Uber

Uber focuses primarily on the ride-hailing industry, which puts the company in direct competition with regular taxis. The company is like a lot of tech-driven, fast growing entrepreneurial firms in that it still struggles for profitability. Also, the popularity of this new form of transportation has put the company and its close competitors, such as Lyft, in the spotlight of government lawmakers and regulators. If they classify Uber drivers as employees rather than independent contractors, it could dramatically alter the Uber business model. This case is written in the aftermath of the ouster of one of the company’s co-founders as CEO, a not-so-successful initial public offering (IPO), and some very serious human resources issues associated with widely publicized instances of sexual harassment and mistreatment of drivers

Conditional Beliefs of Primary-Care Patients with Treatment-Resistant Depression

Background:Cognitive behaviour therapy (CBT) for patients with treatment-resistant depression (TRD) aims to reframe underlying conditional beliefs that are thought to maintain depression.Aim:To systematically explore conditional beliefs expressed by primary-care based patients with TRD, defined as non-response to at least 6 weeks of antidepressants.Method:Conditional beliefs (stated in an “If. . .then. . .” format) were extracted from a random sample of 50 sets of therapist notes from the CoBalT trial, a large randomized controlled trial of CBT for TRD in primary care. The beliefs were separated into their two constituent parts; the demands (Ifs) and consequences (thens). An approach based on framework analysis provided a systematic way of organizing the data, and identifying key themes.Results:Four main themes emerged from the demand part of the conditional beliefs (Ifs): 1. High standards; 2. Putting others first/needing approval; 3. Coping; and 4. Hiding “true” self. Three main themes emerged from the consequence part of the conditional beliefs (thens): 1. Defectiveness; 2. Responses of others; 3. Control of emotions.Conclusions: Identifying common themes in the conditional beliefs of patients with TRD adds to our clinical understanding of this client group, providing useful information to facilitate the complex process of collaborative case conceptualization and working with conditional beliefs within CBT interventions.</jats:p

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1

Inferring bacterial transmission dynamics using deep sequencing genomic surveillance data

Within host variation is increasingly being cited as a tool to distinguish transmission pairs. However, the role of within-host diversity in transmission is understudied due to a lack of experimental and clinical datasets that capture within-host diversity in both donors and recipients. Here, we assess the utility of deep-sequenced genomic surveillance within a mouse transmission model where the gastrointestinal pathogen Citrobacter rodentium was controllably spread during co-housing of infected and naïve animals. We observed that within 38 host variants were maintained over multiple transmission steps until fixation or elimination and present a model for inferring the likelihood that a given pair of samples are linked by transmission, by comparing the allelic frequency at variant genomic loci. Because within-host single nucleotide variants (iSNVs) can repeatedly pass from donor to recipient along the transmission chain, sharing of iSNVs offers limited discriminatory power in identifying a transmission pair. Beyond the presence and absence of within-host variants, we show that differences arising in the relative abundance of iSNVs (allelic frequency) can infer transmission pairs more precisely. However, in applying this method it is important to carefully consider routes of transmission, bottleneck sizes and mutation rates. Additionally, genomic artefacts must be carefully curated to avoid spurious inferences of transmission. An important component of our approach is that the inference is based solely on sequence data, without incorporating epidemiological or demographic data for context. Therefore, it can be adapted and used to complement existing epidemiologic tools

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale