The nematode (Ascaris suum) intestine is a location of synergistic anthelmintic effects of Cry5B and levamisole.

A novel group of biocidal compounds are the Crystal 3D (Cry) and Cytolytic (Cyt) proteins produced by Bacillus thuringiensis (Bt). Some Bt Cry proteins have a selective nematocidal activity, with Cry5B being the most studied. Cry5B kills nematode parasites by binding selectively to membrane glycosphingolipids, then forming pores in the cell membranes of the intestine leading to damage. Cry5B selectively targets multiple species of nematodes from different clades and has no effect against mammalian hosts. Levamisole is a cholinergic anthelmintic that acts by selectively opening L-subtype nicotinic acetylcholine receptor ion-channels (L-AChRs) that have been found on muscles of nematodes. A synergistic nematocidal interaction between levamisole and Cry5B at the whole-worm level has been described previously, but the location, mechanism and time-course of this synergism is not known. In this study we follow the timeline of the effects of levamisole and Cry5B on the Ca2+ levels in enterocyte cells in the intestine of Ascaris suum using fluorescence imaging. The peak Ca2+ responses to levamisole were observed after approximately 10 minutes while the peak responses to activated Cry5B were observed after approximately 80 minutes. When levamisole and Cry5B were applied simultaneously, we observed that the responses to Cry5B were bigger and occurred sooner than when it was applied by itself. It is proposed that the synergism is due to the cytoplasmic Ca2+ overload that is induced by the combination of levamisole opening Ca2+ permeable L-subtype nAChRs and the Ca2+ permeable Cry5B toxin pores produced in the enterocyte plasma membranes. The effect of levamisole potentiates and speeds the actions of Cry5B that gives rise to bigger Ca2+ overloads that accelerates cell-death of the enterocytes.

Comparing body composition between the sweet-liking phenotypes: experimental data, systematic review and individual participant data meta-analysis.

BACKGROUND: Legislation aimed at reducing sugar intake assumes that sweet-liking drives overconsumption. However, evidence that a greater liking for sweet taste is associated with unhealthier body size is mixed and complicated by relatively small samples, an overreliance on body mass index (BMI) and lack of classification using sweet-liking phenotypes. METHODS: We first examined body size data in two larger samples with sweet-liking phenotyping: extreme sweet-likers, moderate sweet-likers and sweet-dislikers. Adults (18-34yrs), attended a two-session lab-based experiment involving phenotyping for sweet-liking status and a bioelectrical impedance body composition measurement (Experiment One: N = 200; Experiment Two: N = 314). Secondly, we conducted an individual participant data (IPD) meta-analysis: systematic searches across four databases identified 5736 potential articles. Of these, 53 papers met our search criteria: a taste assessment that measured liking using sucrose (>13.7% w/v), which allowed sweet-liking phenotyping and included either BMI, body fat percentage (BF%), fat-free mass (FFM) or waist-circumference. RESULTS: A significant effect of sweet-liking phenotype on FFM was found in both Experiment One and Two, with extreme sweet-likers having significantly higher FFM than sweet-dislikers. In Experiment One, sweet-dislikers had a significantly higher BF% than extreme sweet-likers and moderate sweet-likers. However, as these data are from one research group in a young, predominantly westernised population, and the results did not perfectly replicate, we conducted the IPD meta-analyses to further clarify the findings. Robust one-stage IPD meta-analyses of 15 studies controlling for sex revealed no significant differences in BF% (n = 1836) or waist-circumference (n = 706). For BMI (n = 2368), moderate sweet-likers had slightly lower BMI than extreme sweet-likers, who had the highest overall BMI. Most interestingly, for FFM (n = 768), moderate sweet-likers and sweet-dislikers showed significantly lower FFM than extreme sweet-likers. CONCLUSION: The higher BMI often seen in sweet-likers may be due to a larger FFM and questions the simple model where sweet liking alone is a risk factor for obesity.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Exploring the associations between adverse childhood experiences (ACEs) and adolescent cancer risk behaviours in the ALSPAC cohort.

BACKGROUND: Some modifiable risk factors for cancer originate during adolescence. While there is evidence indicating relationships between adverse childhood experiences and health risk behaviours generally, little is known about how childhood adversity influences the engagement of adolescents in cancer risk behaviours. This study aimed to determine the relationship between adverse childhood experiences and adolescent cancer risk behaviours. METHODS: Data were collected prospectively from birth to age 18 years on children born to mothers enrolled into the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study. Multivariable linear regression models assessed relationships of a composite exposure measure comprised of adverse childhood experiences (total number of childhood adversities experienced from early infancy until age 9 years) with multiple cancer risk behaviours. The latter was expressed as a single continuous score for tobacco smoking, alcohol consumption, obesity, unsafe sex, and physical inactivity, at ages 11, 14, 16 and 18 years. Analysis was carried out on the complete case and imputation samples of 1,368 and 7,358 participants respectively. RESULTS: All adolescent cancer risk behaviours increased in prevalence as the adolescents grew older, except for obesity. Each additional adverse childhood experience was associated with a 0.25 unit increase in adolescent cancer risk behaviour (95% CI 0.16-0.34; p < 0.001). Individually, parental substance misuse (ß 0.64, 95% CI 0.25-1.03, p < 0.001) and parental separation (ß 0.56, 95% CI 0.27-0.86, p < 0.001) demonstrated the strongest evidence of association with engagement in adolescent cancer risk behaviour. CONCLUSION: Childhood adversity was associated with a greater degree of engagement in adolescent cancer risk behaviours. This finding demonstrates the need for targeted primary and secondary prevention interventions that reduce engagement across multiple cancer risk behaviours for children and adolescents who have experienced adversity in childhood, such as parental substance misuse and separation, and reduce exposure to adversity.

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Convicting Peaceful Protesters: Proportionality's Proper Place at Criminal Trial.

Suppose that a defendant's conviction would amount to an interference with their right to peaceful protest, protected by articles 10 and 11 of the European Convention on Human Rights. Is a court then obliged to make a conviction turn on a fact-sensitive proportionality assessment justifying the interference? Drawing on the jurisprudence of the domestic and Strasbourg courts, this article argues that the case law has crystallised into two paradigms that provide distinct answers: the 'justificatory paradigm' in European human rights law and the 'offence-centric' paradigm in domestic law. The article exposes how and why this divergence has developed, what is at stake at the level of constitutional values and how this conflict might be resolved. It is argued that compliance with Strasbourg now depends on the integration of the justificatory paradigm into domestic law. The article imagines how this might be done in a manner sensitive to domestic constitutional values, using the mechanics on offer in the Human Rights Act 1998.

Feature-preserving synthesis of termite-mimetic spinodal nest morphology.

Termite-built topology is complex due to group interactions and environmental feedback. Being interlinked with material characteristics and related to functionality, an accurate synthesis of termite mound topology has never been achieved. We scanned inner termite mound pieces via high-resolution micro-computed tomography. A wavelet scattering transform followed by optimization extracts features that are fed into a Gaussian Random Fields (GRFs) approach to synthesize termite-mimetic spinodal topology. Compared to natural structures the GRF topology is more regular. Irregularity is related to anisotropy, indicative of directionality caused by porous network connectivity of chambers and corridors. Since GRFs are related to diffusion, we assume that deterministic behavioral traits play a significant role in the development of these local differences. We pioneer a framework to reliably mimic termite mound spinodal features. Engineering termite-inspired structures will allow to inspect aspects of termite architectures and their behavior to manufacture novel material concepts with imprinted multi-functionality.

Causal Estimation of Long-term Intervention Cost-effectiveness Using Genetic Instrumental Variables: An Application to Cancer.

BACKGROUND: This article demonstrates a means of assessing long-term intervention cost-effectiveness in the absence of data from randomized controlled trials and without recourse to Markov simulation or similar types of cohort simulation. METHODS: Using a Mendelian randomization study design, we developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate, and thyroid cancers on health care costs and quality-adjusted life-years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used these estimates in a simulation model to estimate the cost-effectiveness of a hypothetical population-wide preventative intervention based on a repurposed class of antidiabetic drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer. RESULTS: Genetic liability to prostate cancer and breast cancer had material causal impacts on either or both health care costs and QALYs. Mendelian randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anticancer indication. IMPLICATIONS: Our new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision-analytic models of cancer interventions such as screening programs or simulations of longer-term outcomes associated with therapies investigated in randomized controlled trials with short follow-ups. Our method allowed us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anticancer intervention to inform and complement other means of assessing long-term intervention value. HIGHLIGHTS: The article demonstrates a novel method of assessing long-term intervention cost-effectiveness without relying on randomized controlled trials or cohort simulations.Mendelian randomization was used to estimate the causal effects of certain cancers on health care costs and quality-adjusted life-years (QALYs) using data from the UK Biobank cohort.Given causal data on the association of different cancer exposures on costs and QALYs, it was possible to simulate the cost-effectiveness of an anticancer intervention.Genetic liability to prostate cancer and breast cancer significantly affected health care costs and QALYs, but the hypothetical intervention using SGLT2 inhibitors for prostate cancer may not be cost-effective, depending on the drug's price for the new anticancer indication. The methods we propose and implement can be used to efficiently estimate intervention cost-effectiveness and to inform decision making in all manner of preventative and therapeutic contexts.

Investigating the causal effect of previously reported therapeutic agents for colorectal cancer prevention: protocol for a Mendelian randomization analysis.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. Methods and analysis: We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.

Colorectal cancer is the third most common cancer worldwide and the second most common cause of cancer-related death. An individual's chances of surviving the disease are increased if it is caught early or even prevented from developing in the first place. Currently, screening in the UK is offered to everyone over the age of 50 and whilst this can be effective in early cancer detection and secondary prevention, additional prevention strategies are needed to reduce cancer rates. Previous research has investigated whether intake of certain medications, dietary micronutrients or hormones can help prevent colorectal cancer development. There is some evidence to show that taking aspirin can reduce your risk of developing colorectal cancer, however, given potential adverse side effects to taking aspirin (e.g. gastrointestinal bleeding), this medication is not suitable for everyone. We wanted to assess whether other previously identified medications, micronutrients or hormones have any effect on reducing risk of cancer development. If we can identify a compound that could reduce an individual's risk of developing colorectal cancer, it could be used as an additional cancer prevention strategy. We curated a list of potential preventive compounds from previously conducted studies that used observational epidemiological (i.e. non-randomised) methods. Distinguishing statistical correlations from causal relationships when using observational methods can be difficult. This can be due to additional factors in the study affecting both the use of potential preventive compounds and an individual's risk of cancer development (e.g. those taking vitamin supplements having a healthier diet) or the observed relationship may be causal but in the opposite direction (e.g. a cancer diagnosis has a subsequent effect on dietary habits). We will use an alternative epidemiological method, called Mendelian randomization, which uses genetics to attempt to overcome this issue and enable us to determine if a specific compound is reducing cancer risk.

Investigating the association between genetically proxied circulating levels of immune checkpoint proteins and cancer survival: protocol for a Mendelian randomisation analysis.

INTRODUCTION: Compared with the traditional drug development pathway, investigating alternative uses for existing drugs (ie, drug repurposing) requires substantially less time, cost and resources. Immune checkpoint inhibitors are licensed for the treatment of certain breast, colorectal, head and neck, lung and melanoma cancers. These drugs target immune checkpoint proteins to reduce the suppression of T cell activation by cancer cells. As T cell suppression is a hallmark of cancer common across anatomical sites, we hypothesise that immune checkpoint inhibitors could be repurposed for the treatment of additional cancers beyond the ones already indicated. METHODS AND ANALYSIS: We will use two-sample Mendelian randomisation to investigate the effect of genetically proxied levels of protein targets of two immune checkpoint inhibitors-programmed cell death protein 1 and programmed death ligand 1-on survival of seven cancer types (breast, colorectal, head and neck, lung, melanoma, ovarian and prostate). Summary genetic association data will be obtained from prior genome-wide association studies of circulating protein levels and cancer survival in populations of European ancestry. Various sensitivity analyses will be performed to examine the robustness of findings to potential violations of Mendelian randomisation assumptions, collider bias and the impact of alternative genetic instrument construction strategies. The impact of treatment history and tumour stage on the findings will also be investigated using summary-level and individual-level genetic data where available. ETHICS AND DISSEMINATION: No separate ethics approval will be required for these analyses as we will be using data from previously published genome-wide association studies which individually gained ethical approval and participant consent. Results from analyses will be submitted as an open-access peer-reviewed publication and statistical code will be made freely available on the completion of the analysis.

Selective Preservation of Tooth (SPOT): A Step-by-Step Protocol for a Precise, Reproducible, Socket-Shield Technique.

The socket-shield technique is a clinical procedure aimed at preventing both hard- and soft-tissue collapse following immediate implant placement. The technique can be challenging as multiple factors influence the precision of this treatment. Selective preservation of tooth (SPOT) is a standardized, reproducible tooth-guided preparation protocol for achieving a socket shield and for immediate post-extraction implant site preparation and placement. SPOT emphasizes the utilization of osseodensification burs in both forward (ie, clockwise) rotation, to allow for simultaneous precise root apex removal and shield preparation, and reverse (ie, counterclockwise) rotation, to allow for implant site preparation with further compaction-autografting of bone and dentin, thereby improving implant primary stability and its subsequent early healing. This article presents SPOT in a step-by-step protocol for socket-shield and implant site preparation with immediate post-extraction implant placement. The article describes the stepwise application for single-rooted teeth.

Impact of connected dispensing technology with advanced analytics in a multicenter health system.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: This study was designed to evaluate the impact of enterprise inventory optimization (EIO) technology and analytics on pharmacy labor, costs, and medication availability within a large integrated delivery network (IDN). METHODS: This article describes a mixed-methods, postmarket observational study assessing the impact of a solution of disparate technologies including automated dispensing cabinets (ADCs), centralized pharmacy inventory software, and controlled substance vaults connected by an inventory optimization analytics (IOA) tool. Four study modules were implemented over a 10-month period. The intervention consisted of implementation of the IOA software, linking the disparate automated technologies. Transactional data was collected and aggregated with user perception survey data in both the pre- and postintervention periods. Descriptive and comparative statistical testing was used to assess outcomes. RESULTS: A total of 11 facilities with bed counts ranging between 22 and 908 beds were included in this study. At an enterprise level, users were able to complete an average of 2.8 times more periodic automated replenishment (PAR) level changes post intervention, resulting in an estimated enterprise labor avoidance of over 1 full-time equivalent (2,099 labor hours) annually. Despite an enterprise decision to increase ADC inventory on hand from a 3-day supply to a 5-day supply, 5 sites (45%) had a decrease in total inventory, while 9 sites (82%) saw a decrease in ADC inventory costs. Additionally, 7 sites (64%) saw a reduction in the ADC stockout percentage and all 11 sites (100%) saw a decrease in the central pharmacy stockout percentage post intervention. CONCLUSION: Integration and optimization of connected inventory management technology was observed to have positive impacts on improving labor productivity, reducing ADC inventory carrying costs, and increasing medication availability.

Exploring melanoma shifts: a two-decade analysis in New Zealand.

AIMS: New Zealand melanoma incidence rates are amongst the highest in the world. The study aims to provide information on the incidence of cutaneous melanoma in New Zealand from 2000 to 2022. METHODS: De-identified data were extracted from the New Zealand Cancer Registry using the ICD-10 code for malignant melanoma (C34) and melanoma in situ (MIS) (D03) from 2000 to 2022. Statistical analysis was performed to calculate melanoma incidence rates. RESULTS: Invasive melanoma (IM) incidence rates demonstrated an increasing trend from 2000 to 2008 (+1.10 per 100,000 person-years per year), followed by an inflection point at 2008 and then a decreasing trend from 2008 to 2022 (-0.28 per 100,000 person-years per year), which was not statistically different from zero/no change. MIS incidence increased from 30.3 to 72.1 per 100,000 person-years between 2000 and 2022. CONCLUSIONS: The incidence of IM in New Zealand has plateaued in the last decade and was associated with an increase in MIS incidence over the same period. While this trend is encouraging, further research is required to investigate whether there is an actual decline in IM incidence.

Use of drugs for hyperlipidaemia and diabetes and risk of primary and secondary brain tumours: nested case-control studies using the UK Clinical Practice Research Datalink (CPRD).

OBJECTIVES: Previous studies have suggested that fibrates and glitazones may have a role in brain tumour prevention. We examined if there is support for these observations using primary care records from the UK Clinical Practice Research Datalink (CPRD). DESIGN: We conducted two nested case-control studies using primary and secondary brain tumours identified within CPRD between 2000 and 2016. We selected cases and controls among the population of individuals who had been treated with any anti-diabetic or anti-hyperlipidaemic medication to reduce confounding by indication. SETTING: Adults older than 18 years registered with a general practitioner in the UK contributing data to CPRD. RESULTS: We identified 7496 individuals with any brain tumour (4471 primary; 3025 secondary) in total. After restricting cases and controls to those prescribed any anti-diabetic or anti-hyperlipidaemic medication, there were 1950 cases and 7791 controls in the fibrate and 480 cases with 1920 controls in the glitazone analyses. Longer use of glitazones compared with all other anti-diabetic medications was associated with a reduced risk of primary (adjusted OR (aOR) 0.89 per year, 95% CI 0.80 to 0.98), secondary (aOR 0.87 per year, 95% CI 0.77 to 0.99) or combined brain tumours (aOR 0.88 per year, 95% CI 0.81 to 0.95). There was little evidence that fibrate exposure was associated with risk of either primary or secondary brain tumours. CONCLUSIONS: Longer exposure to glitazones was associated with reduced primary and secondary brain tumour risk. Further basic science and population-based research should explore this finding in greater detail, in terms of replication and mechanistic studies.

Association between Intermittent Hypoxemia and NICU Length of Stay in Preterm Infants.

INTRODUCTION: Length of hospitalization varies widely in preterm infants and can be affected by multiple maternal and neonatal factors including respiratory instability. Therefore, we aimed to determine the association between postnatal intermittent hypoxemia (IH) and prolonged hospitalization. METHODS: This prospective single-center cohort study followed infants born at <31 weeks of gestational age through 2 years corrected age with detailed oxygen saturation data captured from days 7 to 30 of age. RESULTS: 51/164 (31%) of infants were discharged after 400/7 weeks of corrected gestational age (CGA). A greater average daily number of IH events (OR per 10 events/day 1.33 [95% CI 1.03-1.72]), duration of events (OR per minute 1.14 [1.07-1.21]), and percent time with oxygen saturation <80% (OR per percent 1.88 [1.25-2.85]) on days 7-30 of age were all significantly associated with prolonged hospitalization past 400/7 weeks CGA. In survival analyses, infants with a greater average daily number of IH events (HR per 10 events/day 0.89 [0.81-0.98]), percent time with oxygen saturation <80% (HR per percent 0.79 [0.67-0.94]), and duration of events (HR per minute 0.93 [0.91-0.95]) on days 7-30 of age all had significantly lower probability of earlier discharge. In addition, there was a significant interaction with gestational age; the association between IH and prolonged hospitalization was stronger in more mature infants (p = 0.024). CONCLUSIONS: Physiological instability on days 7-30 of age, as manifested by IH, is significantly associated with prolonged hospitalization. IH likely represents both a marker of initial severity of illness and the beginning of biological cascades, leading to prematurity-associated morbidities.

Elevated Urine Hyaluronan Concentrations Are Associated with an Unfavorable Respiratory Outcome in Preterm Neonates at 40 Weeks Postmenstrual Age.

INTRODUCTION: Hyaluronan (HA) is a major component of the extracellular matrix. Increased pulmonary HA concentrations are associated with several respiratory disorders and is a pathophysiological feature of lung disease. We investigated whether elevated urine HA is a biomarker of an unfavorable 40-week respiratory outcome in preterm infants. METHODS: Infants comprised a cohort of preterm neonates <31 weeks gestational age (GA) from the Prematurity-Related Ventilatory Control (Pre-Vent) multicenter study. HA was quantified in urine obtained at 1 week and 1 month of age. Respiratory status at 40 weeks post-menstrual age (PMA) was classified as unfavorable [either (1) deceased at or before 40 weeks PMA, (2) an inpatient on respiratory medication, O2 or other respiratory support at 40 weeks, or (3) discharged prior to 40 weeks on medications/O2/other respiratory support], or favorable (alive and previously discharged, or inpatient and off respiratory medications, off O2, and off other respiratory support at 40 weeks PMA). The association between urine HA and the unfavorable 40 week PMA outcome was examined using a multivariate logistic generalized estimation equation model. RESULTS: Infants with higher HA at 1 week (but not 1 month) showed increased odds of unfavorable respiratory outcome at 40 weeks PMA (OR [95% CI] = 1.87 per 0.01 mg [1.27, 2.73]). DISCUSSION AND CONCLUSION: Neonatal urine screening for HA could identify infants at risk for death or need for respiratory support at term-corrected age (40 weeks PMA). The relationship between elevated HA at 1 week and an unfavorable 40 week outcome was stronger in infants with lower GA.

Understanding the Utility of Less Than Six-Month Prognosis Using Administrative Data Among U.S. Nursing Home Residents With Cancer.

Background: There is a dearth of studies evaluating the utility of reporting prognostication among nursing home (NH) residents with cancer. Objective: To study factors associated with documented less than six-month prognosis, and its relationship with end-of-life (EOL) care quality measures among residents with cancer. Methods: The Surveillance, Epidemiology, and End Results linked with Medicare, and the Minimum Data Set databases was used to identify 20,397 NH residents in the United States with breast, colorectal, lung, pancreatic, or prostate cancer who died between July 2016 and December 2018. Of these, 2205 residents (10.8%) were documented with less than six-month prognosis upon NH admission. Main outcomes were more than one hospitalization, more than one emergency department visit, and any intensive care unit admission within the last 30 days of life as aggressive EOL care markers, as well as admission to hospice, receipt of advance care planning and palliative care, and survival. Specificity and sensitivity of prognosis were assessed using six-month mortality as the outcome. Propensity score matching adjusted for selection biases, and logistic regression examined association. Results: Specificity and sensitivity of documented less than six-month prognosis for mortality were 94.2% and 13.7%, respectively. Residents with documented less than six-month prognosis had greater odds of being admitted to hospice than those without (adjusted odds ratio: 3.27, 95% confidence interval: 2.86-3.62), and lower odds to receive aggressive EOL care. Conclusion: In this cohort study, documented less than six-month prognosis was associated with less aggressive EOL care. Despite its high specificity, however, low sensitivity limits its utility to operationalize care on a larger population of residents with terminal illness.