Search

•The presence of CLL cells delays T-cell receptor–mediated CAR T-cell activation and impairs proliferation and restimulation.•Blocking CD24 and CD52 expression on CLL cells reverses T-cell dysfunction.

Reviewing and editing draft after draft of your budget is time consuming, frustrating, and may even risk disengagement from your stakeholders. Reviewing the three practices below will help companies get [...]

T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naïve OT-I CD8+cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.

The use of intravenous (IV) acetaminophen (APAP) for fever has not been thoroughly studied in neurocritical care (NCC) patients, in whom a temperature of ≥38°C is associated with poor outcomes and treatment to normothermia is common practice. This retrospective study evaluated NCC patients admitted between May 1, 2012, and April 30, 2013, and received at least one dose of IV or oral (PO) APAP for a body temperature of ≥38°C. The primary aim of this study was to compare the reduction in body temperature (RIT) between IV and PO APAP, calculated as the change in temperature before and 0.5, 1, 2, 3, and 6 hours after administration. Descriptive statistics were used to assess use characteristics, and Kruskal–Wallis and Mann–Whitney Utests were used for between-group differences. There were 142 NCC patients who received a total of 405 IV APAP and 253 PO APAP doses. Seventy percent of all APAP doses resulted in a temperature of <38°C within 6 hours. The median oral body temperature before APAP was 38.8°C and 38.6°C for IV and PO APAP, respectively (p< 0.01). The median RIT at 0.5 (IV 0.25°C vs. PO 0.2°C), 1 (IV 0.4°C vs. PO 0.2°C), 2 (IV 0.7°C vs. PO 0.5°C), 3 (IV 0.9°C vs. PO 0.6°C), and 6 (IV 1°C vs. PO 0.8°C) hours was significantly greater for IV APAP than for PO APAP at all time points (p< 0.05). Patients with an acute ischemic stroke and patients with an intracerebral hemorrhage had a statistically significantly greater RIT with IV APAP therapy. IV APAP administered to febrile NCC patients was associated with a significantly greater RIT than PO, but 70% of all APAP doses resulted in a body temperature of <38°C within 6 hours. Further prospective studies are needed to determine if IV APAP improves clinical outcomes.

Risks pose a financial and reputational threat to organizations that can be disastrous if left unchecked. The good news is that the warning signs of risks are often hiding in [...]

Companies with intellectual property or intangibles (1) often contemplate tax considerations in determining the best and most profitable IP strategy for the business as a whole. Such considerations include where [...]

Cash-to-cash cycle time, also known as the cash con version cycle (CCC), measures the amount of time it takes for a company to convert resources like inventory or investments in [...]

In a chaotic business environment hampered by a global pandemic, many vendors, suppliers, and other businesses are holding 'bad debt' in the form of payments owed that will never be [...]

As the economic impacts of COVID-19 continue to unfold in the United States and around the world, many organizations face hard decisions. If your company is slashing discretionary spending, lengthening [...]

Objective: This longitudinal follow-up study examined the predictive validity of relatives' expressed emotion in a group of patients diagnosed with borderline personality disorder. Method: thirty-five patients with DSM-III-R-diagnosed borderline personality disorder were followed up 1 year after they were discharged from a psychiatric hospital. Clinical outcome was assessed through interviews with patients and their family members. Expressed emotion in the patients' relatives, assessed at the time of the index admission, was then used to predict patients' subsequent clinical outcomes. Results: Contrary to prediction, relatives' criticism and hostility did not predict how well patients did in the year after discharge. Neither did they predict rates of rehospitalization. Clinical outcome was strongly associated with family levels of emotional overinvolvement, however. Patients whose families scored higher on emotional overinvolvement had better clinical outcomes over the course of the follow-up period. Conclusions: These findings suggest that the association between expressed emotion and patient outcome may be different for patients with borderline personality disorder than it is for patients with schizophrenia or mood disorders.

Background. In human brain tumors, sensitivity to procarbazine as measured by sensitivity in a xenograft tumor model correlated inversely with amounts of the DNA repair enzyme [O.sup.6]-alkylguanine DNA alkyltransferase (AT). Methods. To test the hypothesis that mutations of the p53 tumor suppressor gene in human tumors also can correlate with the response to chemotherapy, p53 mutations were identified in primary human malignant brain tumors and cell lines in which AT activity and procarbazine sensitivity in a xenograft model was ascertained. Results. Mutations were identified in 7 of 21 (33%) specimens tested. Specimens containing p53 mutations tended to exhibit an increased growth delay in procarbazine-treated xenografts and lower amounts of AT. Conclusions. p53 mutations in brain tumors may contribute to procarbazine sensitivity by failing to induce arrest at the [G.sub.1]/S cell-cycle checkpoint, thereby preventing the repair of procarbazine-induced genetic alterations. Cancer 1995; 75:1339-42.

A comparison of the US tax system to those of other Group of 7 countries reveals that the US has the lowest overall tax burden on its citizens and the lowest total government outlay as a percentage of GDP. The US has the lowest corporate income tax of the group, and the only one that has declined since 1970, but also has the highest taxes on corporate investments. The tax systems and resulting tax burdens of the Group of 7 countries are discussed in detail.

Background. Little is known about the molecular genetic events that contribute to the pathogenesis of squamous cell carcinoma of the upper aerodigestive tract. Previous molecular genetic studies have been limited to the identification of mutations of the p53 (also known as TP53) tumor suppressor gene, activation of a limited set of oncogenes, allelic loss at 3p and other locations, and occasional association with human papillomavirus infection. Purpose: Our purpose was to screen tumor tissue and blood from patients with squamous cell carcinoma of the upper aerodigestive tract for loss of heterozygosity at polymorphic loci corresponding to each of the autosomal chromosomes and to identify the locations of additional putative tumor suppressor genes, other than RB (also known as RB1) and p53, that may contribute to the pathogenesis of this disease. Methods: Tumor tissue and blood were obtained from 68 consecutive patients with squamous cell carcinoma of the upper aerodigestive tract. In all cases, tumor tissue was obtained from the center of the surgical specimen. The relative absence of non-neoplastic tissue was confirmed by frozen-section histologic examination of immediately adjacent tissue. Initially, 30 paired tissue and blood samples were tested for loss of heterozygosity by polymerase chain reaction (PCR) to amplify 43 different highly polymorphic sequences containing small oligonucleotide repeats. After PCR amplification, with unique oligonucleotides flanking the repeat, visualization and sizing of the alleles on DNA sequencing gels were performed. Specific loss of heterozygosity was distinguished from random genetic loss due to generalized chromosomal instability if it occurred in more than 20% of specimens tested for a particular marker. Results: Significant loss of heterozygosity (>20%) occurred at alleles at chromosome bands 3p21 (32%), 3p25-26 (56%), 8pter-21.1 (31%), 13q14 (27%), and 17p12 (45%). Loss of heterozygosity at more than two loci was significant with a poor prognosis (P = .039). Conclusions: These findings demonstrate that squamous cell carcinoma of the upper aerodigestive tract exhibits genetic alterations at multiple loci and that allelic loss at more than two locations is indicative of a poor prognosis (the likelihood of the patient dying of disease). Implications: While tumor suppressor genes at 3p (VHL), 13q (RB), and 17p (p53) have been identified, altered genes at other loci on 3p and on 8p have not yet been characterized. Furthermore, the genotype at these loci for squamous cell carcinoma of the upper aerodigestive tract has prognostic importance and may identify the patients who should receive the most aggressive treatment. [J Natl Cancer Inst 86:1524-1529, 1994]

A study on the effects of elements of flexible manufacturing systems (FMEs) in US tooling and machining enterprises was conducted on 63 businesses. Results indicate that 56 enterprises received competitive advantages due to elements of FMEs. These advantages include increased product quality, engineering tolerance, productive use of direct labor, faster response to market changes, shorter turn-around time and lower prices.

Background. Alteration of the ras family of oncogenes and of the tumor suppressor genes p53 and RB are the most common genetic events in human tumors. Although there have been no reports of the prevalence of these alterations in Wilms tumors, overexpression of the N-myc and insulin-like growth factor-II (IGF-II) genes have been observed, and alteration of another tumor suppressor gene (WT1) has been demonstrated. Methods. Forty-four Wilms tumor specimens were tested for the presence of N-, K-, and H-ras mutations in codons 12, 13, and 61 by single-strand conformation polymorphism (SSCP) analysis and direct DNA sequence analysis. Sixteen tumors were tested for abnormalities of WT1 by Southern and northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). N-myc, c-myc, WT1, and IGF-II mRNA expression was measured in 16 tumors by Northern blot analysis. Thirty-eight tumors were screened for p53 mutations by SSCP analysis and direct DNA sequence analysis. Nine tumors were analyzed for loss of heterozygosity (LOH) of RB. Results. Although the authors confirmed that N-myc and IGF-II are overexpressed in Wilms tumors, no mutations of ras family, p53, or RB genes were identified, and no gross alterations of WT1 were detected by Southern or Northern blot analysis. Conclusions. These findings suggest that H-ras, K-ras, N-ras, p53, and RB are not involved in the pathogenesis of Wilms tumor.

Background. Congenital mesoblastic nephroma (CMN) is a rare tumor of the neonatal kidney. It was once thought to be a variant of Wilms tumor that also arises from primitive renal cells. Methods. Molecular characteristics of two CMN were studied to clarify their potential relationship to Wilms tumors. Patterns of gene expression were assayed by Northern blot hybridization analysis. Tumors were tested for loss of heterozygosity (LOH) at chromosomes 11p13 and 11p15 using Southern blot analysis. Results. The CMN, like Wilms tumors, demonstrated high-level expression of insulin-like growth factor II. Unlike Wilms tumors, however, the CMN expressed neither the N-myc oncogene nor the putative Wilms tumor suppressor gene, WT1. Using a panel of probes spanning 11p13 and 11p15, no LOH was detected in the CMN, nor was there evidence of deletion or rearrangements of WT1. Conclusions. Although Wilms tumor and CMN both arise from the developing kidney, molecular characterization suggests that different factors are involved in the pathogenesis of these two tumors. Cancer 1992; 70:2358-2361.

AimsHip fractures are associated with high morbidity, mortality, and costs. One strategy for improving outcomes is to incentivize hospitals to provide better quality of care. We aimed to determine whether a pay-for-performance initiative affected hip fracture outcomes in England by using Scotland, which did not participate in the scheme, as a control.Materials and MethodsWe undertook an interrupted time series study with data from all patients aged more than 60 years with a hip fracture in England (2000 to 2018) using the Hospital Episode Statistics Admitted Patient Care (HES APC) data set linked to national death registrations. Difference-in-differences (DID) analysis incorporating equivalent data from the Scottish Morbidity Record was used to control for secular trends. The outcomes were 30-day and 365-day mortality, 30-day re-admission, time to operation, and acute length of stay.ResultsThere were 1 037 860 patients with a hip fracture in England and 116 594 in Scotland. Both 30-day (DID -1.7%; 95% confidence interval (CI) -2.0 to -1.2) and 365-day (-1.9%; 95% CI -2.5 to -1.3) mortality fell in England post-intervention when compared with outcomes in Scotland. There were 7600 fewer deaths between 2010 and 2016 that could be attributed to interventions driven by pay-for-performance. A pre-existing annual trend towards increased 30-day re-admissions in England was halted post-intervention. Significant reductions were observed in the time to operation and length of stay.ConclusionThis study provides evidence that a pay-for-performance programme improved the outcomes after a hip fracture in England.Cite this article: Bone Joint J2019;101-B:1015–1023.

AimsThe aim of this study was to establish the incidence of developmental dysplasia of the hip (DDH) diagnosed after one-year of age in England, stratified by age, gender, year, and region of diagnosis.Patients and MethodsA descriptive observational study was performed by linking primary and secondary care information from two independent national databases of routinely collected data: the United Kingdom Clinical Practice Research Datalink and Hospital Episode Statistics. The study examined all children from 1 January 1990 to 1 January 2016 who had a new first diagnostic code for DDH aged between one and eight years old.ResultsThe incidence of late-diagnosed DDH was 1.28 per 1000 live births. Within the study population, 754 children were identified with a diagnosis of DDH after one-year of age. Of all late diagnoses, 536 (71.1%) were detected between one to two years of age. There were 608 female patients (80.6%) and 146 male patients (19.4%), giving a female-to-male ratio of 4.2:1. Distribution was evenly spread throughout England.ConclusionThe incidence of late-diagnosed DDH has not been reduced from that reported 35 years ago, prior to the introduction of the national selective screening programme for DDH.Cite this article: Bone Joint J2019;101-B:281–287.

PURPOSE: The purpose of this study was to determine the immediate and cumulative effects of a myofascial release (MFR) technique of the respiratory diaphragm on heart rate (HR), respiratory rate (RR), blood pressure (BP), ribcage expansion (RCE), and forced vital capacity (FVC). SUBJECTS: Thirty subjects from a community hospital chronic pain rehabilitation program were randomly selected and assigned to a treatment or a control group for this study. METHODS AND MATERIALS: All subjects were studied after one session of a MFR technique of the respiratory diaphragm for the immediate effects. Sixteen of these subjects were studied after four sessions for the cumulative effects. Measurements were taken after a 5-10 minute rest period. Standard instrumentation was used. One examiner performed the technique on the treatment group, while the control group received touch only. Another examiner performed the measurements. ANALYSES: Multi-analysis of variance was performed on difference scores. Post hoc univariate tests were used on individual dependent variables. RESULTS: A significant immediate and cumulative effect existed in lowering respiratory rate for the treatment group (p [is less than] .05) using within subjects multivariate testing. Significant differences were not found immediately or cumulatively for HR, BP, RCE or FVC. CONCLUSIONS: Results indicate MFR of the respiratory diaphragm may be clinically useful in immediately and cumulatively lowering respiratory rate for patients with chronic pain. Several factors contribute to variance in individual responses. Non-standardized rest period prior to initial measurements at each visit may be one of these contributing factors. Future investigation on the effects of this technique in an acute care population is suggested., Carey M, Kegerreis S, Worrell T, Perry D. Indiana University, Indianapolis, IN; University of Indianapolis, Indianapolis, IN; Duke University, Durham, NC; Indiana University, Indianapolis, IN, [...]

When a lessee's rights under a lease are assigned, the lessor typically requires the successor lessee to execute an 'assumption agreement' promising to assume and perform all lessee obligations. The [...]

The efficacy of autologous (αβ) T-cell–based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex–independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T–cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell–based therapy with ibrutinib.

AimsThe aim of this study was to describe temporal trends and survivorship of total hip arthroplasty (THA) in very young patients, aged ≤ 20 years.Patients and MethodsA descriptive observational study was undertaken using data from the National Joint Registry (NJR) for England, Wales, Northern Ireland and the Isle of Man between April 2003 and March 2017. All patients aged ≤ 20 years at the time of THA were included and the primary outcome was revision surgery. Descriptive statistics were used to summarize the data and Kaplan–Meier estimates calculated for the cumulative implant survival.ResultsA total of 769 THAs were performed in 703 patients. The median follow-up was 5.1 years (interquartile range (IQR) 2.6 to 7.8). Eight patients died and 35 THAs were revised. The use of metal-on-metal (MoM) bearings and resurfacing procedures declined after 2008. The most frequently recorded indications for revision were loosening (20%) and infection (20%), although the absolute risk of these events occurring was low (0.9%). Factors associated with lower implant survival were MoM and metal-on-polyethylene (MoP) bearings and resurfacing arthroplasty (vsceramic-on-polyethylene (CoP) and ceramic-on-ceramic (CoC) bearings, p = 0.002), and operations performed by surgeons who undertook few THAs in this age group as recorded in the NJR (vsthose with five or more recorded operations, p = 0.030). Kaplan–Meier estimates showed 96% (95% confidence interval (CI) 94% to 98%) survivorship of implants at five years.ConclusionWithin the NJR, the overall survival for very young patients undergoing THA exceeded 96% during the first five postoperative years. In the absence of studies that can better account for differences in the characteristics of the patients, surgeons should consider the association between early revision and the type of implant, the number of THAs performed in these patients, and the bearing surface when performing THA in very young patients.Cite this article: Bone Joint J2018;100-B:1320–9.

AimsHigh-quality clinical research in children’s orthopaedic surgery has lagged behind other surgical subspecialties. This study used a consensus-based approach to identify research priorities for clinical trials in children’s orthopaedics.MethodsA modified Delphi technique was used, which involved an initial scoping survey, a two-round Delphi process and an expert panel formed of members of the British Society of Children’s Orthopaedic Surgery. The survey was conducted amongst orthopaedic surgeons treating children in the United Kingdom and Ireland.ResultsA total of 86 clinicians contributed to both rounds of the Delphi process, scoring priorities from one (low priority) to five (high priority). Elective topics were ranked higher than those relating to trauma, with the top ten elective research questions scoring higher than the top question for trauma. Ten elective, and five trauma research priorities were identified, with the three highest ranked questions relating to the treatment of slipped capital femoral epiphysis (mean score 4.6/ 5), Perthes’ disease (4.5) and bone infection (4.5).ConclusionThis consensus-based research agenda will guide surgeons, academics and funders to improve the evidence in children’s orthopaedic surgery and encourage the development of multicentre clinical trials.Cite this article: Bone Joint J2018;100-B:680–4.

While combination therapy completely suppresses HIV-1 replication in blood, functional virus persists in CD4+T cell subsets in non-peripheral compartments that are not easily accessible. To fill this gap, we investigated tissue-homing properties of cells that transiently appear in the circulating blood. Through cell separation and in vitrostimulation, the HIV-1 “Gag and Envelope reactivation co-detection assay” (GERDA) enables sensitive detection of Gag+/Env+ protein-expressing cells down to about one cell per million using flow cytometry. By associating GERDA with proviral DNA and polyA-RNA transcripts, we corroborate the presence and functionality of HIV-1 in critical body compartments utilizing t-distributed stochastic neighbor embedding (tSNE) and density-based spatial clustering of applications with noise (DBSCAN) clustering with low viral activity in circulating cells early after diagnosis. We demonstrate transcriptional HIV-1 reactivation at any time, potentially giving rise to intact, infectious particles. With single-cell level resolution, GERDA attributes virus production to lymph-node-homing cells with central memory T cells (TCMs) as main players, critical for HIV-1 reservoir eradication.

AimsIt is well established that there is a strong association between Perthes’ disease and worsening socioeconomic deprivation. It has been suggested that the primary determinant driving this association is exposure to tobacco smoke. This study aimed to examine this hypothesis.Patients and MethodsA hospital case-control study (n = 149/146) examined the association between tobacco smoke exposure and Perthes’ disease, adjusting for area-level socioeconomic deprivation. Tobacco smoke exposure was assessed by parental questionnaire of smoking habits during pregnancy, and by quantitative assay of current exposure using the urinary cotinine-creatinine ratio, which is a widely used and validated measure of tobacco smoke exposure.ResultsThe odds of Perthes’ disease significantly increased with reported in uteroexposure after adjustment for socioeconomic deprivation (maternal smoking odds ratio (OR) 2.06, 95% confidence interval (CI) 1.17 to 3.63; paternal smoking OR 2.09, 95% CI 1.26 to 3.46). The cotinine-creatinine ratio was significantly greater in cases, OR 1.63 (95% CI 1.09 to 2.43), suggesting a greater ‘dose’ of current tobacco exposure.ConclusionAn association exists between tobacco smoke exposure and Perthes’ disease but we remain unable to disentangle the association with socioeconomic deprivation.Cite this article: Bone Joint J2017;99-B:1102–8.

A goal of vaccination is to elicit and maintain tissue-resident memory T cells. Amsen and colleagues show human lung-resident memory CD8+T cells express distinct transcriptional programs, including a role for Notch in cellular metabolism and maintenance.