Top 10 research priorities for congenital diaphragmatic hernia in Australia: James Lind Alliance Priority Setting Partnership.

OBJECTIVES: The Gaps in the Congenital Diaphragmatic Hernia (CDH) Journey Priority Setting Partnership (PSP) was developed in collaboration with CDH Australia, James Lind Alliance (JLA) and the Murdoch Children's Research Institute to identify research priorities for people with CDH, their families and healthcare workers in Australasia. DESIGN: Research PSP in accordance with the JLA standardised methodology. SETTING: Australian community and institutions caring for patients with CDH and their families. PATIENTS: CDH survivors, families of children born with CDH (including bereaved) and healthcare professionals including critical care physicians and nurses (neonatal and paediatric), obstetric, surgical, allied health professionals (physiotherapists, speech pathologists and speech therapists) and general practitioners. MAIN OUTCOME MEASURE: Top 10 research priorities for CDH. RESULTS: 377 questions, from a community-based online survey, were categorised and collated into 50 research questions. Through a further prioritisation process, 21 questions were then discussed at a prioritisation workshop where they were ranked by 21 participants (CDH survivors, parents of children born with CDH (bereaved and not) and 11 multidisciplinary healthcare professionals) into their top 10 research priorities. CONCLUSION: Stakeholders' involvement identified the top 10 CDH-related research questions, spanning from antenatal care to long-term functional outcomes, that should be prioritised for future research to maximise meaningful outcomes for people with CDH and their families.

Timeliness of Health Technology Assessments and Price Negotiations for Oncology Drugs in Canada.

Purpose: To evaluate whether time targets for Canadian Agency for Drugs and Technologies in Health (CADTH) reimbursement reviews and pan-Canadian Pharmaceutical Alliance (pCPA) price negotiations are being achieved for oncology drugs. Materials and Methods: Recommendations, dates of submission and publication, and indications for oncology medicines issued between January 2014 and December 2023 were recorded from CADTH's reimbursement reports webpage. The date any negotiation began and the date it was completed (successfully or not), or when a decision was made not to pursue negotiation was extracted from the pCPA's webpage. The duration of each CADTH review and pCPA negotiation was calculated, together with time between CADTH's recommendation and start of the pCPA negotiation or a decision not to negotiate. Percentages of reviews completed within CADTH's target and of times taken by the pCPA to decide whether to negotiate and by its price negotiations completed within the relevant targets were calculated. Results: CADTH achieved its 270-days target in 88.2% to 100% of reviews issued between 2015 and 2019 but only in 65.9% to 73.1% of reviews issued in the last three years of the decade. CADTH's "typical timeline" of 180 days was achieved in under 40% of reviews issued in 2015 and not attained in any review in 2021, 2022 or 2023. The pCPA's target of 60 days for deciding whether to negotiate was achieved for all recommendations issued in 2014 but dropped below 40% for the last seven years of the decade; its target of 130 days for negotiations was achieved for over 85% of the recommendations in 2014 but decreased to only 14.3% in 2016 and then gradually increased to 61.5% in 2023. Conclusion: CADTH's "typical timeline" and the pCPA's targets were not met sufficiently to be meaningful. Their processes take too long for cancer drugs.

Canadian patients and providers are often frustrated and concerned about the timeliness of the country's health technology assessment (HTA) and price negotiation processes, especially for cancer drugs. HTAs are carried out to evaluate the benefit of a medicine in comparison with its cost to see whether the drug is of sufficient value to add it to the benefit lists of government drug plans. HTAs are performed by the Canadian Agency for Drugs and Technologies in Health (CADTH) for all of Canada, except the province of Quebec, and price negotiations with drug developers are carried out by the pan-Canadian Pharmaceutical Alliance (pCPA) on behalf of all government drug plans. We used data from the websites of CADTH and the pCPA on HTA reviews of cancer drugs issued between January 2014 and December 2023 and price negotiations for these drugs to assess whether CADTH and the pCPA complied with their stated target times for completing their processes. We found that CADTH's reviews and the pCPA's price negotiations failed to meet their targets for cancer drugs in the past 10 years and that the timeliness of their performance has, in most cases, deteriorated. HTA and price negotiation processes for cancer drugs take too long in Canada.

New Anticancer Drugs: Reliably Assessing "Value" While Addressing High Prices.

Countries face challenges in paying for new drugs. High prices are driven in part by exploding drug development costs, which, in turn, are driven by essential but excessive regulation. Burdensome regulation also delays drug development, and this can translate into thousands of life-years lost. We need system-wide reform that will enable less expensive, faster drug development. The speed with which COVID-19 vaccines and AIDS therapies were developed indicates this is possible if governments prioritize it. Countries also differ in how they value drugs, and generally, those willing to pay more have better, faster access. Canada is used as an example to illustrate how "incremental cost-effectiveness ratios" (ICERs) based on measures such as gains in "quality-adjusted life-years" (QALYs) may be used to determine a drug's value but are often problematic, imprecise assessments. Generally, ICER/QALY estimates inadequately consider the impact of patient crossover or long post-progression survival, therapy benefits in distinct subpopulations, positive impacts of the therapy on other healthcare or societal costs, how much governments willingly might pay for other things, etc. Furthermore, a QALY value should be higher for a lethal or uncommon disease than for a common, nonlethal disease. Compared to international comparators, Canada is particularly ineffective in initiating public funding for essential new medications. Addressing these disparities demands urgent reform.

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.

Approximately 22% of Alzheimer's disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling. Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance. We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-ß pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.

Risk factors predicting the need for intensive care unit admission within forty-eight hours of emergency department presentation: A case-control study.

BACKGROUND: Patients admitted from the emergency department to the wards, who progress to a critically unwell state, may require expeditious admission to the intensive care unit. It can be argued that earlier recognition of such patients, to facilitate prompt transfer to intensive care, could be linked to more favourable clinical outcomes. Nevertheless, this can be clinically challenging, and there are currently no established evidence-based methods for predicting the need for intensive care in the future. OBJECTIVES: We aimed to analyse the emergency department data to describe the characteristics of patients who required an intensive care admission within 48 h of presentation. Secondly, we planned to test the feasibility of using this data to identify the associated risk factors for developing a predictive model. METHODS: We designed a retrospective case-control study. Cases were patients admitted to intensive care within 48 h of their emergency department presentation. Controls were patients who did not need an intensive care admission. Groups were matched based on age, gender, admission calendar month, and diagnosis. To identify the associated variables, we used a conditional logistic regression model. RESULTS: Compared to controls, cases were more likely to be obese, and smokers and had a higher prevalence of cardiovascular (39 [35.1%] vs 20 [18%], p = 0.004) and respiratory diagnoses (45 [40.5%] vs 25 [22.5%], p = 0.004). They received more medical emergency team reviews (53 [47.8%] vs 24 [21.6%], p < 0.001), and more patients had an acute resuscitation plan (31 [27.9%] vs 15 [13.5%], p = 0.008). The predictive model showed that having acute resuscitation plans, cardiovascular and respiratory diagnoses, and receiving medical emergency team reviews were strongly associated with having an intensive care admission within 48 h of presentation. CONCLUSIONS: Our study used emergency department data to provide a detailed description of patients who had an intensive care unit admission within 48 h of their presentation. It demonstrated the feasibility of using such data to identify the associated risk factors to develop a predictive model.

Clostridioides difficile infection is associated with differences in transcriptionally active microbial communities.

Clostridioides difficile infection (CDI) is responsible for around 300,000 hospitalizations yearly in the United States, with the associated monetary cost being billions of dollars. Gut microbiome dysbiosis is known to be important to CDI. To the best of our knowledge, metatranscriptomics (MT) has only been used to characterize gut microbiome composition and function in one prior study involving CDI patients. Therefore, we utilized MT to investigate differences in active community diversity and composition between CDI+ (n = 20) and CDI- (n = 19) samples with respect to microbial taxa and expressed genes. No significant (Kruskal-Wallis, p > 0.05) differences were detected for richness or evenness based on CDI status. However, clustering based on CDI status was significant for both active microbial taxa and expressed genes datasets (PERMANOVA, p ≤ 0.05). Furthermore, differential feature analysis revealed greater expression of the opportunistic pathogens Enterocloster bolteae and Ruminococcus gnavus in CDI+ compared to CDI- samples. When only fungal sequences were considered, the family Saccharomycetaceae expressed more genes in CDI-, while 31 other fungal taxa were identified as significantly (Kruskal-Wallis p ≤ 0.05, log(LDA) ≥ 2) associated with CDI+. We also detected a variety of genes and pathways that differed significantly (Kruskal-Wallis p ≤ 0.05, log(LDA) ≥ 2) based on CDI status. Notably, differential genes associated with biofilm formation were expressed by C. difficile. This provides evidence of another possible contributor to C. difficile's resistance to antibiotics and frequent recurrence in vivo. Furthermore, the greater number of CDI+ associated fungal taxa constitute additional evidence that the mycobiome is important to CDI pathogenesis. Future work will focus on establishing if C. difficile is actively producing biofilms during infection and if any specific fungal taxa are particularly influential in CDI.

Outcomes for Young Adults With Suicide Admitted to Adult Versus Pediatric Hospitals.

OBJECTIVES: To evaluate differences in care and outcomes for young adults admitted with suicide ideation (SI) or attempt (SA) to medical units of an adult (AH) versus pediatric hospital (PH). METHODS: Demographic and clinical characteristics were collected on patients aged 18 to 25 years admitted to either an AH or PH at an academic health system from September 2017 through June 2023 with a diagnosis of SI or SA. Outcomes measured were discharge location, length of stay (LOS), emergency department (ED) visit or hospital readmission, and inpatient consultations. Bivariate tests and multivariate regression were used to determine association of admission location and outcomes. RESULTS: Of 212 patients included, 54% were admitted to an AH and 46% to a PH. Admission to a PH compared with an AH was associated with shorter ED LOS (4.3 vs 7.3 hours, P < .01) and discharge to home (57% vs 42%, P = .028) on bivariate but not adjusted analysis. Admission location was not associated with hospital LOS, ED visit or medical readmission after discharge, or psychiatry consultation. Admission to a PH compared with an AH was associated with higher odds of psychology consultation (29 vs 3%, P < .01). CONCLUSIONS: Although young adults admitted to a PH for SI/SA had higher rates of psychology consultation, they otherwise had similar care and outcomes regardless of admission to an AH versus a PH. Further work is needed to determine if observed differences are generalizable and how they affect hospital throughput and long-term outcomes.

Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Population Survival Kinetics Derived from Clinical Trials of Potentially Curable Lung Cancers.

Using digitized data from progression-free survival (PFS) and overall survival Kaplan-Meier curves, one can assess population survival kinetics through exponential decay nonlinear regression analyses. To demonstrate their utility, we analyzed PFS curves from published curative-intent trials of non-small cell lung cancer (NSCLC) adjuvant chemotherapy, adjuvant osimertinib in resected EGFR-mutant NSCLC (ADAURA trial), chemoradiotherapy for inoperable NSCLC, and limited small cell lung cancer (SCLC). These analyses permit assessment of log-linear curve shape and estimation of the proportion of patients cured, PFS half-lives for subpopulations destined to eventually relapse, and probability of eventual relapse in patients remaining progression-free at different time points. The proportion of patients potentially cured was 41% for adjuvant controls, 58% with adjuvant chemotherapy, 17% for ADAURA controls, not assessable with adjuvant osimertinib, 15% with chemoradiotherapy, and 12% for SCLC. Median PFS half-life for relapsing subpopulations was 11.9 months for adjuvant controls, 17.4 months with adjuvant chemotherapy, 24.4 months for ADAURA controls, not assessable with osimertinib, 9.3 months with chemoradiotherapy, and 10.7 months for SCLC. For those remaining relapse-free at 2 and 5 years, the cure probability was 74%/96% for adjuvant controls, 77%/93% with adjuvant chemotherapy, 51%/94% with chemoradiation, and 39%/87% with limited SCLC. Relatively easy population kinetic analyses add useful information.

Screening tools for the detection of clinically silent cardiac sarcoidosis.

BACKGROUND: clinically silent cardiac sarcoidosis (CS) may be associated with adverse outcomes, hence the rationale for screening patients with extracardiac sarcoidosis. The optimal screening strategy has not been clearly defined. METHODS: patients with extra-cardiac sarcoidosis were prospectively included and underwent screening consisting of symptom history, electrocardiography (ECG), transthoracic echocardiogram, Holter, and signal-averaged ECG (SAECG). Cardiac magnetic resonance (CMR) was performed in all patients. Clinically silent CS was defined as CMR demonstrating late gadolinium enhancement (LGE) in a pattern compatible with CS according to a majority of independent and blinded CMR experts. Significant cardiac involvement was defined as the presence of LGE ≥6% and/or a positive fluorodeoxyglucose-positron emission tomography. RESULTS: among the 129 patients included, clinically silent CS was diagnosed in 29/129 (22.5%), and 19/129 patients (14.7%) were classified as CS with significant cardiac involvement. There was a strong association between hypertension and CS (p < 0.05). Individual screening tools provided low diagnostic yield; however, combination of tests performed better, for example, a normal Holter and a normal SAECG had negative predictive values of 91.7%. We found consistently better diagnostic accuracy for the detection of CS with significant cardiac involvement. CONCLUSION: clinically silent CS and CS with significant cardiac involvement were found in 22.5% and 14.7% of patients with extra-cardiac sarcoidosis. The association with hypertension raises the possibility that some cases of hypertensive cardiomyopathy may be mistaken for CS. Screening with readily available tools, for example Holter and SAECG, may help identifying patients without CS where additional CMR is not needed.

Factors Associated With Myocardial Infarction in a Rural Population With Peripheral Arterial Diseases.

Peripheral arterial disease (PAD) studies in rural populations are limited. The incidence of myocardial infarction (MI) is higher in patients with PAD. This study examined the association between sociodemographic and clinical risk factors and MI in patients with PAD in Central Appalachia, comprising of 230 counties across six states in the United States. Data from electronic medical records of 13,455 patients with PAD were extracted from a large health system in Central Appalachia. Bivariate and logistic regression analyses were conducted. The final sample consisted of 5574 patients with PAD, of whom 24.85% were also diagnosed with MI. The mean age was 71 ± 11.23 years, and the majority were male (56.40%). After adjusting for confounders, patients with hypertension had three times higher odds of MI (adjusted Odds Ratio [aOR] = 3.21; 95% CI: 2.50-4.14) compared with those without hypertension. The likelihood of MI increased by 51% among patients with diabetes (aOR = 1.51; 95% CI: 1.33-1.71), 34% among ever-smokers (aOR = 1.34; 95% CI: 1.18-1.52), and 45% in males (aOR = 1.45; 95% CI: 1.27-1.65). Hypertension, diabetes, smoking, and male sex were identified as significant risk factors for MI. Screening and effective management of these risk factors in rural areas could potentially prevent MI incidence among patients with PAD.

Prehospital Lessons From the War in Ukraine: Damage Control Resuscitation and Surgery Experiences From Point of Injury to Role 2.

The ongoing war in Ukraine presents unique challenges to prehospital medical care for wounded combatants and civilians. The purpose of this article is to identify, describe, and address gaps in prehospital care, casualty evacuation, and medical evacuation throughout Ukraine to share lessons for other providers. Observations and experiences of medical personnel were collected and analyzed, focusing on pain management, antibiotic use, patient assessment, mass casualty triage, blood loss, hypothermia, transport immobilization, and clinical governance. Gaps identified include limited access to pain management, lack of antibiotic guidance, inadequate patient assessment and triage, access to damage control resuscitation and blood, challenged transport immobilization practices, and challenges with clinical governance for both local and foreign providers. Improved prehospital care and casualty and medical evacuation in Ukraine are required, through increased use of empiric pain management, focused antibiotic guidance, enhanced patient assessment and triage in the form of training, access to prehospital blood, and better transport immobilization practices. A robust and active lessons learned program, trauma data capture, and quality improvement process is needed to reduce preventable morbidity and mortality in the war zone. The recommendations presented in this article serve as a starting point for improvements in prehospital care in Ukraine with potential to change prehospital training for the NATO alliance and other organizations operating in similar areas of conflict. Graphical Abstract.

Climate change and ecosystem shifts in the southwestern United States.

Climate change shifts ecosystems, altering their compositions and instigating transitions, making climate change the predominant driver of ecosystem instability. Land management agencies experience these climatic effects on ecosystems they administer yet lack applied information to inform mitigation. We address this gap, explaining ecosystem shifts by building relationships between the historical locations of 22 ecosystems (c. 2000) and abiotic data (1970-2000; bioclimate, terrain) within the southwestern United States using 'ensemble' machine learning models. These relationships identify the conditions required for establishing and maintaining southwestern ecosystems (i.e., ecosystem suitability). We projected these historical relationships to mid (2041-2060) and end-of-century (2081-2100) periods using CMIP6 generation BCC-CSM2-MR and GFDL-ESM4 climate models with SSP3-7.0 and SSP5-8.5 emission scenarios. This procedure reveals how ecosystems shift, as suitability typically increases in area (~ 50% (~ 40% SD)), elevation (12-15%) and northing (4-6%) by mid-century. We illustrate where and when ecosystems shift, by mapping suitability predictions temporally and within 52,565 properties (e.g., Federal, State, Tribal). All properties had ≥ 50% changes in suitability for ≥ 1 ecosystem within them, irrespective of size (≥ 16.7 km2). We integrated 9 climate models to quantify predictive uncertainty and exemplify its relevance. Agencies must manage ecosystem shifts transcending jurisdictions. Effective mitigation requires collective action heretofore rarely instituted. Our procedure supplies the climatic context to inform their decisions.