Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial.

PURPOSE: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness. METHODS: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation. RESULTS: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019). CONCLUSION: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness.

Fixed versus individualized treatment for five common bacterial infectious syndromes: a survey of the perspectives and practices of clinicians.

Background: Traditionally, bacterial infections have been treated with fixed-duration antibiotic courses; however, some have advocated for individualized durations. It is not known which approach currently predominates. Methods: We conducted a multinational clinical practice survey asking prescribers their approach to treating skin and soft tissue infection (SSTI), community-acquired pneumonia (CAP), pyelonephritis, cholangitis and bloodstream infection (BSI) of an unknown source. The primary outcome was self-reported treatment approach as being fully fixed duration, fixed minimum, fixed maximum, fixed minimum and maximum, or fully individualized durations. Secondary questions explored factors influencing duration of therapy. Multivariable logistic regression with generalized estimating equations was used to examine predictors of use of fully fixed durations. Results: Among 221 respondents, 170 (76.9%) completed the full survey; infectious diseases physicians accounted for 60.6%. Use of a fully fixed duration was least common for SSTI (8.5%) and more common for CAP (28.3%), BSI (29.9%), cholangitis (35.7%) and pyelonephritis (36.3%). Fully individualized therapy, with no fixed minimum or maximum, was used by only a minority: CAP (4.9%), pyelonephritis (5.0%), cholangitis (9.9%), BSI (13.6%) and SSTI (19.5%). In multivariable analyses, a fully fixed duration approach was more common among Canadian respondents [adjusted OR (aOR) 1.76 (95% CI 1.12-2.76)] and for CAP (aOR 4.25, 95% CI 2.53-7.13), cholangitis (aOR 6.01, 95% CI 3.49-10.36), pyelonephritis (aOR 6.08, 95% CI 3.56-10.39) and BSI (aOR 4.49, 95% CI 2.50-8.09) compared with SSTI. Conclusions: There is extensive practice heterogeneity in fixed versus individualized treatment; clinical trials would be helpful to compare these approaches.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot randomised controlled trial.

BACKGROUND: Self-reported penicillin allergies are highly prevalent in hospitalised patients and are associated with poor health and health service outcomes. Critically ill patients have historically been underrepresented in prospective delabelling studies in part due to concerns around clinical stability and reliability of penicillin skin testing. Allergy assessment tools exist to identify low-risk penicillin allergy phenotypes and facilitate direct oral challenge delabelling. PEN-FAST is a clinical decision rule that has been validated to predict true penicillin allergy in a cohort of non-critically ill patients. There is however limited evidence regarding the feasibility, safety and efficacy of direct oral challenges and the use of delabelling clinical decisions rules in the intensive care setting. METHODS: Critically ill patients in the intensive care unit (ICU) with low-risk penicillin allergy phenotypes (PEN-FAST score < 3) will be randomised 1:1 to direct oral penicillin challenge (single dose 250 mg oral amoxicillin or implicated penicillin) or routine care, followed by a 2-h observation period. Patients will receive a second oral challenge/observation prior to hospital discharge (with subsequent observation for 2 h). An assessment for antibiotic-associated adverse events will also be undertaken at 24 h and 5 days post each challenge/observation and again at 90 days post-randomisation. The primary outcome measures are feasibility (proportion of eligible patients recruited and protocol compliance) and safety (proportion of patients who experience an antibiotic-associated immune-mediated adverse event or serious adverse event). DISCUSSION: We will report the feasibility and safety of point-of-care penicillin direct oral challenge in this first randomised controlled trial of low-risk penicillin allergy in critically ill hospitalised patients. Upon completion of the project, important findings will inform the design of planned large prospective multi-centre clinical trials in Australian and international ICUs, further examining safety and efficacy and exploring antimicrobial prescribing-related outcomes following penicillin oral challenge. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Registration Number: ACTRN12621000051842 Date registered: 20/01/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379735&isReview=true.

Risk factors for invasive fungal infection in 5-azacytidine treated patients with acute myeloid leukemia and myelodysplastic syndrome.

The rate of invasive fungal infection (IFI) in patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) receiving 5-azacytidine is incompletely defined and published recommendations for mold-active fungal prophylaxis in such patients vary according to source. We performed a retrospective cohort study in order to identify contemporary IFI rates and infection-related mortality in relation to known risk factors and the use of antifungal prophylaxis. One hundred and seventeen patients receiving 5-azacytidine for MDS and low blast count AML were identified, of whom 71 (61%) received antifungal prophylaxis. The IFI rate was 7.7% across the entire cohort: 5.6% in those receiving prophylaxis vs 10.9% in the subgroup who did not (P = .30). The presence of neutropenia at three months of treatment was associated with increased IFI risk (hazard ratio [HR] 8.29; (95% confidence interval [CI)] 1.61-42.6; P = .01), and on multivariate analysis, IFI was independently associated with increased all-cause mortality risk (HR 8.37; 95% CI 3.67 - 19.11; P < .0001). These data further highlight the risk of IFI in this population and support the use of mold-active prophylaxis in neutropenic patients receiving 5-azacytidine for MDS and AML.

Alcohol and fast food sponsorship in sporting clubs with junior teams participating in the 'Good Sports' program: a cross-sectional study.

OBJECTIVE: To examine: alcohol and fast food sponsorship of junior community sporting clubs; the association between sponsorship and club characteristics; and parent and club representative attitudes toward sponsorship. METHODS: A cross-sectional telephone survey of representatives from junior community football clubs across New South Wales and Victoria, Australia, and parents/carers of junior club members. Participants were from junior teams with Level 3 accreditation in the 'Good Sports' program. RESULTS: A total of 79 club representatives and 297 parents completed the survey. Half of participating clubs (49%) were sponsored by the alcohol industry and one-quarter (27%) were sponsored by the fast food industry. In multivariate analyses, the odds of alcohol sponsorship among rugby league clubs was 7.4 (95%CI: 1.8-31.0, p=<0.006) that of AFL clubs, and clubs located in regional areas were more likely than those in major cities to receive fast food industry sponsorship (OR= 9.1; 95%CI: 1.0-84.0, p=0.05). The majority (78-81%) of club representatives and parents were supportive of restrictions to prohibit certain alcohol sponsorship practices, but a minority (42%) were supportive of restrictions to prohibit certain fast food sponsorship practices. CONCLUSIONS: Large proportions of community sports clubs with junior members are sponsored by the alcohol industry and the fast food industry. There is greater acceptability for prohibiting sponsorship from the alcohol industry than the fast food industry. Implications for public health: Health promotion efforts should focus on reducing alcohol industry and fast food industry sponsorship of junior sports clubs.

The Relationship Between Glutamate Dynamics and Activity-Dependent Synaptic Plasticity.

The spatiotemporal dynamics of excitatory neurotransmission must be tightly regulated to achieve efficient synaptic communication. By limiting spillover, glutamate transporters are believed to prevent excessive activation of extrasynaptically located receptors that can impair synaptic plasticity. While glutamate transporter expression is reduced in numerous neurodegenerative diseases, the contributions of transporter dysfunction to disease pathophysiology remain ambiguous as the fundamental relationship between glutamate dynamics and plasticity, and the mechanisms linking these two phenomena, remain poorly understood. Here, we combined electrophysiology and real-time high-speed imaging of extracellular glutamate transients during LTP induction and characterized the sensitivity of the relationship between glutamate dynamics during theta burst stimulation (TBS) and the resulting magnitude of LTP consolidation, both in control conditions and following selective and nonselective glutamate transporter blockade. Glutamate clearance times were negatively correlated with LTP magnitude following nonselective glutamate transporter inhibition but not following selective blockade of a majority of GLT-1, the brain's most abundant glutamate transporter. Although glutamate transporter inhibition reduced the postsynaptic population response to TBS, calcium responses to TBS were greatly exaggerated. The source of excess calcium was dependent on NMDARs, L-type VGCCs, GluA2-lacking AMPARs, and internal calcium stores. Surprisingly, inhibition of L-type VGCCs, but not GluA2-lacking AMPARs or ryanodine receptors, was required to restore robust LTP. In all, these data provide a detailed understanding of the relationship between glutamate dynamics and plasticity and uncover important mechanisms by which poor glutamate uptake can negatively impact LTP consolidation.SIGNIFICANCE STATEMENT Specific patterns of neural activity can promote long-term changes in the strength of synaptic connections through a phenomenon known as synaptic plasticity. Synaptic plasticity is well accepted to represent the cellular mechanisms underlying learning and memory, and many forms of plasticity are initiated by the excitatory neurotransmitter glutamate. While essential for rapid cellular communication in the brain, excessive levels of extracellular glutamate can negatively impact brain function. In this study, we demonstrate that pharmacological manipulations that increase the availability of extracellular glutamate during neural activity can have profoundly negative consequences on synaptic plasticity. We identify mechanisms through which excess glutamate can negatively influence synaptic plasticity, and we discuss the relevance of these findings to neurodegenerative diseases and in the aging brain.

Promotion of healthy eating in clubs with junior teams in Australia: A cross-sectional study of club representatives and parents.

ISSUES ADDRESSED: To: (i) describe the prevalence of policies and practices promoting healthy eating implemented by sports clubs with junior teams; (ii) examine differences in such practices across geographic and operational characteristics of clubs; and (iii) describe the attitudes of club representatives and parents regarding the acceptability of sports clubs implementing policies and practices to promote healthy eating. METHODS: Cross-sectional telephone surveys of junior community football club management representatives and parents/carers of junior players were conducted in the states of New South Wales and Victoria, Australia in 2016. RESULTS: Seventy-nine of the 89 club representatives approached to participate completed the telephone survey. All clubs (100%; 95% CI 96.2-100.0) reported recommending fruit or water be provided to players after games or at half-time, 24% (95% CI 14.4-33.7) reported promoting healthy food options through prominent positioning at point of sale and only 8% (95% CI 1.6-13.6) of clubs had a written healthy eating policy. There were no significant differences between the mean number of healthy eating policies and practices implemented by club socio-economic or geographic characteristics. Club representatives and parents/carers were supportive of clubs promoting healthy eating for junior players. CONCLUSIONS: While there is strong support within sporting clubs with junior teams for policies and practices to promote healthy eating, their implementation is highly variable. SO WHAT?: A considerable opportunity remains for health promotion policy and practice improvement in clubs with junior teams, particularly regarding policies related to nutrition.

Virtual fracture clinic management of fifth metatarsal, including Jones', fractures is safe and cost-effective.

Virtual clinics have been shown to be safe and cost-effective in many specialties, yet barriers exist to their implementation in orthopaedics. The aims of this study were to look at whether the management of 5th metatarsal fractures using a virtual fracture clinic model is safe, cost effective and avoids adverse outcomes whilst being acceptable to patients using the service. All patients with a fifth metatarsal fracture between September 2013 and September 2015 had a standardised management plan initiated (blackboot, full weightbearing) in the emergency department (ED). 663 patients met inclusion criteria, 251 (37.5%) Type 1, 111 (17%) Type 2 (Jones'), 281 (42%) Type 3 or distal, 20 (3%) were misdiagnosed, and 4 (0.5%) patient's images were unavailable. 499 (75%) patients were discharged immediately, 47 (7%) had further imaging, 114 (17%) had either ESP or consultant clinic review, and 3 (<1%) transferred their care privately. The average number of clinic visits per patient was 0.17. At a conservative estimate of 1.3 visits per patient in a traditional pathway this saved 779 clinic visits with a cost saving of £60,000 on clinic visits alone. There were 8 (7%) asymptomatic non-unions in Type 2 (Jones') fractures. One patient required surgical intervention. Fifth metatarsal fractures have excellent outcomes with conservative management yet traditionally have required clinic visits to confirm the diagnosis and explain the management and prognosis. Our study supports the use of a virtual fracture clinic model that is standardised, initiated in ED, that is both safe and cost-effective.

Genetic control of lithium sensitivity and regulation of inositol biosynthetic genes.

Lithium (Li(+)) is a common treatment for bipolar mood disorder, a major psychiatric illness with a lifetime prevalence of more than 1%. Risk of bipolar disorder is heavily influenced by genetic predisposition, but is a complex genetic trait and, to date, genetic studies have provided little insight into its molecular origins. An alternative approach is to investigate the genetics of Li(+) sensitivity. Using the social amoeba Dictyostelium, we previously identified prolyl oligopeptidase (PO) as a modulator of Li(+) sensitivity. In a link to the clinic, PO enzyme activity is altered in bipolar disorder patients. Further studies demonstrated that PO is a negative regulator of inositol(1,4,5)trisphosphate (IP(3)) synthesis, a Li(+) sensitive intracellular signal. However, it was unclear how PO could influence either Li(+) sensitivity or risk of bipolar disorder. Here we show that in both Dictyostelium and cultured human cells PO acts via Multiple Inositol Polyphosphate Phosphatase (Mipp1) to control gene expression. This reveals a novel, gene regulatory network that modulates inositol metabolism and Li(+) sensitivity. Among its targets is the inositol monophosphatase gene IMPA2, which has also been associated with risk of bipolar disorder in some family studies, and our observations offer a cellular signalling pathway in which PO activity and IMPA2 gene expression converge.