Long-term risk prediction after major lower limb amputation: 1-year results of the PERCEIVE study

Background: Decision-making when considering major lower limb amputation is complex and requires individualized outcome estimation. It is unknown how accurate healthcare professionals or relevant outcome prediction tools are at predicting outcomes at 1-year after major lower limb amputation. Methods: An international, multicentre prospective observational study evaluating healthcare professional accuracy in predicting outcomes 1 year after major lower limb amputation and evaluation of relevant outcome prediction tools identified in a systematic search of the literature was undertaken. Observed outcomes at 1 year were compared with: healthcare professionals' preoperative predictions of death (surgeons and anaesthetists), major lower limb amputation revision (surgeons) and ambulation (surgeons, specialist physiotherapists and vascular nurse practitioners); and probabilities calculated from relevant outcome prediction tools. Results: A total of 537 patients and 2244 healthcare professional predictions of outcomes were included. Surgeons and anaesthetists had acceptable discrimination (C-statistic = 0.715), calibration and overall performance (Brier score = 0.200) when predicting 1-year death, but performed worse when predicting major lower limb amputation revision and ambulation (C-statistics = 0.627 and 0.662 respectively). Healthcare professionals overestimated the death and major lower limb amputation revision risks. Consultants outperformed trainees, especially when predicting ambulation. Allied healthcare professionals marginally outperformed surgeons in predicting ambulation. Two outcome prediction tools (C-statistics = 0.755 and 0.717, Brier scores = 0.158 and 0.178) outperformed healthcare professionals' discrimination, calibration and overall performance in predicting death. Two outcome prediction tools for ambulation (C-statistics = 0.688 and 0.667) marginally outperformed healthcare professionals. Conclusion: There is uncertainty in predicting 1-year outcomes following major lower limb amputation. Different professional groups performed comparably in this study. Two outcome prediction tools for death and two for ambulation outperformed healthcare professionals and may support shared decision-making

What to expect from a third step in treatment resistant depression: A prospective open study on escitalopram

Objectives. Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. Methods. A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). Results. Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. Conclusions. Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters

HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism

Context: Mutations in the transcription factor HESX1 have previously been described in association with septooptic dysplasia ( SOD) as well as isolated defects of the hypothalamic-pituitary axis. Objective: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an in-depth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism. Design: Nonfamilial patients ( 724) with either SOD ( n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurological abnormalities ( n = 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents. Patients: All patients studied had at least one of the three classical features associated with SOD ( optic nerve hypoplasia, hypopituitarism, midline forebrain defects). Results: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue ( E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%. Conclusions: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis

Lack of genetic association between the phospholipase A2 gene and bipolar mood disorder in a European multicentre case-control study

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder

Temperament and character influence on depression treatment outcome

Background: : personality features have been repeatedly associated with depression treatment outcome in Major Depressive Disorder (MDD), however conclusive results are still lacking. Moreover, as for Bipolar Disorder (BD), results are only few and preliminary. Aim: : the aim of the present study was to perform an exploratory investigation of the influence of personality traits as assessed by the Temperament and Character Inventory (TCI), on principal depression treatment outcomes (non remission, non response and resistance). Methods: : 743 mood disorders patients (455 MDD (61.24%) and 288 BD (38.76%)) were recruited in the context of 6 European studies. Generalized logit models were performed to test the effects of TCI dimensions on treatment outcomes, considering possible confounders such as age, gender and education. Positive results were controlled for comorbidities (anxiety and substance use disorders) as well. Results: : MDD Non-Remitters showed high Harm Avoidance (HA) and Self Transcendence (ST) (p = 0.0004, d = 0.40; p = 0.007, d = 0.36 respectively) and low Persistence (P) and Self Directedness (SD) (p = 0.05; d = 0.18; p = 0.002, d = 0.40, respectively); MDD Non-Responders showed a slightly different profile with high HA and low Reward Dependence (RD) and SD; finally, MDD Resistants showed low RD, P and Cooperativeness (C). In BD patients, only higher HA in non response was observed. Limitations: : the retrospective cross-sectional design, the TCI assessment regardless of the mood state and the small number of bipolar patients represent the main limitations. Conclusion: : specific TCI personality traits are associated with depression treatment outcome in MDD patients. The inclusion of such personality traits, together with other socio-demographic and clinical predictors, could ameliorate the accuracy of the prediction models available to date

{Search for direct production of GeV-scale resonances decaying to a pair of muons in proton-proton collisions at s \sqrt{s} = 13 TeV}

A search for direct production of low-mass dimuon resonances is performed using = 13 TeV proton-proton collision data collected by the CMS experiment during the 2017–2018 operation of the CERN LHC with an integrated luminosity of 96.6 fb−1. The search exploits a dedicated high-rate trigger stream that records events with two muons with transverse momenta as low as 3 GeV but does not include the full event information. The search is performed by looking for narrow peaks in the dimuon mass spectrum in the ranges of 1.1–2.6 GeV and 4.2–7.9 GeV. No significant excess of events above the expectation from the standard model background is observed. Model-independent limits on production rates of dimuon resonances within the experimental fiducial acceptance are set. Competitive or world’s best limits are set at 90% confidence level for a minimal dark photon model and for a scenario with two Higgs doublets and an extra complex scalar singlet (2HDM+S). Values of the squared kinetic mixing coefficient ε2 in the dark photon model above 10−6 are excluded over most of the mass range of the search. In the 2HDM+S, values of the mixing angle sin(θH) above 0.08 are excluded over most of the mass range of the search with a fixed ratio of the Higgs doublets vacuum expectation tan β = 0.5