Hyperbaric oxygen treatment for paracentral acute middle maculopathy: a case study.

A 47-year-old active-duty Navy diver with a complicated past medical history which resulted in his designation as not physically qualified (NPQ) for diving duty in 2016 presented on 07 May 2021 complaining of left-sided blurred vision. On exam by the attending undersea medical officer, he was found to have a left upper inner and upper outer quadrant visual field defect and a central scotoma. Urgent referral to ophthalmology ruled out retinal detachment but resulted in an initial diagnosis of a left branch retinal artery occlusion without embolus. Considering this a variant of central retinal artery occlusion, hyperbaric oxygen (HBO2) therapy was initiated approximately 12 hours after symptom onset, resulting in complete, though temporary, resolution of the visual field defect. He reported that after completion of his first HBO2 treatment, his visual field deficit began to return, but the deficit again resolved after initiating surface oxygen therapy between HBO2 treatments. After two days of continuous surface oxygen and daily HBO2 treatments, which minimized his visual field defect, his deficits changed to a persistent left lateral peripheral defect and a recurrent central nasal defect. At this time, his periodic ophthalmology evaluation revised his diagnosis to cilioretinal artery occlusion (CrAO). Further evaluation by ophthalmology revealed retinal changes consistent with a secondary diagnosis of paracentral acute middle maculopathy (PAMM), an ophthalmologic condition only recently defined in the literature (2013) [10] secondary to advances in retinal imaging technology. This case is presented to share the findings of this complicated case and to postulate a benefit from using HBO2 for cilioretinal artery occlusion with PAMM.

A Reactivity-Based 18F-Labeled Probe for PET Imaging of Oxidative Stress in Chemotherapy-Induced Cardiotoxicity.

Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.

Detecting Validated Intracellular ROS Generation with 18F-dihydroethidine-Based PET.

PURPOSE: To determine the sensitivity of the 18F-radiolabelled dihydroethidine analogue ([18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. PROCEDURES: The sensitivity of [18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [18F]DHE (50-150 kBq.min-1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 µm), validated by parallel measures of cardiac oxidative stress. RESULTS: [18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. CONCLUSION: [18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.

Synthesis and ex vivo biological evaluation of gallium-68 labelled NODAGA chelates assessing cardiac uptake and retention.

Radiolabelled lipophilic cations can be used to non-invasively report on mitochondrial dysfunction in diseases such as cardiovascular disease, cardiotoxicity and cancer. Several such lipophilic cations are currently used clinically to map myocardial perfusion using SPECT imaging. Since PET offers significant advantages over SPECT in terms of sensitivity, resolution and the capacity for dynamic imaging to allow pharmacokinetic modelling, we have synthesised and radiolabelled a series of NODAGA-based radiotracers, with triarylphosphonium-functionalisation, with gallium-68 to develop PET-compatible cationic complexes. To evaluate their capacity to report upon mitochondrial membrane potential, we assessed their pharmacokinetic profiles in isolated perfused rat hearts before and after mitochondrial depolarisation with the ionophore CCCP. All three tracers radiolabel with over 96% RCY, with log D7.4 values above -0.4 observed for the most lipophilic example of this family of radiotracers. The candidate tracer [68Ga]Ga4c exhibited non-preferential uptake in healthy cardiac tissue over CCCP-infused cardiac tissue. While this approach does show promise, the lipophilicity of this family of probes needs improving in order for them to be effective cardiac imaging agents.

Open Dialogue, need-adapted mental health care, and implementation fidelity: A discussion paper.

Open Dialogue is a need-adapted approach to mental health care that was originally developed in Finland. Like other need-adapted approaches, Open Dialogue aims to meet consumer's needs and promote collaborative person-centred dialogue to support recovery. Need-adapted mental health care is distinguished by flexibility and responsiveness. Fidelity, defined from an implementation science perspective as the delivery of distinctive interventions in a high quality and effective fashion is a key consideration in health care. However, flexibility presents challenges for evaluating fidelity, which is much easier to evaluate when manualization and reproducible processes are possible. Hence, it remains unclear whether Open Dialogue and other need-adapted mental health interventions can be meaningfully evaluated for fidelity. The aim of this paper was to critically appraise and advance the evaluation of fidelity in need-adapted mental health care, using Open Dialogue as a case study. The paper opens a discussion about how fidelity should be evaluated in flexible, complex interventions, and identifies key questions that need to be asked by practitioners working in need-adapted mental health care to ensure they deliver these interventions as intended and in an evidence-based fashion.

The Epworth sleepiness scale: Reliably unreliable in a sleep clinic population.

The Epworth Sleepiness Scale is used frequently to measure excessive daytime sleepiness in research and clinical settings, although there is limited evidence on test-retest reliability, particularly among sleep clinic populations. The objective of this study was to evaluate the reliability of this instrument among adult patients recruited from a public hospital sleep clinic in Sydney, Australia. English-speaking participants self-completed the Epworth Sleepiness Scale on two occasions, at the specialist clinic visit and on the night of diagnostic polysomnography. Of the 108 participants included in the study, the majority were male (64%) and the mean age was 51 years. The median retest interval was 64 days. The primary outcome of test-retest reliability as measured using the intraclass correlation coefficient was 0.73 (95% confidence interval, 0.61-0.82). Despite moderate statistical reliability and a low mean difference of 1.1, Bland-Altman analysis showed an unacceptably wide distribution of between-score differences. The 95% limits of agreement were -8.5 to +10.6, and an absolute difference in scores of at least 3 was observed in 60 (56%) of the participants. Our results suggest that the Epworth Sleepiness Scale should not be used in clinical settings to make individual-level comparisons, such as the effect of therapeutic interventions, or to prioritise access to services.

Association of environmental risk factors and trachoma in Gashoho Health District, Burundi.

BACKGROUND: Burundi is currently not meeting targets for elimination of trachoma and trichiasis by 2020 (GET2020). The recommended SAFE strategy (Surgery, antibiotics, face washing and environmental improvement) is currently not fully implemented in many areas of Burundi. The existence of associations between face-washing, sanitation and trachoma prevalence remain undocumented. METHODS: A convenience sample of 468 individuals from 117 households was drawn from attendees at trachoma clinics set up in four villages. Trachoma status, sex and age were recorded for all household members. Adult household members were surveyed about access to clean water and toilets, and knowledge of trachoma risk factors. Associations between cases of active trachoma per household and environmental risk factors were evaluated using generalised estimating equations. RESULTS: The overall prevalence of active trachoma was 7.1% (95% CI 5.0-9.6%), but 19.5% (95% CI13.7-26.4%) in children under nine years old. 0.9% (95% CI 0.3-2.0) of participants had trichiasis. Access to a sanitary toilet more than halved the odds of active trachoma (OR 0.43, 95% CI 0.25-0.74%), however, participants did not appreciate this association. CONCLUSION: Access to sanitation was associated with the occurrence of active trachoma. Future research should focus on whether improving knowledge of and access to sanitation might reduce trachoma prevalence.

Detection of anthracycline-induced cardiotoxicity using perfusion-corrected 99mTc sestamibi SPECT.

By the time cardiotoxicity-associated cardiac dysfunction is detectable by echocardiography it is often beyond meaningful intervention. 99mTc-sestamibi is used clinically to image cardiac perfusion by single photon emission computed tomography (SPECT) imaging, but as a lipophilic cation its distribution is also governed by mitochondrial membrane potential (ΔΨm). Correcting scans for variations in perfusion (using a ΔΨm-independent perfusion tracer such as (bis(N-ethoxy-N-ethyldithiocarbamato)nitrido 99mTc(V)) (99mTc-NOET) could allow 99mTc-sestamibi to be repurposed to specifically report on ΔΨm as a readout of evolving cardiotoxicity. Isolated rat hearts were perfused within a γ-detection apparatus to characterize the pharmacokinetics of 99mTc-sestamibi and 99mTc-NOET in response to mitochondrial perturbation by hypoxia, ionophore (CCCP) or doxorubicin. All interventions induced 99mTc-sestamibi washout; hypoxia from 24.9 ± 2.6% ID to 0.4 ± 6.2%, CCCP from 22.8 ± 2.5% ID to -3.5 ± 3.1%, and doxorubicin from 23.0 ± 2.2% ID to 17.8 ± 0.7, p < 0.05. Cardiac 99mTc-NOET retention (34.0 ± 8.0% ID) was unaffected in all cases. Translating to an in vivo rat model, 2 weeks after bolus doxorubicin injection, there was a dose-dependent loss of cardiac 99mTc-sestamibi retention (from 2.3 ± 0.3 to 0.9 ± 0.2 ID/g with 10 mg/kg (p < 0.05)), while 99mTc-NOET retention (0.93 ± 0.16 ID/g) was unaffected. 99mTc-NOET therefore traps in myocardium independently of the mitochondrial perturbations that induce 99mTc-sestamibi washout, demonstrating proof-of-concept for an imaging approach to detect evolving cardiotoxicity.

Can a child and family health service improve early childhood health outcomes in an urban Aboriginal community?

AIMS: To describe the engagement of a cohort of urban Aboriginal families with an Early Childhood Health Service, and to assess any association of engagement with the service with screening by the Edinburgh Post-Natal Depression Scale (EPDS), full breastfeeding rates and post-natal smoking status. METHODS: Routine electronic medical record data collected by a Child and Family Health Nurse between 2011 and 2014 was analysed retrospectively. Associations between use of the service and acceptance of EPDS, breastfeeding rates and post-natal smoking status were determined using binary and multinomial multiple logistic regression analyses. RESULTS: There were 424 Aboriginal babies and 215 mothers included in the study. Each occasion of service increased the odds of accepting screening with the EPDS (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = 0.04) and complete breastfeeding (OR 1.11, CI 1.01-1.23, P = 0.04), but not of quitting smoking (OR 0.99, CI 0.96-1.02, P = 0.34). Despite accounting for engagement with the service, overall uptake of the EPDS remained low; of 267 offers for EPDS screening, only 115 were accepted (43%). CONCLUSION: The service was accessed in increasing numbers during the study period. Mothers who utilised the service more frequently were more likely to accept EPDS screening and exclusively breastfeed; however, acceptance of EPDS screening remained low overall. Further research is recommended to investigate the low acceptance of EPDS in this Aboriginal population and whether those results are transferable to other communities.

Spirituality/Religiosity (SpR), Leisure-Time Physical Activity, and Sedentary Behaviour in Students at a Catholic University.

Some studies have found an association between spirituality and/or religiosity (SpR) and cardiovascular health, for reasons which remain unclear. This study explores whether SpR is linked to physical activity whilst young, which in turn is linked to long-term cardiovascular health. Students at a Catholic University in Australia completed a survey combining the SpREUK-P SF 17 SpR questionnaire with elements of the long-form 7-day recall International Physical Activity Questionnaire. Respondents who scored highly in the unconventional spiritual practices components of SpREUK-P engaged in moderate intensity physical activity more frequently. This finding may have implications for health promotion.

Zoonotic Transmission of Waterborne Disease: A Mathematical Model.

Waterborne parasites that infect both humans and animals are common causes of diarrhoeal illness, but the relative importance of transmission between humans and animals and vice versa remains poorly understood. Transmission of infection from animals to humans via environmental reservoirs, such as water sources, has attracted attention as a potential source of endemic and epidemic infections, but existing mathematical models of waterborne disease transmission have limitations for studying this phenomenon, as they only consider contamination of environmental reservoirs by humans. This paper develops a mathematical model that represents the transmission of waterborne parasites within and between both animal and human populations. It also improves upon existing models by including animal contamination of water sources explicitly. Linear stability analysis and simulation results, using realistic parameter values to describe Giardia transmission in rural Australia, show that endemic infection of an animal host with zoonotic protozoa can result in endemic infection in human hosts, even in the absence of person-to-person transmission. These results imply that zoonotic transmission via environmental reservoirs is important.

Estimating global arthropod species richness: refining probabilistic models using probability bounds analysis.

A key challenge in the estimation of tropical arthropod species richness is the appropriate management of the large uncertainties associated with any model. Such uncertainties had largely been ignored until recently, when we attempted to account for uncertainty associated with model variables, using Monte Carlo analysis. This model is restricted by various assumptions. Here, we use a technique known as probability bounds analysis to assess the influence of assumptions about (1) distributional form and (2) dependencies between variables, and to construct probability bounds around the original model prediction distribution. The original Monte Carlo model yielded a median estimate of 6.1 million species, with a 90 % confidence interval of [3.6, 11.4]. Here we found that the probability bounds (p-bounds) surrounding this cumulative distribution were very broad, owing to uncertainties in distributional form and dependencies between variables. Replacing the implicit assumption of pure statistical independence between variables in the model with no dependency assumptions resulted in lower and upper p-bounds at 0.5 cumulative probability (i.e., at the median estimate) of 2.9-12.7 million. From here, replacing probability distributions with probability boxes, which represent classes of distributions, led to even wider bounds (2.4-20.0 million at 0.5 cumulative probability). Even the 100th percentile of the uppermost bound produced (i.e., the absolutely most conservative scenario) did not encompass the well-known hyper-estimate of 30 million species of tropical arthropods. This supports the lower estimates made by several authors over the last two decades.

Fixed sized samples for type-specific surveillance of human papillomavirus in genital warts.

Surveillance data suggest that human papillomavirus (HPV) vaccination in Australia is reducing the incidence of genital warts. However, existing surveillance measures do not assess the proportion of the remaining cases of warts that are caused by HPV types other than 6 or 11, against which the vaccine has no demonstrated effectiveness. Using computer simulation rather than sample size formulae, we established that genotyping at least 60 warts can accurately test whether the proportion of warts due to HPV types not targeted by the vaccine has increased (Type I error probability ≤ 0.05, Type II error probability <0.07). Standard formulae for calculating sample size, in contrast, suggest that a sample size of more than 130 would be required for this task, but using these formulae entails making several strong assumptions. Our methods require fewer assumptions and demonstrate that a smaller sample size than anticipated could be used to address the question of what proportion of post-vaccination cases of warts are due to nonvaccine types. In conjunction with indications of incidence and prevalence provided by existing surveillance measures, this could indicate the number of cases of post-vaccination warts due to nonvaccine types and hence whether type replacement is occurring.

Tracking type specific prevalence of human papillomavirus in cervical pre-cancer: a novel sampling strategy.

BACKGROUND: Surveillance designed to detect changes in the type-specific distribution of HPV in cervical intraepithelial neoplasia grade 3 (CIN-3) is necessary to evaluate the effectiveness of the Australian vaccination programme on cancer causing HPV types. This paper develops a protocol that eliminates the need to calculate required sample size; sample size is difficult to calculate in advance because HPV's true type-specific prevalence is imperfectly known. METHOD: A truncated sequential sampling plan that collects a variable sample size was designed to detect changes in the type-specific distribution of HPV in CIN-3. Computer simulation to evaluate the accuracy of the plan at classifying the prevalence of an HPV type as low (< 5%), moderate (5-15%), or high (> 15%) and the average sample size collected was conducted and used to assess its appropriateness as a surveillance tool. RESULTS: The plan classified the proportion of CIN-3 lesions positive for an HPV type very accurately, with >90% of simulations correctly classifying a simulated data-set with known prevalence. Misclassifying an HPV type of high prevalence as being of low prevalence, arguably the most serious kind of potential error, occurred < 0.05 times per 100 simulations. A much lower sample size (21-22 versus 40-48) was required to classify samples of high rather than low or moderate prevalence. CONCLUSIONS: Truncated sequential sampling enables the proportion of CIN-3 due to an HPV type to be accurately classified using small sample sizes. Truncated sequential sampling should be used for type-specific HPV surveillance in the vaccination era.

Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research.

BACKGROUND: There is conflicting information as to whether antiretroviral drugs with better central nervous system (CNS) penetration (neuroHAART) assist in improving neurocognitive function and suppressing cerebrospinal fluid (CSF) HIV RNA. The current review aims to better synthesise existing literature by using an innovative two-phase review approach (qualitative and quantitative) to overcome methodological differences between studies. METHODS: Sixteen studies, all observational, were identified using a standard citation search. They fulfilled the following inclusion criteria: conducted in the HAART era; sample size > 10; treatment effect involved more than one antiretroviral and none had a retrospective design. The qualitative phase of review of these studies consisted of (i) a blind assessment rating studies on features such as sample size, statistical methods and definitions of neuroHAART, and (ii) a non-blind assessment of the sensitivity of the neuropsychological methods to HIV-associated neurocognitive disorder (HAND). During quantitative evaluation we assessed the statistical power of studies, which achieved a high rating in the qualitative analysis. The objective of the power analysis was to determine the studies ability to assess their proposed research aims. RESULTS: After studies with at least three limitations were excluded in the qualitative phase, six studies remained. All six found a positive effect of neuroHAART on neurocognitive function or CSF HIV suppression. Of these six studies, only two had statistical power of at least 80%. CONCLUSIONS: Studies assessed as using more rigorous methods found that neuroHAART was effective in improving neurocognitive function and decreasing CSF viral load, but only two of those studies were adequately statistically powered. Because all of these studies were observational, they represent a less compelling evidence base than randomised control trials for assessing treatment effect. Therefore, large randomised trials are needed to determine the robustness of any neuroHAART effect. However, such trials must be longitudinal, include the full spectrum of HAND, ideally carefully control for co-morbidities, and be based on optimal neuropsychology methods.

Unresolved questions concerning human papillomavirus infection and transmission: a modelling perspective.

Mathematical transmission models are widely used to forecast the potential impact of interventions such as vaccination and to inform the development of health policy. Effective vaccines are now available for the prevention of cervical cancer and other diseases attributable to human papillomavirus (HPV). Considerable uncertainties remain regarding the characterisation of HPV infection and its sequelae, infectivity, and both vaccine-conferred and naturally-acquired immunity. In this review, we discuss the key knowledge gaps that impact on our ability to develop accurate models of HPV transmission and vaccination.