Sonothrombolysis before and after percutaneous coronary intervention provides the largest myocardial salvage in ST-segment Elevation Myocardial Infarction.

BACKGROUND: Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation Myocardial Infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increase infarct vessel patency, improve microvascular flow, reduce infarct size, and improve ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel three-arm sham-controlled randomised controlled trial to address this. METHODS: Patients presenting with first STEMI undergoing pPCI within six hours of symptom onset were randomised 1:1:1 into three arms: sonothrombolysis pre/post pPCI (Group 1), Sham pre & sonothrombolysis post pPCI (Group 2), and Sham pre/post pPCI (Group 3). Our primary endpoint was infarct size (% LV mass) assessed by Cardiac MRI at day 4±2. Secondary endpoints included myocardial salvage index (MSI) and echocardiographic parameters at Day 4±2 and six months. RESULTS: Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (Age 60, male 82%) were included post randomisation. Median sonothrombolysis took 5 minutes pre pPCI and 15 minutes post, without significant door-to-balloon delay. There was a trend towards reduction in median infarct size between Group 1 (8%[IQR 4,11]), Group 2 (11%[7,19]) or Group 3 (15%[9,22]). Similarly there was a trend towards improved MSI in Group 1 (79%[64,85]) compared to Groups 2 (51%[45,70]) and 3 (48%[37,73]) No major adverse cardiac events occurred during hospitalization. CONCLUSION: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicentre trials and health economic analyses are required before clinical translation.

Development and validation of observational and qualitative study protocol reporting checklists for novice researchers (ObsQual checklist).

INTRODUCTION: Currently, no reporting guidelines exist for observational and qualitative study protocols. In an effort to enhance the quality of research protocols, we introduce two study protocol reporting checklists that we have developed. MAIN RECOMMENDATIONS: These checklists include educational components and examples intended to assist novice researchers. Through the analysis of 333 study protocols submitted for ethical review, our checklists have been developed and validated, demonstrating their applicability across various observational and qualitative study designs. CHANGES IN MANAGEMENT: We provide insights into the systematic implementation of these checklists alongside complementary elements that support their effectiveness. We recommend longitudinal monitoring and evaluation of checklist utilization.

Beyond the median: Estimating survival times for patients starting endocrine therapy for estrogen receptor-positive, metastatic breast cancer from recent randomized trials.

AIM: To estimate scenarios for survival for patients with estrogen receptor (ER) positive, metastatic breast cancer (MBC) and to help communicate prognosis to patients starting endocrine therapy (ET) METHODS: We searched for randomized trials of ET for ER-positive MBC and extracted the following percentiles (representative survival scenarios) from each overall survival (OS) curve: 90th (worst-case), 75th (lower-typical), 50th (median), 25th (upper-typical), and 10th (best-case). We then assessed the accuracy of estimating these percentiles for each OS curve by multiplying the median OS by four simple multiples: 0.25 (to estimate the 90th percentile), 0.5 (75th), 2 (25th), and 3 (10th). Estimates were deemed accurate if it fell within 0.75-1.33 times the actual value. RESULTS: We identified 25 trials with 10,566 patients. The median OS (interquartile range) was: 61.3 months (53.4-64.8) for first-line ET with cyclin-dependant kinase 4/6 inhibitors (four treatment groups); 42.6 months (40.9-50.4) for first-line ET alone (21 treatment groups) and 29.2 months (24.8-33.4) for subsequent line ET (19 treatment groups). Simple multiples of the median OS accurately estimated the 90th percentile in 80%; 75th percentile in 93%; and 25th percentile in 76% of curves. The 10th percentile was only available for four OS curves and could not be evaluated. CONCLUSION: Simple multiples of the median OS are a helpful and accurate method to assist in estimating and discussing scenarios for survival for MBC patients starting ET. Longer follow-up of trials is required to help clinicians estimate the best-case scenario.

Maternal and neonatal health outcomes for First Nations Australian women and children: A retrospective cohort study in a Western Sydney metropolitan tertiary referral centre.

AIM: To analyse key pregnancy and birth outcomes for First Nations women and children at a Western Sydney metropolitan tertiary referral centre. METHODS: The birth and health-determining characteristics of 470 First Nations infants born at Nepean Hospital in 2018 and their mothers were included in a retrospective audit and compared with a contemporaneous control group of 470 infants and their mothers. RESULTS: Mothers of First Nations infants had significantly higher rates of socioeconomic disadvantage (P < 0.001), psychosocial vulnerability (P < 0.007), mental illness (P < 0.001), teenage pregnancy (P < 0.001), smoking (45.6% vs. 19.4%, P < 0.001) and drug and alcohol use than control mothers (P < 0.001, P < 0.048). First Nations peoples did not have increased rates of maternal morbidity, nor any difference in rates of Caesarean section, resuscitation at birth, NICU admission, preterm birth or low birth weight in multivariable analysis. However, multivariable analysis demonstrated significant associations between low birth weight and maternal smoking (P < 0.001), hypertension (P < 0.01) and drug use (P < 0.01). CONCLUSIONS: Despite challenges facing First Nations mothers and infants, our study found no significant difference in maternal morbidity nor adverse birth outcomes for First Nations infants. The study occurred in the context of culturally specific, First Nations-led antenatal and infant services. Future studies should further investigate relationships between participation in these services and health outcomes. This could identify strengths and areas for improvement in current services, with the goal of further improving outcomes for First Nations peoples through targeted health services that address their psychosocial vulnerabilities and support women to make healthy choices during pregnancy.

Intrafraction Imaging Can Replace the Midtreatment Cone Beam Tomography for Lung Stereotactic Ablative Radiation Therapy Patients for Increased Treatment Efficiency.

Purpose: To determine the feasibility of replacing the mid treatment cone beam computed tomography (MT CBCT) image with Intrafraction Imaging (IFI) acquired concurrently during dose delivery in lung Stereotactic Ablative Body Radiation therapy (SABR) patients, and thus improve treatment efficiency. Methods and Materials: A review of departmental imaging data was performed on ten lung SABR patients treated with dual arc volumetric modulated arc therapy (VMAT) on an Elekta Versa HD linear accelerator with XVI imaging software.IFI data was extracted and a database of the translational (TX, TY, TZ) and the rotational (RX, RY, RZ) position errors was created for retrospective comparison, with the values of the MT CBCT for the same patients, treated between March 2021 and March 2022 at our center. The data was evaluated for correlation between the values in all 6° of freedom. Results: The inter-class correlation (ICC) coefficient for Tx was 0.89 (95% CI, 0.80-0.94), Ty was 0.69 (95% CI, 0.49-0.82), Tz was 0.89 (95% CI, 0.82-0.95) in the translational planes, and Rx was 0.79 (95% CI, 0.65-0.88), Ry was 0.79 (95% CI, 0.65-0.88), and Rz was 0.91 (95% CI, 0.84-0.95) in rotational planes.The Bland-Altman (BA) statistics for Tx had a bias of -1.22 × 10-3, with an upper limit of agreement (UOA) of 0.07, and a lower limit of agreement (LOA) of -0.07, for Ty the bias was 0.01 (UOA: 0.18; LOA: -0.16), Tz bias was 2.6 × 10-3(UOA: 0.10; LOA: -0.09), Rx bias was 0.09 (UOA: 0.82; LOA: -0.64), Ry bias was -0.04 (UOA: 1.08; LOA: -1.16) and Rz was -0.03 (UOA: 0.44; LOA: -0.51). Conclusions: The ICC was excellent for Tx, Tz, Rx, y, z, and good for Ty. The data demonstrated promising correlation between IFI and MT CBCT values, and therefore supports the use of IFI for clinical decision making and improving treatment efficiency.

Prophylaxis to Prevent Cardiotoxicity in Patients Receiving Anthracycline for Breast Cancer: A Combined Bayesian and Frequentist Network Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: The benefits in survivorship gained with anthracycline (ANT)-based chemotherapies for breast cancer are unfortunately mitigated for some patients by irreversible cardiotoxicity. Randomised controlled trials (RCTs) have explored multiple cardioprotection options, however, it remains unclear which drug is most effective in preserving left ventricular ejection fraction (LVEF). This study aimed to perform a systematic review and network meta-analysis, using Bayesian and frequentist approaches, of RCTs evaluating cardioprotective agents. METHODS: Two authors searched four databases (CENTRAL, Cochrane Reviews, MEDLINE, SCOPUS), to find RCTs evaluating cardioprotective agents. Trial populations were limited to patients with breast cancer without prior ANT exposure. The primary outcome was mean LVEF change pre and post ANT dosing. Our primary analysis utilised a Bayesian approach, while our sensitivity analysis used frequentist methodology (Prospero registration number CRD42020199580). RESULTS: From 4,007 search results, we identified 12 RCTs, with their various trial arms considered separately-nine beta-blocker (BB), two angiotensin-converting enzyme inhibitor /angiotensin receptor blockers [(AA)+BB=AABB], one AA, one spironolactone, one statin-evaluating 1,126 patients (age 50.5 years). Bayesian network meta-analysis showed no difference in LVEF preservation between AA (1.3%, 95% credible interval [-0.20, 2.9]), BB (0.77, [-0.21, 1.8]), AABB (0.84 [-1.1, 2.8]), spironolactone (0.72, [-2.3, 3.7]) or statin (0.60, [-2.4, 3.6]) when compared against placebo. However, the frequentist analysis showed benefits from using AA (mean difference, 1.32% [0.32, 2.33]) and BB (mean difference, 0.76% [0.12, 1.4]). CONCLUSIONS: There is insufficient evidence to support prophylactic cardioprotection to prevent EF reduction. However, frequentist analysis suggested that AA or BBs provide cardioprotection. Thus, for those already on other anti-hypertensives, switching to AA or BBs could be considered.

Sex differences in risk factors for incident peripheral artery disease hospitalisation or death: Cohort study of UK Biobank participants.

BACKGROUND: Women with peripheral artery disease (PAD) often have atypical symptoms, late hospital presentations, and worse prognosis. Risk factor identification and management are important. We assessed sex differences in associations of risk factors with PAD. METHODS: 500,207 UK Biobank participants (54.5% women, mean age 56.5 years) without prior hospitalisation of PAD at baseline were included. Examined risk factors included blood pressure, smoking, diabetes, lipids, adiposity, history of stroke or myocardial infarction (MI), socioeconomic status, kidney function, C-reactive protein, and alcohol consumption. Poisson and Cox regressions were used to estimate sex-specific incidence of PAD hospitalisation or death, hazard ratios (HRs), and women-to-men ratios of HRs (RHR) with confidence intervals (CIs). RESULTS: Over a median of 12.6 years, 2658 women and 5002 men had a documented PAD. Age-adjusted incidence rates were higher in men. Most risk factors were associated with a higher risk of PAD in both sexes. Compared with men, women who were smokers or had a history of stroke or MI had a greater excess risk of PAD (relative to those who never smoked or had no history of stroke or MI): RHR 1.18 (95%CI 1.04, 1.34), 1.26 (1.02, 1.55), and 1.50 (1.25, 1.81), respectively. Higher high-density lipoprotein cholesterol (HDL-C) was more strongly associated with a lower risk of PAD in women than men, RHR 0.81 (0.68, 0.96). Compared to HDL-C at 40 to 60 mg/dL, the lowest level of HDL-C (≤40 mg/dL) was related to greater excess risk in women, RHR 1.20 (1.02, 1.41), whereas the highest level of HDL-C (>80 mg/dL) was associated with lower risk of PAD in women, but higher risk in men, RHR 0.50 (0.38, 0.65). CONCLUSIONS: While the incidence of PAD was higher in men, smoking and a history of stroke or MI were more strongly associated with a higher risk of PAD in women than men. HDL-C was more strongly associated with a lower risk of PAD in women than men.

Efficacy of preoxygenation administration in volunteers, in extending the end-expiration breath-hold duration for application to abdominal radiotherapy.

Background and purpose: End expiration breath hold (EEBH) is the preferred motion management method for abdominal Stereotactic Ablative Body Radiotherapy (SABR) treatments. However, multiple short EEBHs are required to complete a single treatment session. The study aimed to determine the efficacy of preoxygenation with hyperventilation in extending an EEBH duration. Materials and methods: We randomised 10 healthy participants into two arms, each included breathing room air and oxygen at a rate of 10 L per minute (l/min) without hyperventilation for four minutes, and normally for four minutes and with hyperventilation for one minute at a rate of 20 breaths/minute for hyperventilation. The type of gas was blinded from the participants for each test. EEBH durations were then recorded, as well as systolic blood pressure, SpO2 and heart rate. A discomfort rating was also recorded after each breath hold. Results: A significant increase in duration of almost 50% was observed between normal breathing of room air and breathing oxygen normally followed by hyperventilation. Vital signs remained consistent between the 4 tests. The tests were well tolerated with 75% of participants recording none or minimal discomfort. Conclusion: Preoxygenation with hyperventilation could be used to increase the EEBH duration for abdominal SABR patients which would assist in the accuracy of these treatments and possibly resulting in a reduction of overall treatment times.

Kidney Adverse Events Associated with Immune Checkpoint Inhibitor Therapy: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: The blockade of immune regulatory sites, CTLA-4, PD-1, and PD-L1 with Immune Checkpoint Inhibitors has revolutionized survival outcomes in cancer patients. However, immune checkpoint inhibitors are associated with a range of immune related adverse events. The aim of this network meta-analysis is to evaluate severe adverse kidney events in patients with oncological or hematological malignancy receiving monotherapy, dual therapy or combined therapy treatment with immune checkpoint inhibitors when compared to either placebo or standard chemotherapy. METHODS: Phase III Randomized Control Trials reporting severe grade (3-5) adverse kidney events were identified across five electronic databases from inception to May 2022. This was supplemented with hand searching of medical journals and the National Clinical Trials registry. A Bayesian network meta-analysis was performed for: acute kidney injury, hypertension, chronic kidney disease and the composite of all acute kidney adverse events. The results are reported as per PRISMA guidelines. RESULTS: 95 randomized control trials reported severe grade adverse kidney events. The risk of developing severe acute kidney injury is higher among patients who received PD-1 plus chemotherapy (OR 1.8 [95% CrI 1.4 to 2.5]) and PD-L1 plus chemotherapy (OR 1.80 [95% CrI 1.2 to 2.7]) compared to standard chemotherapy and placebo (94 studies, 63, 357 participants). The risk of developing the composite of all severe acute kidney adverse events is higher among patients who received PD-1 plus chemotherapy (OR 1.6 [95% CrI 1.1 to 2.3]) and PD-L1 plus chemotherapy (OR 1.7 [95% CrI 1.1 to 2.8) when compared to standard chemotherapy and placebo (95 studies, 63, 973 participants). CONCLUSIONS: The combined regimen of PD-1 + chemotherapy and PD-L1 + chemotherapy was associated with higher incidence of severe acute kidney injury and the composite of all severe acute kidney adverse events.

Sex differences in long-term survival after intensive care unit treatment for sepsis: A cohort study.

OBJECTIVE: To determine the effect of sex on sepsis-related ICU admission and survival for up to 3-years. METHODS: Retrospective cohort study of adults admitted to Australian ICUs between 2018 and 2020. Men and women with a primary diagnosis of sepsis were included. The primary outcome of time to death for up to 3-years was examined using Kaplan Meier plots. Secondary outcomes included the duration of ICU and hospital stay. RESULTS: Of 523,576 admissions, there were 63,039 (12·0%) sepsis-related ICU admissions. Of these, there were 50,956 patients (43·4% women) with 3-year survival data. Men were older (mean age 66·5 vs 63·6 years), more commonly received mechanical ventilation (27·4% vs 24·7%) and renal replacement therapy (8·2% vs 6·8%) and had worse survival (Hazard Ratio [HR] 1·11; 95% Confidence Interval [CI] 1·07 to 1·14, P<0·001) compared to women. The duration of hospital and ICU stay was longer for men, compared to women (median hospital stay, 9.8 vs 9.4 days; p<0.001 and ICU stay, 2.7 vs 2.6 days; p<0.001). CONCLUSION: Men are more likely to be admitted to ICU with sepsis and have worse survival for up to 3-years. Understanding causal mechanisms of sex differences may facilitate the development of targeted sepsis strategies.

Intentional paediatric poisoning presentations to emergency departments during the COVID-19 pandemic.

OBJECTIVE: To characterise paediatric poisoning presentations to EDs and determine if the advent of the COVID-19 pandemic was associated with increased intentional paediatric poisoning presentations. METHODS: We performed a retrospective analysis of paediatric poisoning presentations to three EDs (two regional and one metropolitan). Simple and multiple logistic regression analysis were performed to determine the association between COVID-19 and intentional poisoning events. In addition, we calculated the frequency with which patients reported various psychosocial risk factors as being an implicating factor in engaging in an intentional poisoning event. RESULTS: A total of 860 poisoning events met inclusion criteria during the study period (January 2018-October 2021), with 501 being intentional, and 359 unintentional. There was an increased proportion of intentional poisoning presentations during the COVID-19 pandemic (261 intentional and 218 unintentional in the pre-COVID-19 period vs 241 intentional and 140 unintentional during the COVID-19 period). In addition, we found a statistically significant association between intentional poisoning presentations and an initial COVID-19 lockdown (adjusted odds ratio 26.32, P < 0.05). 'The COVID-19 lockdown' or 'COVID-19' was reported to be implicating factor for psychological stress in patients who presented with intentional poisonings during the COVID-19 pandemic. CONCLUSIONS: Intentional paediatric poisoning presentations increased during the COVID-19 pandemic in our study population. These results may support an emerging body of evidence that the psychological strain of COVID-19 disproportionately impacts adolescent females.

Juvenile otosclerosis and congenital stapes footplate fixation. A systematic review and meta-analysis of surgical outcomes and management.

OBJECTIVE: Juvenile Otosclerosis (JO) and Congenital Stapes Footplate Fixation (CSFF) are rare ossicular chain disorders seen in the paediatric population and present with conductive hearing loss. Ongoing controversy exists regarding the role of surgical intervention in JO and CSFF given the poorer hearing outcomes and complications when compared with surgical intervention for adult otosclerosis. The objective of this study is to assess the published data on the surgical outcomes of JO and CSFF in order to guide clinicians and counsel patients on the various medical options for these disease entities. METHODS: A systematic review of MEDLINE, EMBASE and Cochrane was performed with inclusion criteria of children with JO or CSFF and hearing outcomes following stapes surgery. Studies identified by the search were reviewed and assessed by two independent reviewers in line with the PRISMA guidelines. RESULTS: 464 articles were initially reviewed and 28 articles met inclusion in the systematic review and meta-analysis. A total of 810 ears (473 and 337 cases of JO and CSFF respectively) underwent stapes surgery. Average age at time of surgery for JO and CSFF was 14.3 and 10.2 years old respectively. The mean pre-operative Air-Bone-Gap (ABG) for JO and CSFF was 31.8 ± 5.2 dB and 39.4 ± 10 dB respectively. Following stapes surgery, the mean post-operative ABG for JO and CSFF was 9.6 ± 6 dB and 19.2 ± 12.5 dB respectively. Surgical success rate (defined as ABG <10 dB) was 81% for JO and 41% for CSFF. Mean ABG gain for JO and CSFF was 24.8 dB (95% CI: 18.6-33.1) and 22.6 dB (95% CI: 18.4-27.8) respectively. The reported number of dead ears was 4/473 (0.8%) for JO and 2/337 (0.6%) for CSFF. 23 cases (2.8%) reported sensorineural hearing loss (SNHL) >10 dB. CONCLUSION: CSFF was associated with poorer hearing outcomes compared to JO, however both entities showed similar improvement in ABG post operatively. Counselling patients and their families on the surgical success rates and complications of JO or CSFF is an important part of the decision making process when deciding between a surgical option or conservative measures such as hearing aids.

Routine blood parameters of dengue infected children and adults. A meta-analysis.

The World Health Organization (WHO) has revised dengue case classification in 2009 to better reflect the severity of the disease. However, there was no comprehensive meta-analysis of pooled routine blood parameters according to the age or the categories of the 2009 WHO classification. This study aimed to meta-analyze the routine blood parameters of dengue infected children and adults. Electronic search was performed with eligible articles included for review. Meta-analysis was conducted for six blood parameters stratified into children, adults and all ages, which were further grouped into the three 2009 WHO case classifications (dengue without warning signs, DwoWS; dengue with warning signs, DwWS; severe dengue, SD), non-severe dengue (non-SD) and 'All' cases. A total of 55 articles were included in the meta-analysis. Fifteen studies were conducted in the children's age category, 31 studies in the adult category and nine studies in all ages. The four selected pooled blood parameters for children were white blood cell (WBC) (×103/L) with 5.11 (SD), 5.64 (DwWS), 5.52 (DwoWS) and 4.68 (Non-SD) hematocrit (HCT) (%) with 36.78 (SD), 40.70 (DwWS), 35.00 (DwoWS) and 29.78 (Non-SD) platelet (PLT) (×103/µL) with 78.66 (SD), 108.01 (DwWS), 153.47 (DwoWS) and 108.29 (non-SD); and aspartate aminotransferase (AST) (/µL) with 248.88 (SD), 170.83 (DwWS), 83.24 (DwoWS) and 102.99 (non-SD). For adult, WBC were 4.96 (SD), 6.44 (DwWS), 7.74 (DwoWS) and 3.61 (non-SD); HCT were 39.50 (SD), 39.00 (DwWS), 37.45 (DwoWS) and 41.68 (non-SD); PLT were 49.62 (SD), 96.60 (DwWS), 114.37 (DwoWS) and 71.13 (non-SD); and AST were 399.50 (SD), 141.01 (DwWS), 96.19 (DwoWS) and 118.13 (non-SD). These blood parameters could not differentiate between each dengue severity according to the WHO 2009 classification, SD, DwoWS, DwWS and non-SD, because the timing of blood drawing was not known and there was an overlapping confidence interval among the clinical classification. Hence, these pooled blood parameter values could not be used to guide clinicians in management and did not correlate with severity as in previous scientific literatures and guidelines.

Obstetric risk factors for anal sphincter trauma in a urogynecological population.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter tears are the single major modifiable risk factor for anal incontinence (AI) in women. We undertook a retrospective observational study in a tertiary urogynecology unit to describe the prevalence of sonographic anal sphincter defects in a urogynecological population and investigate obstetric risk factors. METHODS: Files of women seen for investigation of pelvic floor disorders between January 2014 and May 2021 were reviewed. Sonographic defects of the external anal sphincter were analyzed using stored 4D ultrasound imaging data. Explanatory parameters were number of vaginal births, delivery mode, age at first vaginal birth, and birthweight of the first vaginally born baby. RESULTS: Of 3,037 women seen during the inclusion period, data were missing in 219, leaving 2,818. AI was reported by 508 (18%), with a mean St Marks score of 11 (1-23) and a mean bother score of 5.9 (0-10). External sphincter defects were detected in 945 women (34%), with a "residual defect" in 343 (12%). The strongest risk factors for a residual defect were first vaginal birth and forceps, with higher-order multiparity adding risk. On multivariate analysis, forceps and vaginal parity >5 remained significant predictors, as opposed to age at first birth and birthweight of the firstborn. CONCLUSIONS: In this observational study in urogynecological patients, 12% showed a residual EAS defect on imaging. The most obvious risk factors for the diagnosis of a residual defect on exo-anal imaging were the first vaginal birth and forceps, with higher-order vaginal parity conveying additional risk.

Regional tissue oxygenation and conventional indicators of red blood cell transfusion in anaemic preterm infants.

Background: It is unresolved whether low haemoglobin (Hb) and symptoms of anaemia reflect oxygen delivery-consumption imbalances (fractional tissue oxygen extraction [FTOE]). Here, we test whether pre-transfusion Hb and symptoms of anaemia correlate with pre-transfusion cerebral and splanchnic FTOE. Methods: This prospective cohort study was carried out between Sept 1, 2014 and Nov 30, 2016 at Nepean Hospital, Sydney, Australia. The study enroled haemodynamically stable preterm infants: gestation <32 weeks; birth weight <1500 gs; postmenstrual age <37weeks, who received 15 mL/kg packed red blood cell transfusion (PRBCT) based on low Hb and symptoms of anaemia. FTOE was determined using simultaneous monitoring of near-infrared spectroscopy and pulse oximetry for 4 h before PRBCT. Findings: The study enroled 29 infants born with a median gestation of 26.4 weeks (IQR 25.4-28.1), birth weight 922 g (655-1064), at postmenstrual age 33.6 weeks (31.7-34.9), and weight 1487 g (1110-1785). There was no significant correlation between Hb (median 97 g/L, IQR 87-100) and cerebral FTOE (r=-0.12, 95% CI -0.47 to 0.27; p = 0.54, n = 29) as well as splanchnic FTOE (r=-0.09, 95% CI -0.45 to 0.29; p = 0.64, n = 29). Median cerebral FTOE (p = 0.67) and splanchnic FTOE (p = 0.53) did not differ between symptomatic and asymptomatic groups. Interpretation: Our preliminary findings suggest that pre-transfusion Hb and symptoms of anaemia might not accurately reflect oxygen delivery-consumption imbalances in both the brain and the gut. A lack of correlation with cerebral FTOE might be presumed to be due to the brain-sparing effect. However, the lack of correlation with splanchnic FTOE is more concerning. Hence, these results warrant larger studies incorporating FTOE along with the conventional criteria in the transfusion algorithm. Funding: The study was funded (for the purchase of NIRS sensors) by the Australian Women and Children's Research Foundation.

Diagnostic accuracy of genetic markers and nucleic acid techniques for the detection of Leptospira in clinical samples: A meta-analysis.

BACKGROUND: Leptospirosis is often difficult to diagnose because of its nonspecific symptoms. The drawbacks of direct isolation and serological tests have led to the increased development of nucleic acid-based assays, which are more rapid and accurate. A meta-analysis was performed to evaluate the diagnostic accuracy of genetic markers for the detection of Leptospira in clinical samples. METHODOLOGY AND PRINCIPLE FINDINGS: A literature search was performed in Scopus, PubMed, MEDLINE and non-indexed citations (via Ovid) by using suitable keyword combinations. Studies evaluating the performance of nucleic acid assays targeting leptospire genes in human or animal clinical samples against a reference test were included. Of the 1645 articles identified, 42 eligible studies involving 7414 samples were included in the analysis. The diagnostic performance of nucleic acid assays targeting the rrs, lipL32, secY and flaB genes was pooled and analyzed. Among the genetic markers analyzed, the secY gene showed the highest diagnostic accuracy measures, with a pooled sensitivity of 0.56 (95% CI: 0.50-0.63), a specificity of 0.98 (95% CI: 0.97-0.98), a diagnostic odds ratio of 46.16 (95% CI: 6.20-343.49), and an area under the curve of summary receiver operating characteristics curves of 0.94. Nevertheless, a high degree of heterogeneity was observed in this meta-analysis. Therefore, the present findings here should be interpreted with caution. CONCLUSION: The diagnostic accuracies of the studies examined for each genetic marker showed a significant heterogeneity. The secY gene exhibited higher diagnostic accuracy measures compared with other genetic markers, such as lipL32, flaB, and rrs, but the difference was not significant. Thus, these genetic markers had no significant difference in diagnostic accuracy for leptospirosis. Further research into these genetic markers is warranted.

Diagnostic accuracy and predictive value in differentiating the severity of dengue infection.

OBJECTIVE: To review the diagnostic test accuracy and predictive value of statistical models in differentiating the severity of dengue infection. METHODS: Electronic searches were conducted in the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE (complete), PubMed and Scopus. Eligible studies to be included in this review were cohort studies with participants confirmed by laboratory test for dengue infection and comparison among the different severity of dengue infection by using statistical models. The methodological quality of the paper was assessed by independent reviewers using QUADAS-2. RESULTS: Twenty-six studies published from 1994 to 2017 were included. Most diagnostic models produced an accuracy of 75% to 80% except one with 86%. Two models predicting severe dengue according to the WHO 2009 classification have 86% accuracy. Both of these logistic regression models were applied during the first three days of illness, and their sensitivity and specificity were 91-100% and 79.3-86%, respectively. Another model which evaluated the 30-day mortality of dengue infection had an accuracy of 98.5%. CONCLUSION: Although there are several potential predictive or diagnostic models for dengue infection, their limitations could affect their validity. It is recommended that these models be revalidated in other clinical settings and their methods be improved and standardised in future.

OBJECTIF: Analyser la précision des tests de diagnostic et la valeur prédictive des modèles statistiques pour différencier la sévérité de l'infection par la dengue. MÉTHODES: Des recherches électroniques ont été effectuées dans la base de données de revues systématiques Cochrane, le registre central des essais contrôlés Cochrane, MEDLINE (complète), PUBMED et Scopus. Les études éligibles à inclure dans cette revue étaient des études de cohorte avec des participants confirmés par un test de laboratoire pour l'infection par la dengue et une comparaison entre les différentessévérités de l'infection par la dengue à l'aide de modèles statistiques. La qualité méthodologique des articles a été évaluée par des scientifiques indépendants à l'aide de QUADAS-2. RÉSULTATS: 26 études publiées de 1994 à 2017 ont été incluses. La plupart des modèles de diagnostic ont produit une précision de 75% à 80%, sauf un avec 86%. Selon la classification de l'OMS 2009, deux modèles prédisant la dengue sévère présentent une précision de 86%. Ces deux modèles de régression logistique ont été appliqués au cours des trois premiers jours de la maladie. Leur sensibilité et leur spécificité étaient respectivement de 91% à 100% et de 79,3% à 86%. Un autre modèle évaluant la mortalité à 30 jours de la dengue présentait une précision de 98,5%. CONCLUSION: Bien qu'il existe plusieurs modèles prédictifs ou diagnostiques potentiels de l'infection par la dengue, leurs limites pourraient affecter leur validité. Il est recommandé que ces modèles soient revalidées dans d'autres milieux cliniques et leurs méthodes améliorées et normalisées dans le futur.

Predictive and diagnostic test accuracy of ultrasonography in differentiating severe dengue from nonsevere dengue.

Diagnosing severe dengue from those who do not develop complication is important to prevent death. The objective of this systematic review was to evaluate the diagnostic test accuracy of ultrasonography in differentiating severe dengue from nonsevere dengue; and to assess if ultrasonography/ultrasound can be used as a predictive (screening) and diagnostic tool in the course of dengue infection. An electronic search was conducted in different databases via OvidSP platform. The included studies were cohort studies between 1995 and 2016 wherein cases were confirmed by dengue blood test. Severity of dengue was assessed and compared using standard WHO references. The methodological quality of the paper was assessed by two independent reviewers by using QUADAS-2 tool. In total 12 studies were included in this review after suitable screening. Overall, the studies included had a low and unclear risk of bias. Seven out of nine studies that compared severe dengue and nonsevere dengue, performed an ultrasonography on gallbladder (wall thickness cutoff-3 mm) with a sensitivity of 24.2-100% and a specificity of 13.2-98.7%. Other parameters such as splenic subcapsular fluid collection, pericardial fluid and hepatic subcapsular fluid collection had a specificity of >90%, though the sensitivity was poor. There were insufficient evidence that ultrasonography is able to differentiate severe dengue from nonsevere dengue accurately. The predictive and diagnostic value of ultrasonography could not be concluded due to insufficient reporting on the temporality of the ultrasonography performed with regard to the diagnosis. However, it might serve as an adjunct investigation to support the clinical diagnosis.

The predictive and diagnostic accuracy of vascular endothelial growth factor and pentraxin-3 in severe dengue.

This study aimed to evaluate vascular endothelial growth factor (VEGF) and pentraxin 3 (PTX-3) as predictive and diagnostic markers in differentiating severe dengue from non-severe dengue. The study was conducted in Ampang Health Clinic, Ampang Hospital and Serdang Hospital. The plasma levels of VEGF and PTX-3 were compared between severe dengue and non-severe dengue by ELISA from the day of presentation until discharged. Multiple logistic regression was used to develop predictive and diagnostic models by incorporating other clinical parameters. The receiver operating characteristics (ROC) analysis was used to assess the accuracy of the biomarkers and the developed models. Eighty-two patients were recruited, 29 with severe dengue and four died. The Area Under the Curve (AUC) was statistically significant in VEGF as diagnostic marker at Day 2 and 3 of illness with sensitivity of 80.00%-100.00% and specificity of 76.47%-80.00%. The predictive model with AUC of 0.84 (p < 0.01) has a sensitivity of 100.00% and specificity of 79.25% for predicting severe dengue. The diagnostic model with AUC of 0.71 (p < 0.01) has a sensitivity of 76.19% and specificity of 73.58% for diagnosing severe dengue. The AUC for PTX-3 was not statistically significant. VEGF may be used in combination with other clinical parameters to predict the severity of the disease. As a single biomarker, it may be used as an adjunct investigation to support the diagnosis of severe dengue. PTX-3 was not able to differentiate severe dengue from non-severe dengue.

Clinical manifestations of dengue in relation to dengue serotype and genotype in Malaysia: A retrospective observational study.

BACKGROUND: Malaysia experienced an unprecedented dengue outbreak from the year 2014 to 2016 that resulted in an enormous increase in the number of cases and mortality as compared to previous years. The causes that attribute to a dengue outbreak can be multifactorial. Viral factors, such as dengue serotype and genotype, are the components of interest in this study. Although only a small number of studies investigated the association between the serotype of dengue virus and clinical manifestations, none of these studies included analyses on dengue genotypes. The present study aims to investigate dengue serotype and genotype-specific clinical characteristics among dengue fever and severe dengue cases from two Malaysian tertiary hospitals between 2014 and mid-2017. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 120 retrospective dengue serum specimens were subjected to serotyping and genotyping by Taqman Real-Time RT-PCR, sequencing and phylogenetic analysis. Subsequently, the dengue serotype and genotype data were statistically analyzed for 101 of 120 corresponding patients' clinical manifestations to generate a descriptive relation between the genetic components and clinical outcomes of dengue infected patients. During the study period, predominant dengue serotype and genotype were found to be DENV 1 genotype I. Additionally, non-severe clinical manifestations were commonly observed in patients infected with DENV 1 and DENV 3. Meanwhile, patients with DENV 2 infection showed significant warning signs and developed severe dengue (p = 0.007). Cases infected with DENV 2 were also commonly presented with persistent vomiting (p = 0.010), epigastric pain (p = 0.018), plasma leakage (p = 0.004) and shock (p = 0.038). Moreover, myalgia and arthralgia were highly prevalent among DENV 3 infection (p = 0.015; p = 0.014). The comparison of genotype-specific clinical manifestations showed that DENV 2 Cosmopolitan was significantly common among severe dengue patients. An association was also found between genotype I of DENV 3 and myalgia. In a similar vein, genotype III of DENV 3 was significantly common among patients with arthralgia. CONCLUSION: The current data contended that different dengue serotype and genotype had caused distinct clinical characteristics in infected patients.