The role of depression in the association between mobilisation timing and live discharge after hip fracture surgery: Secondary analysis of the UK National Hip Fracture Database.

PURPOSE: The aim was to compare the probability of discharge after hip fracture surgery conditional on being alive and in hospital between patients mobilised within and beyond 36-hours of surgery across groups defined by depression. METHODS: Data were taken from the National Hip Fracture Database and included patients 60 years of age or older who underwent hip fracture surgery in England and Wales between 2014 and 2016. The conditional probability of postsurgical live discharge was estimated for patients mobilised early and for patients mobilised late across groups with and without depression. The association between mobilisation timing and the conditional probability of live discharge were also estimated separately through adjusted generalized linear models. RESULTS: Data were analysed for 116,274 patients. A diagnosis of depression was present in 8.31% patients. In those with depression, 7,412 (76.7%) patients mobilised early. In those without depression, 84,085 (78.9%) patients mobilised early. By day 30 after surgery, the adjusted odds ratio of discharge among those who mobilised early compared to late was 1.79 (95% CI: 1.56-2.05, p<0.001) and 1.92 (95% CI: 1.84-2.00, p<0.001) for those with and without depression, respectively. CONCLUSION: A similar proportion of patients with depression mobilised early after hip fracture surgery when compared to those without a diagnosis of depression. The association between mobilisation timing and time to live discharge was observed for patients with and without depression.

The impact of the frequency, duration and type of physiotherapy on discharge after hip fracture surgery: a secondary analysis of UK national linked audit data.

Additional physiotherapy in the first postoperative week was associated with fewer days to discharge after hip fracture surgery. A 7-day physiotherapy service in the first postoperative week should be considered as a new key performance indicator in evaluating the quality of care for patients admitted with a hip fracture. INTRODUCTION: To examine the association between physiotherapy in the first week after hip fracture surgery and discharge from acute hospital. METHODS: We linked data from the UK Physiotherapy Hip Fracture Sprint Audit to hospital records for 5395 patients with hip fracture in May and June 2017. We estimated the association between the number of days patients received physiotherapy in the first postoperative week; its overall duration (< 2 h, ≥ 2 h; 30-min increment) and type (mobilisation alone, mobilisation and exercise) and the cumulative probability of discharge from acute hospital over 30 days, using proportional odds regression adjusted for confounders and the competing risk of death. RESULTS: The crude and adjusted odds ratios of discharge were 1.24 (95% CI 1.19-1.30) and 1.26 (95% CI 1.19-1.33) for an additional day of physiotherapy, 1.34 (95% CI 1.18-1.52) and 1.33 (95% CI 1.12-1.57) for ≥ 2 versus < 2 h physiotherapy, and 1.11 (95% CI 1.08-1.15) and 1.10 (95% CI 1.05-1.15) for an additional 30-min of physiotherapy. Physiotherapy type was not associated with discharge. CONCLUSION: We report an association between physiotherapy and discharge after hip fracture. An average UK hospital admitting 375 patients annually may save 456 bed-days if current provision increased so all patients with hip fracture received physiotherapy on 6-7 days in the first postoperative week. A 7-day physiotherapy service totalling at least 2 h in the first postoperative week may be considered a key performance indicator of acute care quality after hip fracture.

Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2- breast cancer: results from two prospective trials.

PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer.

BACKGROUND: Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC. PATIENTS AND METHODS: We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC. RESULTS: Intratumoral high levels (above median) of PAR (but not PARP1 protein levels) had a negative prognostic impact in both the training (92 stage I subjects) and validation (133 stage I and II subjects) cohorts, as determined by univariate and multivariate analyses. The simultaneous assessment of PAR and PDXK protein levels improved risk stratification. CONCLUSION: NSCLC patients with high intratumoral PARP1 activity (i.e. elevated PAR levels above median) and low PDXK expression (below median) had a dismal prognosis, while patients with low PARP1 activity and high PDXK expression had a favorable outcome. Altogether, these results underscore the clinical potential and possible therapeutic relevance of these biomarkers.

Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines. PATIENTS AND METHODS: A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs. RESULTS: TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95 P = 0.003; HR 0.89, 95% CI 0.81-0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18-1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20-1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2-, HER2+, ER-/HER2-). CONCLUSIONS: We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy.

Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.

BACKGROUND: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%. RESULTS: TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample. CONCLUSIONS: The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.

Bayesian evidence synthesis for a transmission dynamic model for HIV among men who have sex with men.

Understanding infectious disease dynamics and the effect on prevalence and incidence is crucial for public health policies. Disease incidence and prevalence are typically not observed directly and increasingly are estimated through the synthesis of indirect information from multiple data sources. We demonstrate how an evidence synthesis approach to the estimation of human immunodeficiency virus (HIV) prevalence in England and Wales can be extended to infer the underlying HIV incidence. Diverse time series of data can be used to obtain yearly "snapshots" (with associated uncertainty) of the proportion of the population in 4 compartments: not at risk, susceptible, HIV positive but undiagnosed, and diagnosed HIV positive. A multistate model for the infection and diagnosis processes is then formulated by expressing the changes in these proportions by a system of differential equations. By parameterizing incidence in terms of prevalence and contact rates, HIV transmission is further modeled. Use of additional data or prior information on demographics, risk behavior change and contact parameters allows simultaneous estimation of the transition rates, compartment prevalences, contact rates, and transmission probabilities.

International travels and fever screening during epidemics: a literature review on the effectiveness and potential use of non-contact infrared thermometers.

Several countries plan to introduce non-contact infrared thermometers (NCIT) at international airports in order to detect febrile passengers, thus to delay the introduction of a novel influenza strain. We reviewed the existing studies on fever screening by NCIT to estimate their efficacy under the hypothesis of pandemic influenza. Three Severe Acute Respiratory Syndrome (SARS) or dengue fever interventions in airports were excluded because of insufficient information. Six fever screening studies in other gathering areas, mainly hospitals, were included (N= 176 to 72,327 persons; fever prevalence= 1.2% to 16.9%). Sensitivity varied from 4.0% to 89.6%, specificity from 75.4% to 99.6%, positive predictive value (PPV) from 0.9% to 76.0% and negative predictive value (NPV) from 86.1% to 99.7%. When we fixed fever prevalence at 1% in all studies to allow comparisons, the derived PPV varied from 3.5% to 65.4% and NPV was >or=99%. The low PPV suggests limited efficacy of NCIT to detect symptomatic passengers at the early stages of a pandemic influenza, when fever prevalence among passengers would be =or<1%. External factors can also impair the screening strategy: passengers can hide their symptoms or cross borders before symptoms occur. These limits should be considered when setting up border control measures to delay the pandemic progression.

An approach to estimate the number of SARS cases imported by international air travel.

The worldwide spread of severe acute respiratory syndrome (SARS) raised questions about the risk of importation of such infection, in particular by air travel. Entry screening was implemented in some countries although poor evidence on its effectiveness is reported. We developed a model to estimate the number of imported SARS cases between regions, using the 2003 SARS epidemic data to apply this model for two scenarios: from Beijing to Frankfurt and from Hong Kong to London. We back-calculated the data to estimate individuals' time of infection and built a model where every individual has a probability of being isolated, of traveling, and of being undetected at arrival. The findings, consistent with what was observed in 2003, suggest that entry screening does not affect the predicted number of imported cases. Inversely, importation depends on the transmission dynamic in the country of origin (including control measures in place) and on the intensity of air travel between regions.

Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy.

HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P < 10(-30)). The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10 000 to 9.7 per 10 000 person-years (P < 10(-11)). The analysis of 145 cases of ARL in 3 hospitals showed that known HIV history was longer in the second period than in the first period among patients with systemic ARL (98 versus 75 months; P <.01). Patients had a higher number of CD4 cells at diagnosis during the second period (191 versus 63/microL, P = 10(-3)). Survival of patients with systemic ARL also increased between the periods (from 6 to 20 months; P =.004). Therefore, the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved.

HIV type 1-specific IgG2 antibodies: markers of helper T cell type 1 response and prognostic marker of long-term nonprogression.

The helper T type 1 (Th1) function of CD4(+) T lymphocytes is presumed to be of key importance in host defense against HIV-1. As the production of different antibody isotypes is dependent on this helper T function, we investigated whether HIV-1-specific responses of a particular IgG isotype could be a reliable marker of long-term HIV-1 control. Assessment of the IgG subclass distribution in the plasma of HIV-1-infected patients enrolled in the French prospective Asymptomatic Long-Term (ALT) cohort showed that IgG2 directed against HIV-1 Env gp41 and Gag proteins was associated with low viral load, high CD4(+) lymphocyte count, and weak neutralizing activity. By contrast, levels of anti-Env and anti-Pol IgG1 as well as the magnitude of neutralizing activity were correlated with the viral load and thus merely reflect the level of HIV replication. Furthermore, IgG2 directed against Gag proteins was significantly associated with HIV-1 p24-specific Th1 cell production of interferon gamma and interleukin 2. In multivariate analysis, only two variables, anti-gp41 IgG2 and plasma HIV-1 RNA, were found to be independent prognostic factors of remaining long-term nonprogressive over time. By providing new insight into the nature of an HIV-specific antibody response associated with the control of virus replication, these findings have implications for the design of HIV vaccines.

HIV incidence estimates among women of childbearing age in the area around Paris, France: no evidence for any effect of age or time.

OBJECTIVE: To explore whether there are any age or time effects on the HIV incidence rate among women of childbearing age in the area around Paris (France). DESIGN: Three seroprevalence surveys were conducted among pregnant women in the Paris area (PREVAGEST) during three periods (1990-1991, 1992-1993, 1994-1995); their data were used to derive HIV incidence estimates with Ades and Medley's method. To assess the power of our study, data were also simulated with a demographic model under different assumptions for HIV-incidence rates. RESULTS: No age or time effect was detected on HIV incidence in the Paris area during the period from 1990 to 1995. Analysis of simulated surveys showed that with the sample size of the PREVAGEST surveys, the method was able to detect an age or time effect with a relative risk of about 2.5 between age groups or periods. CONCLUSION: We conclude that the method is applicable to our data. If any existed, age or time effect was quite likely no higher than 2.5. As we previously reported using another method, incidence of HIV infection among women of childbearing age in the Paris area can be estimated at 0.74/1,000 per year (95% confidence interval, 0.62-0.87) from 1990 through 1995.