Stratified primary care versus non-stratified care for musculoskeletal pain: findings from the STarT MSK feasibility and pilot cluster randomized controlled trial.

BACKGROUND: Musculoskeletal (MSK) pain from the five most common presentations to primary care (back, neck, shoulder, knee or multi-site pain), where the majority of patients are managed, is a costly global health challenge. At present, first-line decision-making is based on clinical reasoning and stratified models of care have only been tested in patients with low back pain. We therefore, examined the feasibility of; a) a future definitive cluster randomised controlled trial (RCT), and b) General Practitioners (GPs) providing stratified care at the point-of-consultation for these five most common MSK pain presentations. METHODS: The design was a pragmatic pilot, two parallel-arm (stratified versus non-stratified care), cluster RCT and the setting was 8 UK GP practices (4 intervention, 4 control) with randomisation (stratified by practice size) and blinding of trial statistician and outcome data-collectors. Participants were adult consulters with MSK pain without indicators of serious pathologies, urgent medical needs, or vulnerabilities. Potential participant records were tagged and individuals sent postal invitations using a GP point-of-consultation electronic medical record (EMR) template. The intervention was supported by the EMR template housing the Keele STarT MSK Tool (to stratify into low, medium and high-risk prognostic subgroups of persistent pain and disability) and recommended matched treatment options. Feasibility outcomes included exploration of recruitment and follow-up rates, selection bias, and GP intervention fidelity. To capture recommended outcomes including pain and function, participants completed an initial questionnaire, brief monthly questionnaire (postal or SMS), and 6-month follow-up questionnaire. An anonymised EMR audit described GP decision-making. RESULTS: GPs screened 3063 patients (intervention = 1591, control = 1472), completed the EMR template with 1237 eligible patients (intervention = 513, control = 724) and 524 participants (42%) consented to data collection (intervention = 231, control = 293). Recruitment took 28 weeks (target 12 weeks) with > 90% follow-up retention (target > 75%). We detected no selection bias of concern and no harms identified. GP stratification tool fidelity failed to achieve a-priori success criteria, whilst fidelity to the matched treatments achieved "complete success". CONCLUSIONS: A future definitive cluster RCT of stratified care for MSK pain is feasible and is underway, following key amendments including a clinician-completed version of the stratification tool and refinements to recommended matched treatments. TRIAL REGISTRATION: Name of the registry: ISRCTN. TRIAL REGISTRATION NUMBER: 15366334. Date of registration: 06/04/2016.

The relationship between heparin level and activated clotting time in the adult cardiac surgery population.

The purpose of this descriptive study was to examine the relationship between heparin levels (HL) determined by heparin protamine titration (HPT) and activated clotting time (ACT) for cardiopulmonary bypass (CPB) in an adult cardiac surgery population. We examined institutional databases for all patients who underwent CPB at a single US academic institution from February 2005 until July 2007. Baseline ACT, predicted and actual heparin dose response (HDR), target and actual ACT, heparin concentration and heparin bolus dose were recorded. We examined the ACT and HL after the initial heparin bolus dose (Post-Hep) and 10 minutes after the initiation of CPB (CPB+10). The Post-Hep and CPB+10 ACT and HL are reported for 3802 patients. The distribution of ACTs for HL of 0.7, 1.4, 2.0, 2.7 and 3.4 units heparin/mL blood at both time points are reported. Additional analysis of the relationship of HL to ACTs of 300, 350, 400 and 480 seconds is also presented.

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells.

Angiogenesis is regulated by the balance between pro- and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol+tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

A glycoconjugate vaccine for Neisseria meningitidis induces antibodies in human infants that afford protection against meningococcal bacteremia in a neonate rat challenge model.

The functional activities of serum samples from human infants immunized with a glycoconjugate vaccine for Neisseria meningitidis serogroup C were assessed in a complement-mediated antibody-dependent serum bactericidal assay (SBA) and in a neonate rat model of protection from bacteremia. Selective serum samples from individual human infants were combined to make a panel of 11 serum pools to obtain a sufficient volume for testing. Each pool was assayed (i) for the anti-N. meningitidis serogroup C capsular polysaccharide (PS) immunoglobulin G (IgG) concentration as determined by reactivity in a direct-binding enzyme-linked immunosorbent assay, (ii) for bactericidal activity against N. meningitidis serogroup C strain C11, and (iii) for the ability to reduce bacteremia after passive transfer into a neonate rat model. Representative serum samples from infants who were not previously immunized with any N. meningitidis serogroup C vaccine served as a negative control. The prepared serum pools ranged in antibody concentration from 0.18 to 17.31 micro g of IgG specific for N. meningitidis serogroup C PS per ml. For this serum panel, a direct relationship between concentrations of anti-N. meningitidis serogroup C PS-specific IgG and serum SBA titers (r = 0.9960) was observed. Passive transfer to neonate rats demonstrated the ability of postimmunization serum samples to significantly reduce (> or =2-log(10) reduction compared to control animals) the level of bacteremia following a challenge. Of 79 neonate rats that received > or =0.031 micro g of human infant anti-N. meningitidis serogroup C PS IgG, 75 (94.9%) had a > or =2-log(10) reduction in bacteremia, whereas of the animals that received <0.031 micro g of antigen-specific IgG, 10.3% (4 of 39 rats) showed a > or =2-log(10) reduction in bacteremia. It was concluded that the anti-N. meningitidis serogroup C PS IgG antibody induced by this glycoconjugate vaccine had in vitro functional activity (as determined by a SBA) and also afforded protection against meningococcal bacteremia in an animal model.

Cytomegalovirus infection: a seroepidemiologic comparison of nuns and women from a venereal disease clinic.

A seroepidemiologic study of prevalence of antibody to cytomegalovirus (CMV) was simultaneously done in four populations: group I, nuns working as nurses or school teachers; group II, women admitted to a upper socioeconomic private hospital; group III, women admitted to a lower socioeconomic county hospital, and group and IV women attending a veneral disease clinic. Groups II, III and IV, were not statistically different and showed an abrupt rise in antibody prevalence during your adulthood. Group I, however, did not show the expected abrupt rise in antibody prevalence during young adulthood, and the prevalence in this group was singificantly lower than that in the other three groups at all but the oldest age range. These differences could not be accounted for by race, socioeconomic status or respiratory exposure to CMV. The data suggest that there may be more than one mechanism of CMV transmission and that venereal or intimate salivary contact may be a significant mode of spread in adults.