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Children's school performance is often associated with parenting practices, implying a direct link between parents' behavior, child development, and academic success. Through the case of an Indian forest-dwelling community, I offer an alternative view of child development, learning, and teaching, which prioritizes social skills above--and as a precondition of--academic/practical ones. I discuss the implications of such view to the evaluation of parenting, and more broadly, of formal education for marginalized indigenous communities.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors. Integration of longitudinal single-cell analysis of relapsed and refractory multiple myeloma patients in a prospective clinical trial uncovers new pathways of drug resistance and identifies potential actionable targets., Author(s): Yael C. Cohen [sup.1] [sup.2] , Mor Zada [sup.1] [sup.3] , Shuang-Yin Wang [sup.3] , Chamutal Bornstein [sup.3] , Eyal David [sup.3] , Adi Moshe [sup.3] , Baoguo Li [...]

Objective: To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd). Methods: An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials. Results: Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatmentemergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%). Conclusion: The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall riskbenefit profile favored the SPd-40 regimen. [ABSTRACT FROM AUTHOR]

We examine how hunter-gatherers are imagined in popular debate in Britain and Ireland, demonstrating that aspects of hunter-gatherer lifestyles are presented as both the antithesis and antidote to perceived crises in contemporary society. We apply an anthropological lens to four areas of popular discourse: physical health, mental health, bushcraft, and survivalism. We identify how the imagined hunter-gatherer in these debates is constructed through processes of commodification that often reveal nostalgic colonial values regarding "human nature." This repeats and sustains damaging perceptions of hunter-gatherer lifeways. It also highlights how archaeological, anthropological, and other academic research on hunter-gatherers is manifest in popular debates that reinforce assumptions about human nature and the significance of our evolutionary past within a neoliberal, colonialist context. [ABSTRACT FROM AUTHOR]

Simple Summary: Light-chain amyloidosis is a rare disease, and treatment for relapsed light-chain amyloidosis patients is an unmet need. Venetoclax is an oral medication that has proven great efficacy in many hematological cancers, including multiple myeloma. Venetoclax is considered a promising agent for the treatment of relapsed light-chain amyloidosis. We aimed to report the outcomes of therapy in 26 relapsed light-chain amyloidosis patients treated with venetoclax. We found a very high response rate (88%), and most responses were deep and prolonged. Treatment was effective even when doses were reduced. Venetoclax treatment was safe, and one patient died due to infection. These promising results require confirmation in a randomized trial. Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results of a multi-center retrospective study on 26 R/R AL amyloidosis patients treated off-label with venetoclax. The median lines of therapy prior to venetoclax was 3.5 (range 1–7), and 88% of our cohort had t (11;14). Twenty-two patients (85%) were previously treated with daratumumab. The overall hematologic response rate was 88%, 35% achieved a CR, and 35% achieved VGPR. The median event-free survival was 25 months (m) (95% CI 9.7 m-not reached), and the median overall survival was 33 m (95% CI 25.9–39.2 m). Most of the patients in this cohort are in ongoing deep responses and continuing venetoclax therapy. The treatment was relatively safe. One patient died due to infection, and there were two grade 3 infections in our cohort. Tumor lysis syndrome (TLS) was not seen in any patient. Dose reductions were frequent but did not affect the efficacy. These promising results require confirmation in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Summary: Belantamab mafodotin, an immuno‐conjugate targeting B‐cell maturation antigen, showed single‐agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real‐world data and long‐term follow‐up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One‐hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2–11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow‐up time was 11.9 [95% confidence interval (CI) 10.0–13.8] months. Overall response rate was 45.5%. Median progression‐free survival was 4.7 (95% CI 3.5–5.9) months in the entire cohort and 8.8 (95% CI 6.6–10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5–19.6) months, and not reached for responders. To conclude, in a real‐world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile. [ABSTRACT FROM AUTHOR]

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% – recurrent SP, 36.8% – active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy. [ABSTRACT FROM AUTHOR]

Learning to use, make, and modify tools is key to our species' success. Researchers have hypothesized that play with objects may have a foundational role in the ontogeny of tool use and, over evolutionary timescales, in cumulative technological innovation. Yet, there are few systematic studies investigating children's interactions with objects outside the post-industrialized West. Here, we survey the ethnohistorical record to uncover cross-cultural trends regarding hunter-gatherer children's use of objects during play and instrumental activities. Our dataset, consisting of 434 observations of children's toys and tools from 54 hunter-gatherer societies, reveals several salient trends: Most objects in our dataset are used in play. Children readily manufacture their own toys, such as dolls and shelters. Most of the objects that children interact with are constructed from multiple materials. Most of the objects in our dataset are full-sized or miniature versions of adult tools, reflecting learning for adult roles. Children also engage with objects related to child culture, primarily during play. Taken together, our findings show that hunter-gatherer children grow up playing, making, and learning with objects. [ABSTRACT FROM AUTHOR]

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease (p = 0.036) and mortality (p = 0.023), hypertension with severe/critical disease (p = 0.046) and hospitalization (p = 0.001), active haemato-oncological treatment with hospitalization (p = 0.009), and remdesivir treatment was associated with decreased mortality (p = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective. [ABSTRACT FROM AUTHOR]

Background: Advances in treatment for multiple myeloma (MM) patients entail a high risk for opportunistic infections such as invasive pulmonary aspergillosis (IPA). Objectives: This study was conducted to describe the patient's profile, clinical manifestations, diagnosis and outcome of MM patients with IPA, in our large haemato‐oncology centre. Patients/Methods: We retrospectively analysed patients with MM who underwent Broncho alveolar lavage for pneumonia at Rambam Hospital during a 13‐year period from July 2005 to February 2018. We focused on those with Aspergillus pneumonia. Results: Of the 669 patients with multiple myeloma, mean age 62.6 (±7.6) years, forty‐two patients (6.2%) were diagnosed with IPA. Among them, 60% had a probable diagnosis and 40% possible. Clinical presentation was similar for IPA and other pulmonary infections. Compared to those with other pulmonary infections, IPA was more commonly diagnosed in patients with long‐standing disease (p =.00012) and among patients receiving 3 or more lines of myeloma therapies (p =.04). Thirty‐day mortality rates following diagnostic bronchoscopy did not differ between IPA and non‐IPA patients. (p =.85). Conclusions: Multiple myeloma patients had an increased risk for IPA, most notably in patients with 3 or more lines of anti‐myeloma treatment and more advanced disease. This clearly emphasises the vigilance needed for IPA in these patients. [ABSTRACT FROM AUTHOR]

The BCR-ABL-negative myeloproliferative neoplasms (MPN) are associated with high incidence of venous thrombosis and a significant rate of recurrent events, but there is no consensus regarding their management. In this retrospective study, we analyzed 96 patients with MPN-related venous thrombosis. The index venous thrombosis occurred at a median age of 58 years (IQR 37–71), with 58% of the events involving unusual sites. Patients who were on antiplatelet agents at the time of index thrombosis tended to be older than patients who were not receiving antiplatelets at the time of index thrombosis. The majority of index thromboses occurring after the diagnosis of MPN had uncontrolled blood counts at the time of event and were not receiving antithrombotic agents. Following the thrombotic episode, 75% of patients received long-term anticoagulation. At a median follow-up of 3.4 years, the recurrence rate was 14%. Thrombophilia was significantly more prevalent among patients with recurrent thrombosis compared to patients without recurrence (p < 0.01). Patients who developed a recurrent event early were more likely to have thrombophilia (either inherited or antiphospholipid antibodies), and controlled blood counts, and were likely to receive anticoagulation at the time of recurrence compared to patients with later recurrences. Thrombophilia may contribute to venous thrombosis recurrence, especially early after the index venous thrombosis. Suboptimal anticoagulation and blood count control are factors associated with late venous thrombosis recurrence. [ABSTRACT FROM AUTHOR]

Invasive pulmonary aspergillosis (IPA) has dire consequences in hemato-oncological patients. We report our experience with performing routine baseline chest computed tomography for early diagnosis of IPA. We found high rates of proven or probable IPA diagnosed on admission among patients with newly diagnosed acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 – inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) (p =.001) and overall survivals (OS) (p =.0007). The 1-year RFS and OS were 44.2% vs 88% and 71% vs 96% for chemotherapy and ASCT, respectively. The corresponding TRM was 4/40 (10.0%) and 0/26 (0%), with relapse rates of 70.0% and 19.2% (p =.0002). In multivariate analysis, ASCT was associated with superior OS and RFS. In conclusion, ASCT offers significantly superior RFS and OS in favorable-risk AML in first complete remission. These data support the recent resurgence of interest in ASCT for AML. [ABSTRACT FROM AUTHOR]

Objective: Approximately 10% of Philadelphia (Ph)‐negative myeloproliferative neoplasms (NPM) are diagnosed at young adulthood. We aim to define the features of this group. Methods: A multicenter retrospective study, including patients 18‐45 years of age, diagnosed with Ph‐negative MPN between 1985 and 2017. Results: One hundred nine patients were included, 37 with polycythemia vera (34%), 54 with essential thrombocytosis (50%), 15 with primary myelofibrosis (PMF) (14%), and 3 with MPN unclassifiable (3%). Median age was 33 years and 62 (57%) were females. During a median follow‐up of 8 years, 39 patients (37%) had at least one thrombotic event. 30/39 of events were venous (77%), 23/30 of which were splanchnic (77%). In 14/39 (36%), thrombosis preceded MPN diagnosis. In a multivariable analysis, only splenomegaly predicted for thrombosis (HR 5.6, CI: 1.4‐22). The 10‐year risk for secondary myelofibrosis was similar for ET and PV (0.13 vs 0.19, P = 0.51). The 10‐year risk for leukemic transformation or mortality was significantly higher for PMF (0.3, P = 0.04). Conclusions: The risks of mortality and of progression to MF/leukemia in young adults are similar to older population. Thrombotic events are frequently a presenting sign with a high incidence of venous, in particular splanchnic, events. [ABSTRACT FROM AUTHOR]