Inflammatory Cytokine Levels in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy that causes adult-onset progressive renal failure. Inflammation and the resulting fibrosis play a crucial role in the pathogenesis. In recent years, an increasing number of inflammatory markers such as MCP-1 and TNF-α, that are associated with the development and progression of ADPKD have been identified. The objective of this study was to identify and evaluate potential proinflammatory biomarkers in patients with ADPKD from the German AD(H)PKD registry. METHODS: In this exploratory pilot study, serum concentrations of IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-13, IFN-γ, MCP-1 and TNF-α were measured by multiplex immunoassay in 233 adults patients with ADPKD from the German AD(H)PKD registry and compared to an age- and sex-matched healthy control group (n = 30). RESULTS: IL-6, IL-8, MCP-1, TNF-α and IFN-γ concentrations were significantly higher in patients with ADPKD than in healthy controls. In addition, sex influenced the concentrations of MCP-1 and TNF-α in the ADPKD and control groups (MCP-1 male =134.8 pg/l, female=75.11pg/l; p = 0.0055; TNF-α male=26.22pg/l, female=21.08 pg/l; p = 0.0038). CONCLUSION: In conclusion, patients with ADPKD have significantly higher levels of IL-6, IL-8, MCP-1, TNF-α and IFN-γ compared to healthy individuals. These findings underline that inflammation may play a crucial role in the pathogenesis of ADPKD and may be a potential target, both as biomarkers and for therapeutic interventions.

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.

Optimising the use of the prostate- specific antigen blood test in asymptomatic men for early prostate cancer detection in primary care: report from a UK clinical consensus.

BACKGROUND: Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying. AIM: To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection. DESIGN AND SETTING: Prostate Cancer UK facilitated a RAND/UCLA consensus. METHOD: Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel. RESULTS: Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk. CONCLUSION: Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines.

SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023).

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature.

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.

Proliferating macrophages in human tumours show characteristics of monocytes responding to myelopoietic growth factors.

Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates in situ within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-ß. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate in vitro that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.

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.

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.

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.

Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics.

BACKGROUND: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. METHODS: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. FINDINGS: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. INTERPRETATION: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer. FUNDING: This work was supported by Cancer Research UK (grant no. C8221/A29017).

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.

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

Objective.Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from>700extremely preterm infants to identify physiologic features that predict respiratory outcomes.Approach. We calculated a subset of 33 HCTSA features on>7 M 10 min windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on>3500HCTSA algorithms. We hypothesized that the best HCTSA algorithms would compare favorably to optimal PreVent physiologic predictor IH90_DPE (duration per event of intermittent hypoxemia events below 90%).Main Results.The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90_DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850).Significance. These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.

Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

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.

Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers.

Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.

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.

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.

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.