In clinical trials, individuals are matched using demographic criteria, paired and then randomly assigned to treatment and control groups to determine a drug's efficacy. A chief cause for the ...irreproducibility of results across pilot to Phase-III trials is population stratification bias caused by the uneven distribution of ancestries in the treatment and control groups.
Pair Matcher (PaM) addresses stratification bias by optimizing pairing assignments a priori and/or a posteriori to the trial using both genetic and demographic criteria. Using simulated and real datasets, we show that PaM identifies ideal and near-ideal pairs that are more genetically homogeneous than those identified based on competing methods, including the commonly used principal component analysis (PCA). Homogenizing the treatment (or case) and control groups can be expected to improve the accuracy and reproducibility of the trial or genetic study. PaM's ancestral inferences also allow characterizing responders and developing a precision medicine approach to treatment.
PaM is freely available via Rhttps://github.com/eelhaik/PAM and a web-interface at http://elhaik-matcher.sheffield.ac.uk/ElhaikLab/.
Supplementary data are available at Bioinformatics online.
IN Prince Alfred College Incorporated v ADC 2016 HCA 37, the High Court of Australia (HCA) has once again considered the appropriate test for establishing vicarious liability of employers for the ...wrongful acts of their employees. The decision will be of interest to tort lawyers in the common-law world for at least four reasons. First, the Court looked afresh at the test for vicarious liability in the context of intentional wrongdoing and has accordingly clarified the confusion arising from its earlier decision in New South Wales v Lepore 2003 HCA 4; (2003) 212 C.L.R. 511. Secondly, the Court expressed very strong disagreement with the decision of the UK Supreme Court handed down just months earlier in Mohamud v WM Morrison Supermarkets plc 2016 UKSC 11; 2016 A.C. 677. The Court apparently regarded Mohamud as having in effect abandoned the Lister qualification that mere opportunity was not enough to satisfy the close connection test (Lister v Hesley Hall Ltd. 2001 UKHL 22; 2002 1 A.C. 215). Thirdly, the Court appears to have interpreted the relevant English authorities as espousing a Caparo-like criterion of fairness and justice as a separate stage of the close connection test (Caparo Industries plc v Dickman 1990 2 A.C. 605). That interpretation is questionable. Finally, the Court has articulated a new test in Australian law for vicarious liability reasoning based on whether the employment provided the “occasion” for the wrongdoing to be committed. This prompts a reflection on the difference between “occasion” and “opportunity”, and how this new test is to be applied in practice.
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The duty on employers to provide reasonable accommodation is a well-established component
of disability discrimination legislation, yet it continues to generate litigation in many jurisdictions.
This ...article examines a recent decision of the Irish Supreme Court concerning the extent
of the employer’s obligations where, after having acquired an impairment, a worker is no longer
able to perform all of the functions of her original job. The case also addressed the question of
what procedures should be followed by an employer when considering the provision of reasonable
accommodation, as well as the need for courts to justify awards of compensation. The issues
in Irish law were intertwined with obligations arising from EU and international law instruments.
Therefore, the decision is pertinent for other jurisdictions confronting similar challenges.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, PRFLJ, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
For patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1), therapeutic options are limited. Raltegravir is a new molecule that inhibits HIV integrase. In two phase 3 ...studies, raltegravir was found to be superior to placebo, in the context of optimized background antiviral therapy, in suppressing HIV viral load at 48 weeks (62.1% vs. 32.9%).
In two phase 3 studies, raltegravir was found to be superior to placebo, in the context of optimized background antiviral therapy, in suppressing HIV viral load at 48 weeks (62.1% vs. 32.9%).
Highly active antiretroviral therapy is the standard of care for patients with advanced human immunodeficiency virus (HIV) infection.
1
Combination regimens have resulted in improved survival, decreased morbidity, and cost-effective care for patients with a CD4 count of less than 350 per cubic millimeter.
2
–
8
However, viral suppression cannot always be achieved or sustained with standard treatments because of the development of viral resistance, toxic effects of drugs, or lack of adherence.
9
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18
The majority of HIV-infected patients in whom highly active antiretroviral therapy fails have resistant viral quasispecies.
12
–
15
,
19
,
20
Cross-resistance to agents within a drug class may exhaust . . .
In subgroups of two phase 3 studies, patients with high-risk features for failure of antiretroviral therapy, such as a low CD4 count, high base-line level of human immunodeficiency virus (HIV) type 1 ...RNA, or unfavorable genotypic or phenotypic sensitivity score, raltegravir was superior to placebo in terms of a virologic response at 48 weeks. However, among these patients, in whom antiretroviral therapy had been used previously, 23% of raltegravir recipients had virologic failure by 48 weeks.
In patients with high-risk features for failure of antiretroviral therapy, raltegravir was superior to placebo in terms of a virologic response at 48 weeks. However, among these patients, in whom antiretroviral therapy had been used previously, 23% of raltegravir recipients had virologic failure by 48 weeks.
Despite the substantial decrease in mortality and morbidity rates associated with highly active antiretroviral therapy over the past decade, there is still a substantial need for effective antiretroviral drugs for patients infected with resistant human immunodeficiency virus type 1 (HIV-1).
1
,
2
The majority of licensed antiretroviral drugs belong to three classes targeting either the HIV-1 protease or reverse transcriptase, and considerable cross-resistance exists among drugs within each class.
3
,
4
In patients with resistant virus, use of antiretroviral agents from new classes offers considerable potential benefit because of the absence of cross-resistance.
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HIV-1 integrase represents a new therapeutic target.
8
, . . .
Objectives
To develop a high-performance, rapid semi-automated method (Sheffield TKV Tool) for measuring total kidney volume (TKV) from magnetic resonance images (MRI) in patients with autosomal ...dominant polycystic kidney disease (ADPKD).
Methods
TKV was initially measured in 61 patients with ADPKD using the Sheffield TKV Tool and its performance compared to manual segmentation and other published methods (ellipsoidal, mid-slice, MIROS). It was then validated using an external dataset of MRI scans from 65 patients with ADPKD.
Results
Sixty-one patients (mean age 45 ± 14 years, baseline eGFR 76 ± 32 ml/min/1.73 m
2
) with ADPKD had a wide range of TKV (258–3680 ml) measured manually. The Sheffield TKV Tool was highly accurate (mean volume error 0.5 ± 5.3% for right kidney, − 0.7 ± 5.5% for left kidney), reproducible (intra-operator variability − 0.2 ± 1.3%; inter-operator variability 1.1 ± 2.9%) and outperformed published methods. It took less than 6 min to execute and performed consistently with high accuracy in an external MRI dataset of T2-weighted sequences with TKV acquired using three different scanners and measured using a different segmentation methodology (mean volume error was 3.45 ± 3.96%,
n
= 65).
Conclusions
The Sheffield TKV Tool is operator friendly, requiring minimal user interaction to rapidly, accurately and reproducibly measure TKV in this, the largest reported unselected European patient cohort with ADPKD. It is more accurate than estimating equations and its accuracy is maintained at larger kidney volumes than previously reported with other semi-automated methods. It is free to use, can run as an independent executable and will accelerate the application of TKV as a prognostic biomarker for ADPKD into clinical practice.
Key Points
•
This new semi-automated method (Sheffield TKV Tool) to measure total kidney volume (TKV) will facilitate the routine clinical assessment of patients with ADPKD.
•
Measuring TKV manually is time consuming and laborious.
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TKV is a prognostic indicator in ADPKD and the only imaging biomarker approved by the FDA and EMA.
This paper explores the legal framework concerning the conscientious objection rights of employees in Ireland and critically considers how the various sources within that legal framework may overlap ...and intersect. It specifically considers the uncertainties created by section 22 of the Health (Regulation of Termination of Pregnancy) Act 2018 and its interaction with the Constitution of Ireland, the common law, other statutory regimes in employment law, EU law and the European Convention on Human Rights. In conducting this analysis, the paper attempts to map out likely future directions of travel within the law of conscientious objection in the context of termination of pregnancy in Ireland.
Nickel-Titanium (NiTi) peripheral stents are commonly used for the treatment of diseased femoropopliteal arteries (FPA). However, cyclic deformations of the vessel, induced by limb movements affect ...device performance and fatigue failure may occur. Stent strut fracture has been described in the literature, and is implicated as a potential causative factor in vessel re-occlusion. In this paper, a numerical approach is proposed to predict the fatigue behaviour of peripheral NiTi stents within patient-specific arterial geometries, as additional information to aid clinician intervention planning. The procedure needs some patient-specific vessel features derived from routine clinical images but, when this information is not available, reference data from the literature may be used, obviously increasing the uncertainties of the results. In addition, specific stent material data are required and can be obtained from experimental tests. Several 3D finite element models resembling stented vessel segments are built and used for fatigue analyses. For each model, axial cyclic boundary conditions are obtained from a patient-specific lumped parameter model representing the entire artery as a series of suitable springs. This allows the simplification of stiffness changes along the vessel due to plaque and stent that affect local axial deformations. Imposed local cyclic bending values depend on the stent location along the FPA. The procedure is exemplified by its application to an actual clinical case that showed two strut fractures at 18 months follow-up. Interestingly, despite the lack of some of patient-specific information and the use of data from the literature to inform the model, the numerical approach was able to interpret the
in vivo
fractures.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
THE common law has long recognised that people who engage independent contractors will not ordinarily be liable for the wrongdoing of those contractors, outside a closely guarded class of exceptional ...relationships in which the principal bears a personal liability for their negligent conduct. Selection of a properly qualified and competent contractor will ordinarily suffice to discharge any primary duty of care to victims of the contractor's torts imposed on the principal. Vicarious liability traditionally required finding an employment relationship between the principal and the wrongdoer. However the scope of vicarious liability has recently been expanded. In a quartet of cases ('Catholic Child Welfare Society v Various Claimants' 2012 UKSC 56, 2003 2 A.C. 1 (noted J. Bell 2013 C.L.J. 17)); 'Cox v Ministry of Justice' 2016 UKSC 10, 2016 A.C. 660; 'Mohamud v WM Morrison Supermarkets plc' 2016 UKSC 11, 2016 A.C. 677; 'Armes v Nottinghamshire County Council' 2017 UKSC 60, 2018 A.C. 355 (noted S. Deakin 2018 C.L.J. 15)), the Supreme Court recognised that vicarious liability may also be imposed in respect of the acts of persons who are in a position "akin to employment".
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