The influence of relatives on the efficiency and error rate of familial searching

We investigate the consequences of adopting the criteria used by the state of California, as described by Myers et al. (2011), for conducting familial searches. We carried out a simulation study of randomly generated profiles of related and unrelated individuals with 13-locus CODIS genotypes and YFiler Y-chromosome haplotypes, on which the Myers protocol for relative identification was carried out. For Y-chromosome sharing first degree relatives, the Myers protocol has a high probability (80 - 99%) of identifying their relationship. For unrelated individuals, there is a low probability that an unrelated person in the database will be identified as a first-degree relative. For more distant Y-haplotype sharing relatives (half-siblings, first cousins, half-first cousins or second cousins) there is a substantial probability that the more distant relative will be incorrectly identified as a first-degree relative. For example, there is a 3 - 18% probability that a first cousin will be identified as a full sibling, with the probability depending on the population background. Although the California familial search policy is likely to identify a first degree relative if his profile is in the database, and it poses little risk of falsely identifying an unrelated individual in a database as a first-degree relative, there is a substantial risk of falsely identifying a more distant Y-haplotype sharing relative in the database as a first-degree relative, with the consequence that their immediate family may become the target for further investigation. This risk falls disproportionately on those ethnic groups that are currently overrepresented in state and federal databases.Comment: main text: 19 pages, 4 tables, 2 figures supplemental text: 2 pages, 5 tables all together as single fil

Mistake of Federal Criminal Law: A Study of Coaltions and Costly Information

This article analyzes Supreme Court and other federal court cases, to explain the seemingly disparate incorporation of mistake of law excuses into federal criminal statutes. Most of the cases can be explained from an information cost perspective. If an easily separable subset of the regulated population cannot be induced to learn their legal obligations given credibly low prior probabilities and high information costs, they are excused from criminal liability. Moreover, when criminal statutes are vulnerable to constituent protest, courts require that enforcers increase awareness of the law through information subsidies rather than convicting the ignorant. At least with mistake of law, the federal courts most often interpret federal statutes to enhance both the value and durability of legislative bargains

Evaluating diverse electronic consultation programs with a common framework.

BackgroundElectronic consultation is an emerging mode of specialty care delivery that allows primary care providers and their patients to obtain specialist expertise without an in-person visit. While studies of individual programs have demonstrated benefits related to timely access to specialty care, electronic consultation programs have not achieved widespread use in the United States. The lack of common evaluation metrics across health systems and concerns related to the generalizability of existing evaluation efforts may be hampering further growth. We sought to identify gaps in knowledge related to the implementation of electronic consultation programs and develop a set of shared evaluation measures to promote further diffusion.MethodsUsing a case study approach, we apply the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) and the Quadruple Aim frameworks of evaluation to examine electronic consultation implementation across diverse delivery systems. Data are from 4 early adopter healthcare delivery systems (San Francisco Health Network, Mayo Clinic, Veterans Administration, Champlain Local Health Integration Network) that represent varied organizational structures, care for different patient populations, and have well-established multi-specialty electronic consultation programs. Data sources include published and unpublished quantitative data from each electronic consultation database and qualitative data from systems' end-users.ResultsOrganizational drivers of electronic consultation implementation were similar across the systems (challenges with timely and/or efficient access to specialty care), though unique system-level facilitators and barriers influenced reach, adoption and design. Effectiveness of implementation was consistent, with improved patient access to timely, perceived high-quality specialty expertise with few negative consequences, garnering high satisfaction among end-users. Data about patient-specific clinical outcomes are lacking, as are policies that provide guidance on the legal implications of electronic consultation and ideal remuneration strategies.ConclusionA core set of effectiveness and implementation metrics rooted in the Quadruple Aim may promote data-driven improvements and further diffusion of successful electronic consultation programs

Multiple factors interact to produce responses resembling spectrum of human disease in Campylobacter jejuni infected C57BL/6 IL-10-/- mice

<p>Abstract</p> <p>Background</p> <p><it>Campylobacter jejuni </it>infection produces a spectrum of clinical presentations in humans – including asymptomatic carriage, watery diarrhea, and bloody diarrhea – and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different <it>C. jejuni </it>strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model.</p> <p>Results</p> <p>In the comparative study, C57BL/6 interleukin-10^-/-mice were infected with seven genetically distinct <it>C. jejuni </it>strains. Four strains colonized the mice and caused disease; one colonized with no disease; two did not colonize. A DNA:DNA microarray comparison of the strain that colonized mice without disease to <it>C. jejuni </it>11168 that caused disease revealed that putative virulence determinants, including loci encoding surface structures known to be involved in <it>C. jejuni </it>pathogenesis, differed from or were absent in the strain that did not cause disease. In the experimental study, the five colonizing strains were passaged four times in mice. For three strains, serial passage produced increased incidence and degree of pathology and decreased time to develop pathology; disease shifted from watery to bloody diarrhea. Mice kept on an ~6% fat diet or switched from an ~12% fat diet to an ~6% fat diet just before infection with a non-adapted strain also exhibited increased incidence and severity of disease and decreased time to develop disease, although the effects of diet were only statistically significant in one experiment.</p> <p>Conclusion</p> <p><it>C. jejuni </it>strain genetic background and adaptation of the strain to the host by serial passage contribute to differences in disease manifestations of <it>C. jejuni </it>infection in C57BL/6 IL-10^-/-mice; differences in environmental factors such as diet may also affect disease manifestation. These results in mice reflect the spectrum of clinical presentations of <it>C. jejuni </it>gastroenteritis in humans and contribute to usefulness of the model in studying human disease.</p

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases

Immune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p \u3c 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials

Wintertime Spatial Distribution of Ammonia and its Emission Sources in the Great Salt Lake Region

Ammonium-containing aerosols are a major component of wintertime air pollution in many densely populated regions around the world. Especially in mountain basins, the formation of persistent cold-air pools (PCAPs) can enhance particulate matter with diameters less than 2.5 µm (PM2.5) to levels above air quality standards. Under these conditions, PM2.5 in the Great Salt Lake region of northern Utah has been shown to be primarily composed of ammonium nitrate; however, its formation processes and sources of its precursors are not fully understood. Hence, it is key to understanding the emission sources of its gas phase precursor, ammonia (NH3). To investigate the formation of ammonium nitrate, a suite of trace gases and aerosol composition were sampled from the NOAA Twin Otter aircraft during the Utah Winter Fine Particulate Study (UWFPS) in January and February 2017. NH3 was measured using a quantum cascade tunable infrared laser differential absorption spectrometer (QC-TILDAS), while aerosol composition, including particulate ammonium (pNH4), was measured with an aerosol mass spectrometer (AMS). The origin of the sampled air masses was investigated using the Stochastic Time-Inverted Lagrangian Transport (STILT) model and combined with an NH3 emission inventory to obtain model-predicted NHx (=NH3+pNH4) enhancements. Enhancements represent the increase in NH3 mixing ratios within the last 24 h due to emissions within the model footprint. Comparison of these NHx enhancements with measured NHx from the Twin Otter shows that modelled values are a factor of 1.6 to 4.4 lower for the three major valleys in the region. Among these, the underestimation is largest for Cache Valley, an area with intensive agricultural activities. We find that one explanation for the underestimation of wintertime emissions may be the seasonality factors applied to NH3 emissions from livestock. An investigation of inter-valley exchange revealed that transport of NH3 between major valleys was limited and PM2.5 in Salt Lake Valley (the most densely populated area in Utah) was not significantly impacted by NH3 from the agricultural areas in Cache Valley. We found that in Salt Lake Valley around two thirds of NHx originated within the valley, while about 30 % originated from mobile sources and 60 % from area source emissions in the region. For Cache Valley, a large fraction of NOx potentially leading to PM2.5 formation may not be locally emitted but mixed in from other counties

Targeted Therapy After Brain Radiotherapy for BRAF-Mutated Melanoma With Extensive Ependymal Disease With Prolonged Survival: Case Report and Review of the Literature

Melanoma brain metastasis with ependymal spread/metastases is uncommon. These cases are frequently classified together with leptomeningeal disease. However, the commonalities and differences in the underlying pathophysiology and clinical outcomes between these two types of spread are not clear. Very few reports on long term outcome and durable central nervous system (CNS) disease control have been reported in the literature. Here, we report a case of a 45 year-old Caucasian lady with BRAF-V600E mutant metastatic melanoma to the brain who had whole brain radiotherapy followed by two Gamma knife radiosurgery treatments for localized disease progression. She then developed extensive ependymal disease progression with no evidence of leptomeningeal spread. She was treated with a repeat course of whole brain radiotherapy and maintained on BRAF and MEK inhibitors with durable CNS disease control for more than a year. This study reviews the management of BRAF-V600E mutant melanoma with ependymal involvement. Management using radiation therapy with maintenance targeted therapy seems to be a reasonable approach to this challenging disease

A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway.Brain & Behavior Research Foundation (Young Investigator Award)JPB Foundatio

Investigation of the relationship between phenylalanine in venous plasma and capillary blood using volumetric blood collection devices

Measurement of plasma and dried blood spot (DBS) phenylalanine (Phe) is key to monitoring patients with phenylketonuria (PKU). The relationship between plasma and capillary DBS Phe concentrations has been investigated previously, however, differences in methodology, calibration approach and assumptions about the volume of blood in a DBS sub‐punch has complicated this. Volumetric blood collection devices (VBCDs) provide an opportunity to re‐evaluate this relationship. Paired venous and capillary samples were collected from patients with PKU (n = 51). Capillary blood was collected onto both conventional newborn screening (NBS) cards and VBCDs. Specimens were analysed by liquid‐chromatography tandem mass‐spectrometry (LC–MS/MS) using a common calibrator. Use of VBCDs was evaluated qualitatively by patients. Mean bias between plasma and volumetrically collected capillary DBS Phe was −13%. Mean recovery (SD) of Phe from DBS was 89.4% (4.6). VBCDs confirmed that the volume of blood typically assumed to be present in a 3.2 mm sub‐punch is over‐estimated by 9.7%. Determination of the relationship between plasma and capillary DBS Phe, using a single analytical method, common calibration and VBCDs, demonstrated that once the under‐recovery of Phe from DBS has been taken into account, there is no significant difference in the concentration of Phe in plasma and capillary blood. Conversely, comparison of plasma Phe with capillary DBS Phe collected on a NBS card highlighted the limitations of this approach. Introducing VBCDs for the routine monitoring of patients with PKU would provide a simple, acceptable specimen collection technique that ensures consistent sample quality and produces accurate and precise blood Phe results which are interchangeable with plasma Phe