Data-driven customer acceptance for attended home delivery.

Home delivery services require the attendance of the customer during delivery. Hence, retailers and customers mutually agree on a delivery time window in the booking process. However, when a customer requests a time window, it is not clear how much accepting the ongoing request significantly reduces the availability of time windows for future customers. In this paper, we explore using historical order data to manage scarce delivery capacities efficiently. We propose a sampling-based customer acceptance approach that is fed with different combinations of these data to assess the impact of the current request on route efficiency and the ability to accept future requests. We propose a data-science process to investigate the best use of historical order data in terms of recency and amount of sampling data. We identify features that help to improve the acceptance decision as well as the retailer's revenue. We demonstrate our approach with large amounts of real historical order data from two cities served by an online grocery in Germany.

Clinical value of CT-guided biopsy of small (≤1.5 cm) suspicious lung nodules: Diagnostic accuracy, molecular characterization and long-term clinical outcomes.

Small pulmonary nodules (≤1.5 cm) are frequently detected on routine chest imaging and lung cancer screening studies. Our goal was to determine the clinical value of CT-guided core needle biopsy (CNB) in the evaluation of such nodules. In this single-center study, we retrospectively analyzed patient data (n = 44) for CNBs on lung nodules (≤1.5 cm) performed at our biopsy center between May 2017 and March 2020. We analyzed for the rate of pathology diagnosis, molecular/biomarker analysis, complications, and change in clinical management and outcome over a period ranging up to 60 months after biopsy. A pathology diagnosis of malignancy or benign lesion was obtained in 97.9% of biopsies in this cohort. The rate of complications was low with only 6.8% of patients requiring the insertion of a temporary small profile interventional radiology (IR) pigtail chest tube for pneumothorax. Out of the subset of biopsy specimens that were sent for tissue molecular analysis, 90% had enough tissue preserved after initial pathological analysis to obtain at least one molecular marker. Our data show that CT-guided CNB is safe and reliable, and should be considered for the evaluation of small, suspicious lung nodules found on routine screenings for the early detection and evaluation of malignant lesions.

Assessment of transportation system disruption and accessibility to critical amenities during flooding: Iowa case study.

Natural disasters, such as flooding, can cause severe social, environmental, and economic damage to a community. Transportation infrastructure plays an essential role in flood response and recovery efforts. However, flooding may disturb road functionality and generate direct and indirect adverse impacts, including the loss of access to essential services. This paper presents a comprehensive analysis of flood impacts on road network topology and accessibility to amenities for major communities in the State of Iowa using graph-theoretic methods, including single-source shortest path analyses. We assessed the disruption of transportation networks on the accessibility to critical amenities (e.g., hospitals) under 100 and 500-year flood scenarios. Our analysis methodology leads toward the development of an integrated real-time decision support system that will allow decision-makers to explore "what if" flood scenarios to identify vulnerable areas and population in their authority. These analyses could promote possible improvements (e.g., temporary relocation of critical services) to mitigate the consequences of road system failure during flooding. Due to varying environmental conditions at specific locations and effects on road topology under flood events, the results show differential impacts in edge and node losses as well as access to critical services. Results indicate that floods can lead to edge losses of up to 18%, and not only large cities but also some small cities can experience significant vulnerability to flooding. Some new or reconstructed bridges have failed to operate during analyzed flood events. During the 100 and 500-year flood return periods, the total number of inaccessible bridges within the selected cities is 184 and 294, respectively. Our work found that the shortest path length to the closest critical amenity under baseline condition can flip to the second or higher-orders during flooding. Many critical amenities have been found at risk of flooding in the studied cities.

DRUL for school: Opening Pre-K with safe, simple, sensitive saliva testing for SARS-CoV-2.

To address the need for simple, safe, sensitive, and scalable SARS-CoV-2 tests, we validated and implemented a PCR test that uses a saliva collection kit use at home. Individuals self-collected 300 µl saliva in vials containing Darnell Rockefeller University Laboratory (DRUL) buffer and extracted RNA was assayed by RT-PCR (the DRUL saliva assay). The limit of detection was confirmed to be 1 viral copy/µl in 20 of 20 replicate extractions. Viral RNA was stable in DRUL buffer at room temperature up to seven days after sample collection, and safety studies demonstrated that DRUL buffer immediately inactivated virus at concentrations up to 2.75x106 PFU/ml. Results from SARS-CoV-2 positive nasopharyngeal (NP) swab samples collected in viral transport media and assayed with a standard FDA Emergency Use Authorization (EUA) test were highly correlated with samples placed in DRUL buffer. Direct comparison of results from 162 individuals tested by FDA EUA oropharyngeal (OP) or NP swabs with co-collected saliva samples identified four otherwise unidentified positive cases in DRUL buffer. Over six months, we collected 3,724 samples from individuals ranging from 3 months to 92 years of age. This included collecting weekly samples over 10 weeks from teachers, children, and parents from a pre-school program, which allowed its safe reopening while at-risk pods were quarantined. In sum, we validated a simple, sensitive, stable, and safe PCR-based test using a self-collected saliva sample as a valuable tool for clinical diagnosis and screening at workplaces and schools.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.

Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry. The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro. The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction. The work highlights the some of the key challenges in designing effective protein-protein inhibitors for the Bcl-2 class of proteins.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Violence and abuse against people with disabilities: A comparison of the approaches of the European Court of Human Rights and the United Nations Committee on the Rights of Persons with Disabilities.

This paper explores how, and how effectively, two systems of international law have addressed exploitation, violence and abuse of people with mental disabilities. The two international systems reviewed were the Council of Europe's European Court of Human Rights and the United Nations Committee on the Rights of Persons with Disabilities. The two issues dealt with are (a) forced institutionalisation and denial of community-based services and (b) medically-sanctioned treatment as abuse or violence. The paper offers a comparative analysis of the way in which the two bodies have dealt with exploitation, violence and abuse of people with disabilities, and offers recommendations as to how the two bodies could adjust their approaches to come into closer alignment.

A hierarchy of personal agency for people with life-limiting illness.

The purpose of the study was to discover how individuals diagnosed with a life-limiting illness experienced themselves as agents, even in the face of death. In this qualitative, multiple case study design, 4 female outpatient hospice patients with terminal illnesses received humanistic counseling to explore their experiences of themselves and their illness. A graded set of 8 levels of personal agency emerged from analyses of the texts of their sessions, ranging from a passive, objectified nonagentic mode to an active, autonomous fully agentic mode, with multiple subcategories representing further gradations within levels. Our results are consistent with guidelines for supportive and palliative care with advanced cancer, which specify that dying patients' needs be assessed and that they be involved in decisions about their care.

Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.

Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored.

A spider in the web: role of the palliative care nurse specialist in Uganda--an ethnographic field study.

BACKGROUND: Palliative care is not a priority in developing countries. Hospice Africa Uganda (HAU), where nurses complete a course in clinical palliative care, is considered a model for other African countries. AIM: To explore the role of the palliative care nurse specialist (PCNS) in Uganda. METHODS: This ethnographic field study uses observations, interviews, and group interviews. PARTICIPANTS: In total, 20 participants are included in this study. RESULT: The role of the palliative care nurse specialist is multifaceted. Beyond prescribing drugs, their role is to deliver holistic care. They encounter numerous challenges in their work, but they also have the possibility to improve the quality of the patient's life.

Cell therapy for cardiovascular disease: a comparison of methods of delivery.

The field of myocardial regeneration utilizing novel cell-based therapies, gene transfer, and growth factors may prove to play an important role in the future management of ischemic heart disease and cardiomyopathy. Phases I and II clinical trials have been published for a variety of biologics utilizing four methods of delivery: systemic infusion, intracoronary infusion, transvenous coronary sinus, and intramyocardial. This review discusses the advantages and disadvantages of the delivery approaches above.

Regulation of PURA gene transcription by three promoters generating distinctly spliced 5-prime leaders: a novel means of fine control over tissue specificity and viral signals.

BACKGROUND: Purα is an evolutionarily conserved cellular protein participating in processes of DNA replication, transcription, and RNA transport; all involving binding to nucleic acids and altering conformation and physical positioning. The distinct but related roles of Purα suggest a need for expression regulated differently depending on intracellular and external signals. RESULTS: Here we report that human PURA (hPURA) transcription is regulated from three distinct and widely-separated transcription start sites (TSS). Each of these TSS is strongly homologous to a similar site in mouse chromosomal DNA. Transcripts from TSS I and II are characterized by the presence of large and overlapping 5'-UTR introns terminated at the same splice receptor site. Transfection of lung carcinoma cells with wild-type or mutated hPURA 5' upstream sequences identifies different regulatory elements. TSS III, located within 80 bp of the translational start codon, is upregulated by E2F1, CAAT and NF-Y binding elements. Transcription at TSS II is downregulated through the presence of adjacent consensus binding elements for interferon regulatory factors (IRFs). Chromatin immunoprecipitation reveals that IRF-3 protein binds hPURA promoter sequences at TSS II in vivo. By co-transfecting hPURA reporter plasmids with expression plasmids for IRF proteins we demonstrate that several IRFs, including IRF-3, down-regulate PURA transcription. Infection of NIH 3T3 cells with mouse cytomegalovirus results in a rapid decrease in levels of mPURA mRNA and Purα protein. The viral infection alters the degree of splicing of the 5'-UTR introns of TSS II transcripts. CONCLUSIONS: Results provide evidence for a novel mechanism of transcriptional control by multiple promoters used differently in various tissues and cells. Viral infection alters not only the use of PURA promoters but also the generation of different non-coding RNAs from 5'-UTRs of the resulting transcripts.

Gender differences in psychiatric symptomatology in adolescents attending a community drug and alcohol treatment program.

This study examines mental health symptoms in a cohort of adolescents with substance use disorder (SUD), and attempts to determine if mental health symptoms differed by gender. We retrospectively looked at the Beck's Youth Inventory Second Edition (BYI-II) scores of 88 clients attending a community drug and alcohol treatment service in Dublin, Ireland that were completed at intake as part of their assessment. The raw and T-scores of the male patients were compared against their female counterparts and both against their age- and gender-matched normative population. Participants were 65 boys and 23 girls with a mean age of 16.2 years. Polysubstance use was the norm. As a group, the girls had higher T scores than the boys in all the domains of the BYI-II, and these were statistically significant. Sixty (68%) of the participants had a psychological problem which was moderate or severe in at least one of the five domains. This study found that SUD girls differ from their male counterparts in having both more internalizing and externalizing psychiatric problems. We also note that comorbid psychological problems are not universal. Thus we should avoid a "one size fits all" approach to treatment such as delivering universal self-esteem enhancement interventions to all adolescents with SUD.

Murine cytomegalovirus US22 protein pM140 protects its binding partner, pM141, from proteasome-dependent but ubiquitin-independent degradation.

Stable assembly of murine cytomegalovirus (MCMV) virions in differentiated macrophages is dependent upon the expression of US22 family gene M140. The M140 protein (pM140) exists in complex with products of neighboring US22 genes. Here we report that pM140 protects its binding partner, pM141, from ubiquitin-independent proteasomal degradation. Protection is conferred by a stabilization domain mapping to amino acids 306 to 380 within pM140, and this domain is functionally independent from the region that confers binding of pM140 to pM141. The M140 protein thus contains multiple domains that collectively confer a structure necessary to function in virion assembly in macrophages.

One-year follow-up of feasibility and safety of the first U.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAuSMIC study).

OBJECTIVES: The aim of this study was to test safety and feasibility of myoblast transplantation with the Biosense-NOGA (Diamond Bar, California) 3-dimensional-guided endomyocardial delivery system. BACKGROUND: Previous Phase-1 trials showed feasibility of epicardial injection of myoblasts. However, catheter-based delivery has several advantages: it can be applied on high-risk patients, the procedure can be repeated, and it is associated with less morbidity and mortality. METHODS: Twenty-three subjects, with previous myocardial infarction and heart failure, New York Heart Association (NYHA) functional class II to IV, were enrolled, 11 control and 12 treatment subjects. To assess safety, physical exam, electrocardiogram, continuous rhythm monitoring, quality of life assessments, and heart function were evaluated at baseline and follow-up until 1 year. RESULTS: There was favorable safety: no difference between groups in arrhythmias, and no deaths. Treated subjects showed sustained improvements in NYHA and Minnesota Living with Heart Failure Questionnaire (MLHFQ) compared with control subjects (NYHA, -1.0 point in treatment vs. +0.3 point in control group, p < 0.0004; MLHFQ, -14 point in treatment vs. +1 point in the control group, p = 0.004). Blinded core laboratory echocardiography evaluations showed sustained reductions in the treatment versus control in end diastolic diameter (-0.03 cm vs. +0.05 cm, p = 0.07) and end systolic diameter (-0.05 cm vs. +0.1 cm, p = 0.07). Finally, NOGA voltage mapping demonstrated improved voltage measurements (+1.0 mV, p = 0.008). CONCLUSIONS: This trial of myoblast transplantation via catheter into heart failure patients demonstrated safety and feasibility. Treated patients showed improvement in NYHA, MLHFQ, ventricular viability, and evidence of reverse ventricular remodeling. These data demonstrate positive safety outcomes and warrant initiation of larger phase 2, double-blind, placebo-controlled clinical trials.

Murine cytomegalovirus capsid assembly is dependent on US22 family gene M140 in infected macrophages.

Macrophages are an important target cell for infection with cytomegalovirus (CMV). A number of viral genes that either are expressed specifically in this cell type or function to optimize CMV replication in this host cell have now been identified. Among these is the murine CMV (MCMV) US22 gene family member M140, a nonessential early gene whose deletion (RVDelta140) leads to significant impairment in virus replication in differentiated macrophages. We have now determined that the defect in replication is at the stage of viral DNA encapsidation. Although the rate of RVDelta140 genome replication and extent of DNA cleavage were comparable to those for revertant virus, deletion of M140 resulted in a significant reduction in the number of viral capsids in the nucleus, and the viral DNA remained sensitive to DNase treatment. These data are indicative of incomplete virion assembly. Steady-state levels of both the major capsid protein (M86) and tegument protein M25 were reduced in the absence of the M140 protein (pM140). This effect may be related to the localization of pM140 to an aggresome-like, microtubule organizing center-associated structure that is known to target misfolded and overexpressed proteins for degradation. It appears, therefore, that pM140 indirectly influences MCMV capsid formation in differentiated macrophages by regulating the stability of viral structural proteins.

Impact of the patient-provider relationship on the survival of foreign born outpatients with tuberculosis.

BACKGROUND: Managing tuberculosis in foreign born patients entails a complex interaction between patient and provider. METHODS: Using a retrospective cohort study and survival analysis, this study evaluates the impact of patient and provider factors on the survival of foreign born outpatients with active tuberculosis. The primary outcome of the study is 1 year all-cause mortality. RESULTS: In our cohort, patient-provider language discordance was associated with an increased risk of death [HR: 2.33; 95% CI: 1.39-3.88], while receiving treatment from a tuberculosis experienced physician [HR: 0.41; 95% CI: 0.22-0.77] and treatment in a dedicated tuberculosis clinic [HR: 0.53; 95% CI: 0.29-0.98] was associated with a lower risk of death. DISCUSSION: Patient-provider communication and health systems factors played a large role in the survival of our cohort of foreign born tuberculosis outpatients. These findings suggest that language barriers and the provision of care by experienced providers in specialized clinic settings may have important effects on health outcomes.

Night nursing - staff's working experiences.

BACKGROUND: Although the duties and working conditions of registered, and enrolled nurses have previously been described from different perspectives, they have not been examined from the night nursing aspect. The aim of the study was to describe the night nursing staff's working experiences. METHODS: The design of the study is qualitative and descriptive. Interviews were conducted with 10 registered and 10 enrolled nurses working as night staff at a Swedish University Hospital. The interview guide was thematic and concerned the content of their tasks, as well as the working conditions that constitute night nursing. In addition, the interviews were transcribed verbatim and analyzed using content analysis. RESULTS: The night duties have to be performed under difficult conditions that include working silently in dimmed lighting, and making decisions when fatigue threatens. According to the night staff, its main goals are to provide the patients with rest and simultaneously ensure qualified care. Furthermore, the night nursing staff must prepare the ward for the daytime activities. CONCLUSION: The most important point is the team work, which developed between the registered and enrolled nurses and how necessary this team work is when working at night. In order for nurses working at night to be fully appreciated, the communication between day and night staff in health care organizations needs to be developed. Furthermore, it is important to give the night staff opportunities to use its whole field of competence.