Australian National Standards of Care for Childhood-onset Heart Disease (CoHD Standards). 1st Edition.

These first Australian National Standards of Care for Childhood-onset Heart Disease (CoHD Standards) have been developed to inform the healthcare requirements for CoHD services and enable all Australian patients, families and carers impacted by CoHD (paediatric CoHD and adult congenital heart disease [ACHD]) to live their best and healthiest lives. The CoHD Standards are designed to provide the clarity and certainty required for healthcare services to deliver excellent, comprehensive, inclusive, and equitable CoHD care across Australia for patients, families and carers, and offer an iterative roadmap to the future of these services. The CoHD Standards provide a framework for excellent CoHD care, encompassing key requirements and expectations for whole-of-life, holistic and connected healthcare service delivery. The CoHD Standards should be implemented in health services in conjunction with the National Safety and Quality Health Service Standards developed by the Australian Commission on Safety and Quality in Health Care. All healthcare services should comply with the CoHD Standards, as well as working to their organisation's or jurisdiction's agreed clinical governance framework, to guide the implementation of structures and processes that support safe care.

Unprecedented Packing Polymorphism of Oxindole: An Exploration Inspired by Crystal Structure Prediction.

Crystal polymorphism, characterized by different packing arrangements of the same compound, strongly ties to the physical properties of a molecule. Determining the polymorphic landscape is complex and time-consuming, with the number of experimentally observed polymorphs varying widely from molecule to molecule. Furthermore, disappearing polymorphs, the phenomenon whereby experimentally observed forms cannot be reproduced, pose a significant challenge for the pharmaceutical industry. Herein, we focused on oxindole (OX), a small rigid molecule with four known polymorphs, including a reported disappearing form. Using crystal structure prediction (CSP), we assessed OX solid-state landscape and thermodynamic stability by comparing predicted structures with experimentally known forms. We then performed melt and solution crystallization in bulk and nanoconfinement to validate our predictions. These experiments successfully reproduced the known forms and led to the discovery of four novel polymorphs. Our approach provided insights into reconstructing disappearing polymorphs and building more comprehensive polymorph landscapes. These results also establish a new record of packing polymorphism for rigid molecules.

"Click"-Like η6 -Metalation/Demetalation of Aryl Iodides as a Means of Turning "ON/OFF" Halogen Bond Donor Functionality.

η6 -Metalated aryl halides are recognized as a class of halogen bond (XB) donors. Click-like η6 -metalation/demetalation of aryl iodides by cyclopentadienylruthenium(II) ([CpRuII ]+ ) is shown to turn ON/OFF (amplify/suppress) XB donor functionality. [CpRu(MeCN)3 ][PF6 ] is shown to react quantitatively with iodobenzenes (ArIn , n=1,2) to yield [CpRu(η6 -ArIn )][PF6 ] compounds. Photochemical demetalation (405 nm) quantitatively reverts these compounds to ArIn and [CpRu(MeCN)3 ][PF6 ]. Crystal structures of [CpRu(ArXn )]+ salts show that the [CpRu(ArIn )]+ cations are strong, charge-assisted XB donors analogous to iodopyridinium cations. XB-induced association of [CpRu(C6 H5 I)]+ with diazobicyclo[2.2.2]octane (DABCO) is established by NMR spectroscopy. [CpRu(C6 H5 I)][BPh4 ] and [CpRu(1,4-C6 H4 I2 )][BPh4 ] co-crystallize with DABCO and the structure of [CpRu(1,4-C6 H4 I2 )][BPh4 ]⋅DABCO⋅Et2 O is reported. DFT calculations support amplification of the XBing capabilities of aryl iodides upon [CpRu]+ -metalation.

Retrospective review of Kawasaki disease at the Women's and Children's Hospital, South Australia.

AIM: Kawasaki disease (KD) is one of the most common causes of acquired cardiac disease in children in high-income countries. The incidence of coronary artery disease (CAD), despite treatment with intravenous immunoglobulin, ranges from 5 to 20%. Determining risk factors for CAD may assist with management and reduce long-term complications. METHODS: Retrospective data were collected for all patients presenting to the Women's and Children's Hospital with a discharge diagnosis of KD over a 10.5-year period, from 2007 to 2018. RESULTS: A total of 141 patients were included in the review; 101 patients fulfilled complete criteria for KD; 25 incomplete criteria and 15 did not meet criteria but were treated for KD. CAD was present in 27.7% of all patients, ranging from ectasia to giant aneurysms based on Z-scores and echocardiogram descriptions. Medium to large aneurysms accounted for 8.5% of all patients with suspected KD. Patients with CAD were more likely to: fulfil incomplete criteria (odds ratio (OR) 4.3, 95% confidence interval (CI) 1.7-10.8, P = 0.0027), be less than 12 months of age (OR 11.38, 95% CI 2.94-44.11, P = 0.0001), have CRP > 100 (OR 2.8, 95% CI 1.31-6.02, P = 0.0068) and have a delay in treatment (average day of illness prior to treatment 8.89 vs. 6.78 (OR 1.19, 95% CI 1.05-1.35, P = 0.0055)). Patients with a Kobayashi score ≥4 had a higher rate of re-treatment with intravenous immunoglobulin (OR 3.16, 95% CI 1.27-7.83, P = 0.013). CONCLUSION: Our data are consistent with previously reported risk factors, and high rates of CAD despite standard treatment.

Maxillofacial trauma in children: Association between age and mandibular fracture site.

PURPOSE: To describe the association between age and location of facial fractures in the pediatric population. MATERIALS AND METHODS: A retrospective analysis of the Healthcare Cost and Utilization Project (HCUP) from the 2016 Kids' Inpatient Database (KID) in children aged ≤18 years was conducted. International Statistical Classification of Diseases, 10th Revision (ICD-10) codes were used to extract facial fracture diagnoses. Logistic regression was used to evaluate and compare the contribution of various demographic factors among patients who had different types of facial fractures. RESULTS: A total of 5568 admitted patients were identified who sustained any type of facial bone fracture. Patients who had facial fractures were significantly more likely to be male (68.2% versus 31.8%; p<0.001) and were older with a mean age of 12.86 years (95% confidence interval [CI]: 12.72-12.99). Approximately one-third of patients with a facial fracture had a concomitant skull base or vault fracture. Maxillary fractures were seen in 30.9% of the cohort while mandibular fractures occurred in 36.9% of patients. The most common mandibular fracture site was the symphysis (N=574, 27.9% of all mandibular fractures). Condylar fractures were more common in younger children while angle fractures were more common in teenagers. Regression analysis found that age was the only significant contributor to the presence of a mandibular fracture (ß=0.027, p<0.001) and race was the only significant contributor to maxillary fractures (ß=-0.090, p<0.001). CONCLUSIONS: Facial fractures increase in frequency with increasing age in children. The mandible was the most commonly fractured facial bone, with an age-related pattern in fracture location.

Characterization of Medical Malpractice Litigation After Rhinoplasty in the United States.

BACKGROUND: When complications following rhinoplasty occur or when the desired outcome is not achieved, patients may seek litigation on the premise that there was a violation in the standard of care. Knowledge of malpractice claims can inform rhinoplasty surgeons on how to minimize risk of future litigation as well as improve patient satisfaction. OBJECTIVES: The aims of this study were to identify motives for seeking medical malpractice litigation after rhinoplasty, and to examine outcomes of malpractice litigation after rhinoplasty in the United States. METHODS: The Westlaw legal database was reviewed for all available court decisions related to malpractice after rhinoplasty. Data collected and analyzed included plaintiff gender, location, specialty of defendant(s), plaintiff allegation, and adjudicated case outcomes. RESULTS: Twenty-three cases were identified between 1960 and 2018, located in 12 US states; 70% of the plaintiffs were female. Otolaryngologists were cited in 11 cases, whereas 12 cases involved a plastic surgeon. All cases alleged negligence. Cases involved "technical" errors (69.6%), "unsatisfactory" outcomes (39.1%), inadequate follow-up or aftercare (30.4%), issues with the informed consent process (21.7%), unexpectedly extensive surgery (8.7%), improper medication administration (4.3%), and failure to recognize symptoms (4.3%). Twenty of the 23 adjudicated cases (86.9%) were ruled in favor of the surgeon. The main contributing factor in cases alleging malpractice was poor aesthetic outcome/disfigurement (60.7%). CONCLUSIONS: Malpractice litigation after rhinoplasty favored the surgeon in the majority of the adjudicated cases reviewed. The principal reason for litigating was dissatisfaction with aesthetic outcomes. Rhinoplasty surgeons may mitigate possible litigation by developing a positive doctor-patient relationship, clearly understanding the patient's surgical expectations, and obtaining detailed informed consent while maintaining frequent and caring communication with the patient.

Doxycycline-induced idiopathic intracranial hypertension in a patient with Lyme disease.

ABSTRACT: Doxycycline is widely used to treat early and disseminated Lyme disease. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a rare but serious adverse reaction to this medication. This article reviews the pathophysiology, presentation, diagnosis, and treatment of a patient with disseminated Lyme disease complicated by doxycycline-induced IIH.

Impact of protocolized diuresis for de-resuscitation in the intensive care unit.

OBJECTIVE: Administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. Current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. This study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. METHODS: This was a pre-post single-center pilot study within the medical intensive care unit (ICU) of a large academic medical center. Adult patients admitted to the Medical ICU receiving mechanical ventilation with either (1) clinical signs of volume overload via chest radiography or physical exam or (2) any cumulative fluid balance ≥ 0 mL since hospital admission were eligible for inclusion. Patients received diuresis per clinician discretion for a 2-year period (historical control) followed by a diuresis protocol for 1 year (intervention). Patients within the intervention group were matched in a 1:3 ratio with those from the historical cohort who met the study inclusion and exclusion criteria. RESULTS: A total of 364 patients were included, 91 in the protocol group and 273 receiving standard care. Protocolized diuresis was associated with a significant decrease in 72-h post-shock cumulative fluid balance [median, IQR - 2257 (- 5676-920) mL vs 265 (- 2283-3025) mL; p < 0.0001]. In-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008) and higher ICU-free days (p = 0.03). However, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. CONCLUSIONS: This study showed that a protocol for diuresis for de-resuscitation can significantly improve 72-h post-shock fluid balance with potential benefit on clinical outcomes.

Continuous renal replacement therapy in critically ill patients with acute on chronic liver failure and acute kidney injury: A retrospective cohort study
.

BACKGROUND: Incident acute kidney injury (AKI) in critically ill patients with acute on chronic liver failure (ACLF) is associated with poor prognosis. The role of continuous renal replacement therapy (CRRT) is not well established for patients with ACLF and AKI. MATERIALS AND METHODS: We conducted a retrospective cohort study to examine clinical outcomes in 66 patients with ACLF and AKI requiring CRRT. RESULTS: All-cause hospital mortality was 89.4%. Five (7.6%) patients were listed for liver transplantation, of whom 1 (1.5%) was eventually subjected to transplantation. Etiology of AKI included type 1 hepatorenal syndrome (HRS) with or without some degree of acute tubular necrosis (ATN) in 20 (30.3%) patients, and primarily ATN in 46 (69.7%) patients. When evaluated at the time of CRRT initiation, Child-Pugh-Turcotte (CPT) and Model for End-stage Liver Disease (MELD) (area under the receiver operating characteristics curve (AUROC) 0.67 for both) had fair performance for prediction of mortality, whereas Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure (CLIF)-SOFA performed better for the prediction of mortality (AUROC 0.87 for both). SOFA and CLIF-SOFA also performed well when determined at the time of ICU admission (AUROC 0.86 and 0.85, respectively). Etiology of liver disease or AKI did not influence prognosis. CONCLUSION: Critically ill patients with ACLF and AKI requiring CRRT have poor hospital survival, even with provision of extracorporeal support therapy. SOFA and CLIF-SOFA are good prognostic tools of mortality in this susceptible population.

Why is active travel more satisfying than motorized travel? Evidence from Dublin.

Some trips are better than others, and more and more studies find that active travel (walking and cycling) is more satisfying than motorized forms of travel (using the car or public transport). Why is this the case? Using data on travel satisfaction from 4134 commutes to a large University campus in Dublin, Ireland, this paper replicates the differences in travel satisfaction between active and motorized travel. We attribute these differences in large part to the duration of the trip. Subjective trip characteristics, such as safety and convenience, also play important roles. The trip duration explains rush-hour effects as well as why people starting from less affluent and more difficult-to-reach places are less satisfied with their trips. Longer-term policy options suggested by these results include infrastructure developments and spatial development strategies. A shorter-term initiative would be to delay university schedules in the morning to avoid low travel satisfaction during the slow rush-hour period and simultaneously ease pressure on the transport network at peak times.

Fluid Overload Associates With Major Adverse Kidney Events in Critically Ill Patients With Acute Kidney Injury Requiring Continuous Renal Replacement Therapy.

OBJECTIVES: We examined the association between fluid overload and major adverse kidney events in critically ill patients requiring continuous renal replacement therapy for acute kidney injury. DESIGN: Retrospective cohort study. SETTING: ICU in a tertiary medical center. PATIENTS: Four-hundred eighty-one critically ill adults requiring continuous renal replacement therapy for acute kidney injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fluid overload was assessed as fluid balance from admission to continuous renal replacement therapy initiation, adjusted for body weight. Major adverse kidney events were defined as a composite of mortality, renal replacement therapy-dependence or inability to recover 50% of baseline estimated glomerular filtration rate (if not on renal replacement therapy) evaluated up to 90 days after discharge. Patients with fluid overload less than or equal to 10% were less likely to experience major adverse kidney events than those with fluid overload greater than 10% (71.6% vs 79.4%; p = 0.047). Multivariable logistic regression showed that fluid overload greater than 10% was associated with a 58% increased odds of major adverse kidney events (p = 0.046), even after adjusting for timing of continuous renal replacement therapy initiation. There was also a 2.7% increased odds of major adverse kidney events for every 1 day increase from ICU admission to continuous renal replacement therapy initiation (p = 0.024). Fluid overload greater than 10% was also found to be independently associated with an 82% increased odds of hospital mortality (p = 0.004) and 2.5 fewer ventilator-free days (p = 0.044), compared with fluid overload less than or equal to 10%. CONCLUSIONS: In critically ill patients with acute kidney injury requiring continuous renal replacement therapy, greater than 10% fluid overload was associated with higher risk of 90-day major adverse kidney events, including mortality and decreased renal recovery. Increased time between ICU admission and continuous renal replacement therapy initiation was also associated with decreased renal recovery. Fluid overload represents a potentially modifiable risk factor, independent of timing of continuous renal replacement therapy initiation, that should be further examined in interventional studies.

Efficacy and Pharmacokinetics Evaluation of a Single Oral Dose of Afoxolaner against Sarcoptes scabiei in the Porcine Scabies Model for Human Infestation.

Scabies is a major and potentially growing public health problem worldwide with an unmet need for acaricidal agents with greater efficacy and improved pharmacological properties for its treatment. The objective of the present study was to assess the efficacy and describe the pharmacokinetics profile of a novel acaricide, afoxolaner (AFX), in a relevant experimental porcine model. Twelve pigs were experimentally infested and either treated with 2.5 mg/kg single dose oral AFX (n = 4) or 0.2 mg/kg, two doses 8 days apart, oral ivermectin ([IVM] n = 4) or not treated for scabies (n = 4). The response to treatment was assessed by the reduction of mite counts in skin scrapings as well as clinical and pruritus scores over time. Plasma and skin pharmacokinetics profiles for both AFX and IVM were evaluated. AFX efficacy was 100% at days 8 and 14 posttreatment and remained unchanged until the study end (day 45). IVM efficacy was 86% and 97% on days 8 and 14, respectively, with a few mites recovered at the study end. Clinical and pruritus scores decreased in both treated groups and remained constant in the control group. Plasma mean residence times (MRT) were 7.1 ± 2.4 and 1.1 ± 0.2 days for AFX and IVM, respectively. Skin MRT values were 16.2 ± 16.9 and 2.7 ± 0.5 days for AFX and IVM, respectively. Overall, a single oral dose of AFX was efficacious for the treatment of scabies in experimentally infested pigs and showed remarkably long MRTs in plasma and, notably, in the skin.

Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock.

OBJECTIVES: Mounting evidence has shown that critically ill patients are commonly thiamine deficient. We sought to test the hypothesis that critically ill patients with septic shock exposed to thiamine would demonstrate improved lactate clearance and more favorable clinical outcomes compared with those not receiving thiamine. DESIGN: Retrospective, single-center, matched cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adult patients admitted with an International Classification of Diseases, 9th Edition, or International Classification of Diseases, 10th Edition, diagnosis code of septic shock to either the medicine or surgery ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients who received IV thiamine supplementation within 24 hours of hospital admission were identified and compared with a matched cohort of patients not receiving thiamine. The primary objective was to determine if thiamine administration was associated with a reduced time to lactate clearance in septic shock. Secondary outcomes included 28-day mortality, acute kidney injury, and need for renal replacement therapy, and vasopressor and mechanical ventilation-free days. Two-thousand two-hundred seventy-two patients were screened, of whom 1,049 were eligible. The study consisted of 123 thiamine-treated patients matched with 246 patients who did not receive thiamine. Based on the Fine-Gray survival model, treatment with thiamine was associated with an improved likelihood of lactate clearance (subdistribution hazard ratio, 1.307; 95% CI, 1.002-1.704). Thiamine administration was also associated with a reduction in 28-day mortality (hazard ratio, 0.666; 95% CI, 0.490-0.905). There were no differences in any secondary outcomes. CONCLUSIONS: Thiamine administration within 24 hours of admission in patients presenting with septic shock was associated with improved lactate clearance and a reduction in 28-day mortality compared with matched controls.

The New Politics of US Health Care Prices: Institutional Reconfiguration and the Emergence of All-Payer Claims Databases.

Prices are a significant driver of health care cost in the United States. Existing research on the politics of health system reform has emphasized the limited nature of policy entrepreneurs' efforts at solving the problem of rising prices through direct regulation at the state level. Yet this literature fails to account for how change agents in the states gradually reconfigured the politics of prices, forging new, transparency-based policy instruments called all-payer claims databases (APCDs), which are designed to empower consumers, purchasers, and states to make informed market and policy choices. Drawing on pragmatist institutional theory, this article shows how APCDs emerged as the dominant model for reforming health care prices. While APCD advocates faced significant institutional barriers to policy change, we show how they reconfigured existing ideas, tactical repertoires, and legal-technical infrastructures to develop a politically and technologically robust reform. Our analysis has important implications for theories of how change agents overcome structural barriers to health reform.

Ancient recombination events and the origins of hepatitis E virus.

BACKGROUND: Hepatitis E virus (HEV) is an enteric, single-stranded, positive sense RNA virus and a significant etiological agent of hepatitis, causing sporadic infections and outbreaks globally. Tracing the evolutionary ancestry of HEV has proved difficult since its identification in 1992, it has been reclassified several times, and confusion remains surrounding its origins and ancestry. RESULTS: To reveal close protein relatives of the Hepeviridae family, similarity searching of the GenBank database was carried out using a complete Orthohepevirus A, HEV genotype I (GI) ORF1 protein sequence and individual proteins. The closest non-Hepeviridae homologues to the HEV ORF1 encoded polyprotein were found to be those from the lepidopteran-infecting Alphatetraviridae family members. A consistent relationship to this was found using a phylogenetic approach; the Hepeviridae RdRp clustered with those of the Alphatetraviridae and Benyviridae families. This puts the Hepeviridae ORF1 region within the "Alpha-like" super-group of viruses. In marked contrast, the HEV GI capsid was found to be most closely related to the chicken astrovirus capsid, with phylogenetic trees clustering the Hepeviridae capsid together with those from the Astroviridae family, and surprisingly within the "Picorna-like" supergroup. These results indicate an ancient recombination event has occurred at the junction of the non-structural and structure encoding regions, which led to the emergence of the entire Hepeviridae family. The Astroviridae capsid is also closely related to the Tymoviridae family of monopartite, T = 3 icosahedral plant viruses, whilst its non-structural region is related to viruses of the Potyviridae; a large family of plant-infecting viruses with a flexible filamentous rod-shaped virion. Thus, we identified a separate inter-viral family recombination event, again at the non-structural/structural junction, which likely led to the creation of the Astroviridae. CONCLUSIONS: In summary, we have shown that new viral families have been created though recombination at the junction of the genome that encodes non-structural and structural proteins, and such recombination events are implicated in the genesis of important human pathogens; HEV, astrovirus and rubella virus.

Boutique to Booming: Medicare Managed Care and the Private Path to Policy Change.

In 2014, Medicare Advantage (MA) enrollment surpassed 30 percent of eligible beneficiaries. Twenty-five years earlier, enrollment hovered at just 3 percent. The expansion of private Medicare plans presents a puzzling instance of policy change within Medicare-a program long held to be a quintessential case of policy stasis. This article investigates the policy features that made Medicare susceptible to this dramatic policy shift, as well as the processes by which the initial policy change remade the politics of Medicare and solidified the MA program. The first enrollment surge occurred in the absence of a proximate legislative or administrative change. Instead, increased spending and expanded benefits were the result of the interaction of new market dynamics with an existing legislative framework-demonstrating an expansionary form of policy drift. The 1982 Tax Equity and Fiscal Responsibility Act created a policy space that gave the new and lightly controlled managed care industry considerable operational discretion. As the interests of the government's private partners changed in response to new market dynamics, a change occurred in the output and performance of the Medicare managed care program. As enrollment and spending increased, Medicare's politics were remade by the political empowerment of the managed care industry and the creation of a new subconstituency of beneficiaries.

Echocardiographic screening for rheumatic heart disease in high and low risk Australian children.

BACKGROUND: Echocardiographic screening for rheumatic heart disease (RHD) is becoming more widespread, but screening studies to date have used different echocardiographic definitions. The World Heart Federation has recently published new criteria for the echocardiographic diagnosis of RHD. We aimed to establish the prevalence of RHD in high-risk Indigenous Australian children using these criteria and to compare the findings with a group of Australian children at low risk for RHD. METHODS AND RESULTS: Portable echocardiography was performed on high-risk Indigenous children aged 5 to 15 years living in remote communities of northern Australia. A comparison group of low-risk, non-Indigenous children living in urban centers was also screened. Echocardiograms were reported in a standardized, blinded fashion. Of 3946 high-risk children, 34 met World Heart Federation criteria for definite RHD (prevalence, 8.6 per 1000 [95% confidence interval, 6.0-12.0]) and 66 for borderline RHD (prevalence, 16.7 per 1000 [95% confidence interval, 13.0-21.2]). Of 1053 low-risk children, none met the criteria for definite RHD, and 5 met the criteria for borderline RHD. High-risk children were more likely to have definite or borderline RHD than low-risk children (adjusted odds ratio, 5.7 [95% confidence interval, 2.3-14.1]; P<0.001). CONCLUSIONS: The prevalence of definite RHD in high-risk Indigenous Australian children approximates what we expected in our population, and no definite RHD was identified in the low-risk group. This study suggests that definite RHD, as defined by the World Heart Federation criteria, is likely to represent true disease. Borderline RHD was identified in children at both low and high risk, highlighting the need for longitudinal studies to evaluate the clinical significance of this finding.

Nonnucleoside inhibitors of norovirus RNA polymerase: scaffolds for rational drug design.

Norovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA and is therefore a prime target for antiviral therapies. Using high-throughput screening, nearly 20,000 "lead-like" compounds were tested for inhibitory activity against the NoV genogroup II, genotype 4 (GII.4) RdRp. The four most potent hits demonstrated half-maximal inhibitory concentrations (IC50s) between 5.0 µM and 9.8 µM against the target RdRp. Compounds NIC02 and NIC04 revealed a mixed mode of inhibition, while NIC10 and NIC12 were uncompetitive RdRp inhibitors. When examined using enzymes from related viruses, NIC02 demonstrated broad inhibitory activity while NIC04 was the most specific GII.4 RdRp inhibitor. The antiviral activity was examined using available NoV cell culture models; the GI.1 replicon and the infectious GV.1 murine norovirus (MNV). NIC02 and NIC04 inhibited the replication of the GI.1 replicon, with 50% effective concentrations (EC50s) of 30.1 µM and 71.1 µM, respectively, while NIC10 and NIC12 had no observable effect on the NoV GI.1 replicon. In the MNV model, NIC02 reduced plaque numbers, size, and viral RNA levels in a dose-dependent manner (EC50s between 2.3 µM and 4.8 µM). The remaining three compounds also reduced MNV replication, although with higher EC50s, ranging from 32 µM to 38 µM. In summary, we have identified novel nonnucleoside inhibitor scaffolds that will provide a starting framework for the development and future optimization of targeted antivirals against NoV.

Next-generation sequencing and microarray-based interrogation of microRNAs from formalin-fixed, paraffin-embedded tissue: preliminary assessment of cross-platform concordance.

Next-generation sequencing is increasingly employed in biomedical investigations. Strong concordance between microarray and mRNA-seq levels has been reported in high quality specimens but information is lacking on formalin-fixed, paraffin-embedded (FFPE) tissues, and particularly for microRNA (miRNA) analysis. We conducted a preliminary examination of the concordance between miRNA-seq and cDNA-mediated annealing, selection, extension, and ligation (DASL) miRNA assays. Quantitative agreement between platforms is moderate (Spearman correlation 0.514-0.596) and there is discordance of detection calls on a subset of miRNAs. Quantitative PCR (q-RT-PCR) performed for several discordant miRNAs confirmed the presence of most sequences detected by miRNA-seq but not by DASL but also that miRNA-seq did not detect some sequences, which DASL confidently detected. Our results suggest that miRNA-seq is specific, with few false positive calls, but it may not detect certain abundant miRNAs in FFPE tissue. Further work is necessary to fully address these issues that are pertinent for translational research.

Learning curve analyses in spine surgery: a systematic simulation-based critique of methodologies.

BACKGROUND CONTEXT: Various statistical approaches exist to delineate learning curves in spine surgery. Techniques range from dividing cases into intervals for metric comparison, to employing regression and cumulative summation (CUSUM) analyses. However, their inherent inconsistencies and methodological flaws limit their comparability and reliability. PURPOSE: To critically evaluate the methodologies used in existing literature for studying learning curves in spine surgery and to provide recommendations for future research. STUDY DESIGN: Systematic literature review. METHODS: A comprehensive literature search was conducted using PubMed, Embase, and Scopus databases, covering articles from January 2010 to September 2023. For inclusion, articles had to evaluate the change in a metric of performance during human spine surgery across time/a case series. Results had to be reported in sufficient detail to allow for evaluation of individual performance rather than group/institutional performance. Articles were excluded if they included cadaveric/nonhuman subjects, aggregated performance data or no way to infer change across a number of cases. Risk of bias was assessed using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. Surgical data were simulated using Python 3 and then examined via multiple commonly used analytic approaches including division into consecutive intervals, regression and CUSUM techniques. Results were qualitatively assessed to determine the effectiveness and limitations of each approach in depicting a learning curve. RESULTS: About 113 studies met inclusion criteria. The majority of the studies were retrospective and evaluated a single-surgeon's experience. Methods varied considerably, with 66 studies using a single proficiency metric and 47 using more than 1. Operating time was the most commonly used metric. Interval division was the simplest and most commonly used method yet inherent limitations prevent collective synthesis. Regression may accurately describe the learning curve but in practice is hampered by sample size and model choice. CUSUM analyses are of widely varying quality with some being fundamentally flawed and widely misinterpreted however, others provide a reliable view of the learning process. CONCLUSION: There is considerable variation in the quality of existing studies on learning curves in spine surgery. CUSUM analyses, when correctly applied, offer the most reliable estimates. To improve the validity and comparability of future studies, adherence to methodological guidelines is crucial. Multiple or composite performance metrics are necessary for a holistic understanding of the learning process.