Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma.

Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.

Age and gender differences in the impact of labour-market transitions on subjective health in Germany.

AIMS: Applying a gender- and age group-sensitive approach, we investigated the effect of labour-market transitions (job loss and re-employment) on subjective physical and mental health. METHODS: A combination of the difference-in-differences approach and propensity score matching controls for selectivity and initial health differences. This allowed us to analyse the causal effect of job loss and re-employment on subjective health. We made use of data from the German Panel Study Labour Market and Social Security and combined survey information with administrative records of the Federal Employment Agency for employed and unemployed men and women 31-60 years of age ( n = 2213). We controlled for labour-market experiences before the time period under study and for labour-market transitions between the interviews. Subjective health was assessed using the SF-12 health questionnaire, enabling us to differentiate between subjective mental and physical health functioning. RESULTS: We found that physical health was affected mainly in older persons between 45 and 60 years old. Controlling for covariates using propensity score matching, mental health was affected only when living-wage jobs (i.e. jobs that provide sufficient income to achieve a defined minimum standard of living above the social benefit level) are gained or lost. Younger women showed a significant improvement in mental health after re-employment. In contrast, job loss affected only older individuals' mental health, with a particularly negative effect observed for men. CONCLUSIONS: Our results not only showed that women and men are affected differently by job loss and re-employment, but also that age is an important factor. Older men were affected most severely by job loss, whereas re-employment was found to improve mental health only in women aged 31-44 years. It is therefore important to address the health problems of different socio-demographic groups separately, and to apply active labour-market policies with regard to unemployed men and women with health impairments. Based on our results, we suggest the promotion of employment with income levels above the maximum welfare benefit award.

Masked auditory feedback affects speech motor learning of a plosive duration contrast.

Adult speakers have developed precise forward models of articulation for their native language and seem to rely less on auditory sensory feedback. However, for learning of the production of new speech sounds, auditory perception provides a corrective signal for motor control. We assessed adult German speakers' speech motor learning capacity in the absence of auditory feedback but with clear somatosensory information. Learners were presented with a nonnative singleton-geminate duration contrast of voiceless, unaspirated bilabial plosives /p/ vs. /pp/ which is present in Italian. We found that the lack of auditory feedback had no immediate effect but that deviating productions emerged during the course of learning. By the end of training, speakers with masked feedback produced strong lengthening of segments and showed more variation on their production than speakers with normal auditory feedback. Our findings indicate that auditory feedback is necessary for the learning of precise coordination of articulation even if somatosensory feedback is salient.