalations to 750 mg and 1000 mg over 10 days. In 5 separate magnetic resonance imaging (MRI) sessions, brain anterior cingulate cortex (ACC) glutamate level and resting state network (RSN) functional connectivity (FC) were assessed using MR spectroscopy and functional MRI. Craving was assessed at the same time points, between baseline (before CLAV), 6 days, and 10 days of CLAV. Independent component analysis with dual regression was used to identify RSN FC changes from baseline to Days 6 and 10. Relationships among glutamate, craving, and resting state FC values were analyzed. Results: Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (r = -0.90, P = 0.0009, n = 9). The salience network (SN) and executive control network (ECN) demonstrated an association between increased FC after CLAV treatment and low baseline ACC Glu levels (SN CLAV 750 mg, r = -0.82, P = 0.007) (ECN CLAV 1000 mg, r = -0.667, P = 0.050; n = 9). Conclusions: Glutamate associated changes in craving and FC of the salience and executive control brain networks support CLAV as a potentially efficacious pharmacological treatment for CUD.

Effective protein extraction combined with data independent acquisition analysis reveals a comprehensive and quantifiable insight into the proteomes of articular cartilage and subchondral bone.

OBJECTIVE: The objectives of this study was to establish a sensitive and reproducible method to map the cartilage and subchondral bone proteomes in quantitative terms, and mine the proteomes for proteins of particular interest in the pathogenesis of osteoarthritis (OA). The horse was used as a model animal. DESIGN: Protein was extracted from articular cartilage and subchondral bone samples from three horses in triplicate by pressure cycling technology or ultrasonication. Digested proteins were analysed by data independent acquisition based mass spectrometry. Data was processed using a pre-established spectral library as reference database (FDR 1%). RESULTS: We identified to our knowledge the hitherto most comprehensive quantitative cartilage (1758 proteins) and subchondral bone (1482 proteins) proteomes in all species presented to date. Both extraction methods were sensitive and reproducible and the high consistency of the identified proteomes (>97% overlap) indicated that both methods preserved the diversity among the extracted proteins. Proteome mining revealed a substantial number of quantifiable cartilage and bone matrix proteins and proteins involved in osteogenesis and bone remodeling, including ACAN, BGN, PRELP, FMOD, COMP, ACP5, BMP3, BMP6, BGLAP, TGFB1, IGF1, ALP, MMP3, and collagens. A number of proteins, including COMP and TNN, were identified in different protein isoforms with potential unique biological roles. CONCLUSION: We have successfully developed two sensitive and reproducible non-species specific workflows enabling a comprehensive quantitative insight into the proteomes of cartilage and subchondral bone. This facilitates the prospect of investigating the molecular events at the osteochondral unit in the pathogenesis of OA in future projects.

Viva la VOSCE?

BACKGROUND: The COVID-19 pandemic lockdown precluded face-to-face final Objective Structured Clinical Examinations (OSCE) in the UK. RESULTS: In response, we rapidly developed and then successfully implemented a novel Virtual Objective Structured Clinical Examination (VOSCE). CONCLUSIONS: In this article we both describe and reflect on our experience as well as discuss the implications for future undergraduate assessment as the situation evolves.

Epidemiological risk factors for clinical malaria infection in the highlands of Western Kenya.

BACKGROUND: Understanding the complex heterogeneity of risk factors that can contribute to an increased risk of malaria at the individual and household level will enable more effective use of control measures. The objective of this study was to understand individual and household factors that influence clinical malaria infection among individuals in the highlands of Western Kenya. METHODS: This was a matched case-control study undertaken in the Western Kenya highlands. Clinical malaria cases were recruited from health facilities and matched to asymptomatic individuals from the community who served as controls. Each participant was screened for malaria using microscopy. Follow-up surveys were conducted with individual households to collect socio-economic data. The houses were also checked using pyrethrum spray catches to collect mosquitoes. RESULTS: A total of 302 malaria cases were matched to 604 controls during the surveillance period. Mosquito densities were similar in the houses of both groups. A greater percentage of people in the control group (64.6%) used insecticide-treated bed nets (ITNs) compared to the families of malaria cases (48.3%). Use of ITNs was associated with lower level of clinical malaria episodes (odds ratio 0.51; 95% CI 0.39-0.68; P < 0.0001). Low income was the most important factor associated with higher malaria infections (adj. OR 4.70). Use of malaria prophylaxis was the most important factor associated with less malaria infections (adj OR 0.36). Mother's (not fathers) employment status (adj OR 0.48) and education level (adj OR 0.54) was important malaria risk factor. Houses with open eaves was an important malaria risk factor (adj OR 1.72). CONCLUSION: The identification of risk factors for clinical malaria infection provides information on the local malaria epidemiology and has the potential to lead to a more effective and targeted use of malaria control measures. These risk factors could be used to assess why some individuals acquire clinical malaria whilst others do not and to inform how intervention could be scaled at the local level.

Antenatal Ultrasound Detection of Cleft in Western Australia from 2003 to 2012: A Follow-Up Study.

AIM: To investigate trends in the rate of antenatal detection of cleft lip and palate (CLP) patients referred to the CLP Unit at Princess Margaret Hospital for Children in Perth, Western Australia during the period 2003-2012 and compare data with a previously published report covering the years 1996-2003. METHODS: This is a single-center, retrospective survey of antenatal transabdominal ultrasound screenings of mothers of infants born between July 1, 2003 and June 30, 2012 that were referred to the CLP Unit at Princess Margaret Hospital. RESULTS: Detection rates of oral clefts increased significantly when compared with outcomes reported in the same population between 1996 and 2003 (P < .05). An overall detection rate of 71.7% (165/230) was achieved for clefts involving lip and palate. Detection of isolated cleft palate (1/99) and microform (0/8) remained elusive. Most detections (76.5%) were achieved at 15 to 20 weeks of gestational age, corresponding with routine anatomical screening. A further 16.8% were detected post-20 weeks of gestation. Scans were performed by specialist obstetricians, and sonography clinics reported a detection rate of 84.6% (55/65), whereas nonspecialist clinics reported a detection rate of only 67.1% (110/164). CONCLUSION: The antenatal detection rates of oral clefts involving the lip have improved to the extent that the majority of mothers are now being referred to a cleft unit in Western Australia prior to the births of their children. As a result of this improvement, antenatal counseling is now a common facet of cleft management.

Isospin Mixing Reveals

The thermonuclear ^{30}P(p,γ)^{31}S reaction rate is critical for modeling the final elemental and isotopic abundances of ONe nova nucleosynthesis, which affect the calibration of proposed nova thermometers and the identification of presolar nova grains, respectively. Unfortunately, the rate of this reaction is essentially unconstrained experimentally, because the strengths of key ^{31}S proton capture resonance states are not known, largely due to uncertainties in their spins and parities. Using the ß decay of ^{31}Cl, we have observed the ß-delayed γ decay of a ^{31}S state at E_{x}=6390.2(7) keV, with a ^{30}P(p,γ)^{31}S resonance energy of E_{r}=259.3(8) keV, in the middle of the ^{30}P(p,γ)^{31}S Gamow window for peak nova temperatures. This state exhibits isospin mixing with the nearby isobaric analog state at E_{x}=6279.0(6) keV, giving it an unambiguous spin and parity of 3/2^{+} and making it an important l=0 resonance for proton capture on ^{30}P.

Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.

BACKGROUND: In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed. METHODS: We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. RESULTS: CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs. CONCLUSIONS: These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

Lower incidence of post-dural puncture headache with spinal catheterization after accidental dural puncture in obstetric patients.

BACKGROUND: Accidental dural puncture (ADP) and post-dural puncture headache (PDPH) are important complications of obstetric regional anesthesia. Inserting the catheter intrathecally after ADP to prevent PDPH has gained popularity. Nonetheless, data on the effect of an intrathecal catheter on PDPH and epidural blood patch (EBP) rates are mixed. Our primary objective was to examine if spinal catheterization reduces the incidence of PDPH after ADP in obstetric patients. METHODS: Anesthetic records of 29,749 regional blocks performed between January 1997 and July 2013 were analyzed retrospectively. In all blocks containing an epidural component, 18-gauge epidural needles were used. All patients who experienced a witnessed ADP or PDPH without ADP were identified. Data from patients with or without a prolonged spinal catheter were compared. RESULTS: There were 128 events of witnessed ADP (0.43%). Following known ADP, 39 women had an epidural catheter placed at a different level and 89 had an intrathecal catheter (20-gauge) for at least 24 h. Sixty-one patients developed PDPH after observed ADP (48%). Prolonged intrathecal catheter placement significantly reduced the incidence of PDPH after ADP to 42% compared with 62% in those who have the catheter re-sited epidurally [odds ratio = 2.3 (95% confidence interval 1.04-4.86); P = 0.04]. CONCLUSIONS: The incidence of ADP, PDPH and blood patching is similar with previously published studies. After witnessed ADP, inserting the epidural catheter intrathecally significantly reduced the incidence of PDPH.

Clavulanic Acid Decreases Cocaine Cue Reactivity in Addiction-Related Brain Areas, a Randomized fMRI Pilot Study.

Background: Preclinical studies show that clavulanic acid (CLAV) inhibits cocaine self-administration. This study investigates the effect of CLAV on regions of brain activation in response to cocaine cues during functional magnetic resonance imaging (fMRI) in participants with cocaine use disorder (CUD). Methods: A double-masked, placebo-controlled clinical trial with thirteen individuals with severe CUD who were randomized to treatment with CLAV (N = 10, 9 completers) 500 mg/day or matched placebo (PBO) (N = 3) for 3 days. fMRI was used to assess brain reactivity to 18 alternating six-second video clips of cocaine or neutral scenes. In this paradigm, participants were exposed to three different stimulus conditions: NEUTRAL, WATCH (passive watching), and DOWN (actively inhibiting craving while watching). Results: Participants who received CLAV demonstrated a significant reduction in brain activity in the anterior cingulate gyrus (p = 0.009) and the caudate (p = 0.018) in response to DOWN cocaine cues. There was a trend toward lessened cue reactivity in other regions implicated in CUD. Conclusion: CLAV reduced the response of the brain regions associated with motivation and emotional response during the DOWN condition compared to PBO, suggesting CLAV may strengthen voluntary efforts to avoid cocaine use. This pilot data supports the use of CLAV for CUD. (Trial registered in ClinicalTrials.gov NCT04411914).

Preoperative risk factors in 10 418 patients with prior myocardial infarction and 5241 patients with prior unstable angina undergoing elective coronary artery bypass graft surgery.

BACKGROUND: The EuroSCORE associates coronary artery bypass graft (CABG) surgery with higher perioperative risk in the first 3 months after a myocardial infarction (MI). The optimal scheduling of CABG surgery after unstable angina (UA) is unknown. We investigated the preoperative predictors of adverse outcomes in patients undergoing CABG with prior MI or UA and investigated the importance of time interval between the cardiac event and CABG. METHODS: The Hospital Episode Statistics database (April 2006-March 2010) was analysed for elective admissions for CABG. Independent preoperative patient factors influencing length of stay, readmission rates, and mortality, were identified by logistic regression and presented as adjusted odds ratios (ORs). RESULTS: A total of 10 418 patients with prior MI (mortality 1.8%) and 5241 patients with prior UA (mortality 2.2%) were included in the respective cohorts. Multiple risk factors were identified in each population including liver disease and renal failure. The time interval from cardiac event (MI or UA) to elective CABG surgery did not influence perioperative outcomes when analysed as a continuous measure or using the arbitrary 3-month threshold [MI, OR 1.1 (0.78-1.57) and UA, OR 0.65 (0.39-1.09)]. CONCLUSIONS: Our hypothesis generating data suggest that the increased risk currently allocated in the EuroSCORE for an interval of 3 months between MI and CABG should be critically re-evaluated. Furthermore, prior MI should not be discounted as a risk factor if it is more than 3 months old.

Title: Obesogenic microbial signatures and the development of obesity in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer with survival exceeding 90% for standard-risk groups. A debilitating side-effect of treatment is the development of overweight/obesity (OW/OB), which develops in approximately 40% of children by the end of treatment. The microbiome has been associated with the development of OW/OB. We examined fluctuations in the microbiome with the development of OW/OB during the first six months of treatment at diagnosis, and two subsequent timepoints (N = 62). Shotgun metagenomic sequencing was performed on Illumina Nextseq system, and taxa and functional pathways were extracted from sequences using kraken2 and humann2, respectively. An association of increased presence of several species (e.g., Klebsiella pneumoniae, Escherichia coli) was observed in children with OW/OB, while lean-promoting species (Veillonella, Haemophilus, and Akkermansia) were increased in children who maintained a normal weight. Pathway analysis revealed purine nucleotide biosynthesis, sugar nucleotide biosynthesis, and enzyme cofactor biosynthesis were positively correlated with Bacteroides spp. among children with OW/OB. We identified several taxa and functional pathways that may confer increased risk for the development of OW/OB. The associations observed in this pilot are preliminary and warrant further research in the microbiome and the development of OW/OB in childhood ALL.

Management and outcome of burn injuries during pregnancy: A systematic review and presentation of a comprehensive guideline.

Pregnant women are a vulnerable subgroup of burn patients, due to altered physiological state and possible adverse effect on the fetus. The aim of this study was to develop a guideline for a tailored treatment of pregnant patients with burns to optimally treat both mother and fetus. This study consists of two parts: the first part contains a systematic review that presents a comprehensive overview of the literature on the management and outcome of pregnant women who sustain severe burn injuries and based on the results of this review, a guideline on the general, obstetric and burn management was developed and presented in the second part. A total of 35 studies including 1395 patients were included. Although the clinical outcomes seemed to be similar to non-pregnant patients, one study showed that mortality might be higher in the pregnant population. Predictive factors for maternal and fetal mortality were a total burned surface area of over 40% and inhalation injury. Early surgery may lead to a higher chance of survival of mother and fetus. A comprehensive guideline on the general management of pregnant patients with burns, obstetric management and specific burn management is provided. We encourage international burn organizations and guideline committees to use and evaluate the presented guideline.

Induction of antigen-specific immunosuppression by CD95L cDNA-transfected 'killer' dendritic cells.

Dendritic cells (DCs) are special subsets of antigen-presenting cells characterized by their highly potent capacity to activate immunologically naive T cells. Here we report that DCs that are transfected with CD95 ligand (CD95L) cDNA, called 'killer' DCs, deliver death signals, instead of activation signals, to T cells after antigen-specific interaction. Injection of antigen-pulsed killer DCs into mice before sensitization induced antigen-specific immunosuppression. When administered after sensitization, killer DCs suppressed immune responses almost completely after subsequent challenge. Thus, killer DCs represent an entirely new immunomodulatory protocol, which may become directly applicable in preventing and even treating T cell-mediated inflammatory diseases.

All I want for coagulation.

Evidence-based medicine underpins modern practice of medicine. This paper describes a fictional consultation between Santa Claus and a doctor regarding deep vein thrombosis (DVT) prophylaxis, giving a review of the evidence for DVT prophylaxis in travellers while exposing the difficulty in applying evidence to atypical clinical encounters. Medline and the Cochrane Library were searched, and guidelines reviewed. Keywords used were DVT, thromboembolism, deep vein thrombosis and air travel-related venous thromboembolism. All relevant studies found, have been included in this review, with additional studies identified from the references in these articles. In conclusion, compression stockings, with or without a one-off dose of either aspirin or heparin, are the most evidence-based approaches for prophylaxis in someone with established risk factors for DVT prior to a long-haul flight. Simple exercises should also be encouraged.

Equality of access to "fast-track" stroke services in an older, socio-economically deprived Scottish population.

BACKGROUND AND AIMS: Unequal access to specialist stroke services may contribute to the disproportionate stroke burden in certain populations. We evaluated the relationship between access to TIA services, deprivation and age. METHODS: We prospectively recorded referral pattern data on consecutive TIA service patients. Socio-economic deprivation was derived from postcode and census data. Associations were described using Kruskal-Wallis statistics. RESULTS: Of 3,462 patients assessed, there was no association between time to clinic referral or attendance and increasing deprivation or age. CONCLUSION: Inequality of access to TIA services for older, deprived patients was not evident. However, delay to assessment and prevalence of risk factors was substantial for all patients.

Clinical audit: management of acute severe asthma in west Glasgow.

BACKGROUND: The U.K. has 75,000 hospital admissions and over 1500 deaths from asthma annually. The British Thoracic Society (BTS) guidelines represent the recognised standard for acute asthma management. We assessed the degree of conformity with these guidelines in an acute medical unit. METHODOLOGY: Data from consecutive admissions were collected prospectively. Practice was audited in October December 2005 and October 2006 - January 2007. Between cycles an educational programme was instigated, RESULTS: Fifty-eight patients were included. Clinical parameters were well recorded in both cycles. Peak expiratory flow was consistently under-recorded (72% at admission; 67% in monitoring). in monitoring). Severity assessment was documented at 55% and 66% in cycle one and two respectively. Of these, the assessment was incorrect in 33% in cycle one and 21% in cycle two. All misclassifications of severity were underestimates. All life-threatening attacks were not identified. No improvement occurred between cycles. Overall, 60% of patients were inappropriately treated according to BTS guidelines, 40% due to under-treatment. Under-treatment occurred more frequently in cycle two compared with cycle one (57% vs. 24%, p = 0.007), predominantly due to inadequate treatment of life-threatening asthma. CONCLUSION: Management of acute asthma in a large, urban teaching hospital is suboptimal. Educational intervention failed to improve care; more comprehensive strategies are required.

A brief overview of the most common histiocytic disorders.

Histiocytosis refers to a diverse collection of disorders unified by a proliferation and accumulation of histiocytes into a variety of organs. The following review article will discuss and briefly describe the clinical and histological findings of some of the more common histiocytic disorders. The article is divided into sections according to the current classification system and prevalence of the condition.

CaM kinase IV regulates lineage commitment and survival of erythroid progenitors in a non-cell-autonomous manner.

Developmental functions of calmodulin-dependent protein kinase IV (CaM KIV) have not been previously investigated. Here, we show that CaM KIV transcripts are widely distributed during embryogenesis and that strict regulation of CaM KIV activity is essential for normal primitive erythropoiesis. Xenopus embryos in which CaM KIV activity is either upregulated or inhibited show that hematopoietic precursors are properly specified, but few mature erythrocytes are generated. Distinct cellular defects underlie this loss of erythrocytes: inhibition of CaM KIV activity causes commitment of hematopoietic precursors to myeloid differentiation at the expense of erythroid differentiation, on the other hand, constitutive activation of CaM KIV induces erythroid precursors to undergo apoptotic cell death. These blood defects are observed even when CaM KIV activity is misregulated only in cells that do not contribute to the erythroid lineage. Thus, proper regulation of CaM KIV activity in nonhematopoietic tissues is essential for the generation of extrinsic signals that enable hematopoietic stem cell commitment to erythroid differentiation and that support the survival of erythroid precursors.

Hormone replacement therapy: the risks and benefits of treatment.

Several recent large studies have provoked concern among both health professionals and the general public regarding the safety of hormone replacement therapy (HRT). This article provides a review of the current literature surrounding the risks and benefits of HRT in postmenopausal women, and how the data can be applied safely in everyday clinical practice.