The Identity Criterion: Resuscitating a Cardozian, Relational Approach to Duty of Care in Negligence

Everyone agrees that the canonical case in American negligence law is Palsgraf v. Long Island Railroad Co. In his famous majority opinion in the New York Court of Appeals, Chief Judge Benjamin Cardozo held that the outcome of the case turned on whether the plaintiff, Mrs. Palsgraf, had been owed a duty of care by the Long Island Railroad. He declared that the answer to this question depended on whether the parties had a relevant relationship at the time of the conduct under consideration. “Negligence, like risk,” he said, is “a term of relation. Negligence in the abstract, apart from things related, is surely not a tort, if indeed it is understandable at all.” Over ninety years have passed since then. One thing that everyone agrees upon (including Judge Charles Andrews, who wrote the almost equally famous dissent in Palsgraf) is that not everyone who sustains an injury as the result of someone else’s negligence is entitled to compensation in a court of law. In Andrews’s words, “because of convenience, of public policy, of a rough sense of justice, the law arbitrarily declines to trace a series of events beyond a certain point.” Yet torts lawyers continue to search in vain for a full articulation of a relational approach to duty of care that tells us where that point is. This paper seeks to fill that void

Truncation of POC1A associated with short stature and extreme insulin resistance

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health

A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease.

Alcohol has been implicated in both the popular press and scientific literature as having a protective effect for at least a dozen conditions including coronary heart disease (CHD). Approach. Epidemiological evidence for an apparent protective effect of alcohol on CHD is now being challenged on a number of fronts.This paper is a synopsis of those various challenges as they currently stand. Key Findings. The argument that systematic misclassification of ex-drinkers and occasional drinkers to 'abstainer' categories among epidemiological studies might explain apparent protective effects of moderate alcohol consumption on CHD has recently been supported by new meta-analyses and independent research. The influence of uncontrolled or unknown factors on the relationship between alcohol and disease cannot be ruled out. Exclusion of participants on the basis of ill-health severely reduces study sample size and new analyses suggest that doing so might artificially create the appearance of protective effects.The ability of respondents to accurately recall their own alcohol consumption is in serious doubt and very few individuals maintain one single drinking level or style throughout life.The relationship between alcohol and some conditions might be a function of drinking patterns but few studies have addressed the issue. Implications. Popular perceptions regarding the strength of evidence for alcohol's protective effect on a growing number of conditions might be misguided. Conclusion. It is time for the wider research, health and medical community to seriously reflect on the quality of current evidence for apparent protective effects of alcohol on human disease

Suvorexant, a Novel Dual Orexin Receptor Antagonist, for the Management of Insomnia.

PURPOSE OF REVIEW: The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexant\u27s role in targeting insomnia with other comorbidities. RECENT FINDINGS: Insomnia refers to poor quality and/or quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexant\u27s effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimer\u27s disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment. SUMMARY: Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia

Implementation of Oxygen Enhanced Magnetic Resonance Imaging (OE-MRI) and a Pilot Genomic Study of Hypoxia in Bladder Cancer Xenografts

BACKGROUND/AIM: Patients with hypoxic bladder cancer benefit from hypoxia modification added to radiotherapy, but no biomarkers exist to identify patients with hypoxic tumours. We, herein, aimed to implement oxygen-enhanced MRI (OE-MRI) in xenografts derived from muscle-invasive bladder cancer (MIBC) for future hypoxia biomarker discovery work; and generate gene expression data for future biomarker discovery.MATERIALS AND METHODS: The flanks of female CD-1 nude mice inoculated with HT1376 MIBC cells. Mice with small (300 mm 3) or large (700 mm 3) tumours were imaged, breathing air then 100% O 2, 1 h post injection with pimonidazole in an Agilant 7T 16cm bore magnet interfaced to a Bruker Avance III console with a T2-TurboRARE sequence using a dynamic MPRAGE acquisition. Dynamic Spoiled Gradient Recalled Echo images were acquired for 5 min, with 0.1mmol/kg Gd-DOTA (Dotarem, Guerbet, UK) injected after 60 s (1 ml/min). Voxel size and field of view of dynamic contrast enhanced (DCE)-MRI and OE-MRI scans were matched. The voxels considered as perfused with significant post-contrast enhancement (p&lt;0.05) in DCE-MRI scans and tissue were further split into pOxyE (normoxic) and pOxyR (hypoxic) regions. Tumours harvested in liquid N 2, sectioned, RNA was extracted and transcriptomes analysed using Clariom S microarrays. RESULTS: Imaged hypoxic regions were greater in the larger versus smaller tumour. Expression of known hypoxia-inducible genes and a 24 gene bladder cancer hypoxia score were higher in pimonidazole-high versus -low regions: CA9 (p=0.012) and SLC2A1 (p=0.012) demonstrating expected transcriptomic behaviour.CONCLUSION: OE-MRI was successfully implemented in MIBC-derived xenografts. Transcriptomic data derived from hypoxic and non-hypoxic xenograft regions will be useful for future studies.</p

Maternal proviral load and vertical transmission of Human T cell Lymphotropic Virus type 1 in Guinea-Bissau

The relative importance of routes of transmission of human T cell lymphotropic virus type 1 (HTLV-1) in Guinea-Bissau is largely unknown; vertical transmission is thought to be important, but there are very few existing data. We aimed to examine factors associated with transmission in mothers and children in Guinea-Bissau, where HTLV-1 is endemic (prevalence of 5% in the adult population). A cross-sectional survey was performed among mothers and their children (aged <15 years) in a rural community in Guinea-Bissau. A questionnaire to identify risk factors for infection and a blood sample were obtained. HTLV-1 proviral load in peripheral blood was determined and PCR was performed to compare long terminal repeat (LTR) sequences in mother-child pairs. Fourteen out of 55 children (25%) of 31 HTLV-1-infected mothers were infected versus none of 70 children of 30 uninfected mothers. The only factor significantly associated with HTLV-1 infection in the child was the proviral load of the mother; the risk of infection increased significantly with the log(10) proviral load in the mother's peripheral blood (OR 5.5, 95% CI 2.1-14.6, per quartile), adjusted for weaning age and maternal income. HTLV-1 sequences of the LTR region obtained from mother-child pairs were identical within pairs but differed between the pairs. Vertical transmission plays an important role in HTLV-1 transmission in this community in Guinea-Bissau. The risk of transmission increases with the mother's proviral load in the peripheral blood. Identical sequences in mother-child pairs give additional support to the maternal source of the children's infectio

Managing clinically significant findings in research: The UK10K example

Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs. © 2014 Macmillan Publishers Limited All rights reserved