Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study.

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Conditional Cash Transfers and Migration: Reconciling Feminist Theoretical Approaches With the New Economics of Labor Migration.

In 2019, I published a study titled "Reexamining the Influence of Conditional Cash Transfers on Migration from a Gendered Lens," to which Oded Stark has since issued a formal comment. This response has been written to address the major themes of Stark's comment. While the first three sections focus on specific items related to framing, selection bias, and endogeneity, the fourth and final section tackles a more substantive theoretical debate between Stark and me over how to conceptualize the New Economics of Labor Migration framework in relation to gender. In my original paper, I argued that conditional cash transfers (CCTs) are gendered in their program conditions in ways that promote a normative gendered division of labor and that constrain beneficiary women from migrating. I note here that Stark's primary issue with this point appears to be his contention that CCTs are not necessarily gendered but rather that women have a comparative advantage in completing housework and care work. My response first compares Stark's argument to that made by Gary Becker in A Treatise on the Family and engages with the literature that has emerged to critique Becker's own arguments regarding gendered comparative advantage. I then conclude my final section by offering some suggestions that might open a common theoretical path forward-one that insists on grounding microeconomic analyses of family behavior on assumptions that take gender and other aspects of culture and institutions seriously and one that also moves toward a bargaining model of microeconomic behavior rather than one that assumes consensus among all relevant actors.

Ethno-Caste Influences on Migration Rates and Destinations.

While studies commonly show differences in out-migration between ethnic groups, ethnicity most often features no more than a side note in the emigration literature, and we have very little insight about why people from different ethnic groups migrate at different rates. Understanding ethnic differences in migration rates and destination choice has important implications for the present-day and future potential for either dampening or exacerbating ethnic discrimination and opportunity structures. Building on existing migration theory, we identify three possible mechanisms through which ethnicity might influence out-migration rates and destination choice: human and economic capital, contemporary discrimination, and historical legacies that are perpetuated through social networks. Our empirical investigation uses longitudinal panel survey data from Nepal and we find that all three of these mechanisms likely influence out-migration and destinations of the five major ethno-caste groups. However, we show that historical legacy and human and economic capital emerge as the key drivers of ethnic differences in out-migration here. We discuss what these results mean for migration studies as well as the potential for the institution of migration to affect patterns of ethno-caste-based disadvantage in Nepal. The theoretical basis and empirical evidence from our study also suggest ways to understand the reasoning for and consequence of ethnic and racial differentials in migration patterns in other areas of the world.

When does Social Capital Matter for Migration? A Study of Networks, Brokers, and Migrants in Nepal.

The study of social capital has been one of the strongest areas of recent advance in migration research, but there are still many questions about how it works and why it has varying effects in studies of different places. In this article, we address the contextual variation in social capital's effects on migration by considering migration brokers. We argue that destinations for which migration is logistically difficult to arrange give rise to brokerage industries and hypothesize that brokers in turn substitute for the informational capital typically provided by social networks. Our empirical tests in Nepal support this narrative, showing that social networks matter for migration to destinations where brokers are not available and have little discernible effect on migration to brokered destinations. Our results suggest that migration research should consider the growing role of brokerage agencies, that theorizations of social capital more broadly must contend with how it is delimited by brokers, and that social scientists might also consider other consequences that can arise from these migration brokers that are increasingly common in many countries and provide a marketized replacement for social capital in some cases.

Reexamining the Influence of Conditional Cash Transfers on Migration From a Gendered Lens.

Past research on the influence of conditional cash transfers-widespread antipoverty programs-on migration has tended to focus on beneficiaries as a homogenous unit. Drawing on feminist critiques of the contemporary international antipoverty agenda, this article views both conditional cash transfer programs and migration patterns from a gender-sensitive lens. Conditional cash transfers rely on a gendered division of labor in which the informal work of women is particularly called upon in order to fulfill program requirements. This work contends that conditional cash transfers emphasize gender responsibilities for women as mothers and caretakers, which mark their belonging in the domestic sphere and limit the likelihood of their migration while making no such demands on beneficiary men or nonbeneficiaries. Using logistic and multinomial logistic regression models and data from the Mexican Family Life Survey, the analysis finds evidence supporting the hypothesis that conditional cash transfer participation disproportionately limits migration for beneficiary women. This study broadly argues that the impact of such antipoverty programs is more gendered than previously thought and emphasizes the importance of examining previously studied outcomes in ways that consider the specific subject locations of recipients in order to better understand both the logics underlying development policy and the process of migration itself.

Influences of Material Aspirations on Migration.

In this article, we investigate the influences of material aspirations on migration in Nepal, positing that material aspirations may have important influences on decisions to migrate and where to locate. We discuss a theoretical model explaining how these aspirations might be key influences in the migration decision. Using detailed continuous migration histories from the 2008-2012 Chitwan Valley Family Study, we estimate logistic and alternative-specific conditional logit models to examine how material aspirations in Nepal influence migration rates and destinations. Our empirical analyses provide strong evidence that material aspirations have large effects on overall rates of migration and affect destination-specific migration rates, particularly for relatively wealthy Western and Asian destinations. We also show an interaction effect between material aspirations and destination-specific expected earnings in influencing people's migration choices. It is the people with high aspirations who migrate to destinations with high earning potentials.

Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration.

Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs integrations to the bodies of expressed genes. Replacing the N terminus of LEDGF with chromatin binding domains (CBDs) from other proteins changes the specificity of HIV-1 DNA integration. We chose two well-characterized CBDs: the plant homeodomain (PHD) finger from ING2 and the chromodomain from heterochromatin binding protein 1alpha (HP1alpha). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1alpha chromodomain binds H3K9me2,3, histone marks that are widely distributed throughout the genome. A fusion protein in which the ING2 PHD finger was linked to the LEDGF IBD directed integrations near the start sites of expressed genes. A similar fusion protein in which the HP1alpha chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion-directed and LEDGF-directed integration sites. The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy.

Modifiable comorbidities and disability in multiple sclerosis.

Multiple sclerosis is a common neurological disease that results in disability in early adulthood that may progress through a relatively normal lifespan. Other comorbid health conditions can increase the likelihood of progression of MS and independently contribute to limitations in activities and social participation. We examine common modifiable health conditions and behaviors, including hypertension, obesity, diabetes mellitus, alcohol, and smoking to determine their impacts on MS and disability. Appropriate identification and treatment can improve health status, diminish disability, and improve quality of life.

The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors.

The CDC73 tumor suppressor gene is mutationally inactivated in hereditary and sporadic parathyroid tumors. Its product, the Cdc73 protein, is a component of the RNA polymerase II and chromatin-associated human Paf1 complex (Paf1C). Here, we show that Cdc73 physically associates with the cleavage and polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF) complexes that are required for the maturation of mRNA 3' ends in the cell nucleus. Immunodepletion experiments indicate that the Cdc73-CPSF-CstF complex is necessary for 3' mRNA processing in vitro. Microarray analysis of CDC73 siRNA-treated cells revealed INTS6, a gene encoding a subunit of the Integrator complex, as an in vivo Cdc73 target. Cdc73 depletion by siRNA resulted in decreased INTS6 mRNA abundance, and decreased association of CPSF and CstF subunits with the INTS6 locus. Our results suggest that Cdc73 facilitates association of 3' mRNA processing factors with actively-transcribed chromatin and support the importance of links between tumor suppression and mRNA maturation.

Barriers and Facilitators Associated with the Adoption of and Adherence to a Mediterranean Style Diet in Adults: A Systematic Review of Published Observational and Qualitative Studies.

The Mediterranean diet (MedDiet) has been linked with physical and mental health benefits. Previous research, however, suggests that adoption and adherence to a Mediterranean diet might be difficult for people who live outside of the Mediterranean region. The aim of this systematic review was to investigate the factors that influence adoption and adherence to a Mediterranean style diet in adults aged 18 years old and over, as identified in published observational and qualitative studies. Following registration of our protocol on PROSPERO (ID: CRD42018116515), observational and qualitative studies of adults' perceptions and experiences relevant to following a Mediterranean style diet were identified using systematic searches of databases: MEDLINE, the Cochane Library, CINAHL, Web of Science and Scopus, over all years of records until February 2022. A narrative synthesis was then undertaken. Of 4559 retrieved articles, 18 studies fulfilled our inclusion criteria and were included. Factors influencing adoption and adherence to a MedDiet were identified and categorized as: financial, cognitive, socio-cultural, motivational, lifestyle, accessibility & availability, sensory & hedonic and demographic. Similar barriers and facilitators are often reported in relation to healthy eating or the consumption of specific healthy foods, with a few exceptions. These exceptions detailed concerns with specific components of the MedDiet; considerations due to culture and traditions, and concerns over a cooler climate. Suggestions for overcoming these barriers and facilitators specific to adoption and adherence to the Mediterranean diet are offered. These data will inform the development of future studies of robust methodology in eating behaviour change which offer pragmatic approaches for people to consume and maintain healthy diets.

Developmental Idealism and Migration: Theorizing their Relationship and an Empirical Example from Nepal.

This paper brings together both theoretically and empirically two strands of social science research: migration and developmental idealism. The paper is motivated by the fact that there are extensive bodies of research about migration and about developmental idealism, but almost no discussion in the literature about how they might be interconnected. We present theoretical arguments concerning the influence of migration in distributing developmental idealism around the world and in developmental idealism being a force influencing the migration decisions of people. We also provide an empirical investigation of how variation in developmental idealism may have been an influence on migration and choice of migration destinations in Nepal. Thus, we extend the developmental idealism literature to include migration and the migration literature to include developmental idealism.

A Systematic Literature Review of the Relationship between Serum Ferritin and Outcomes in Myelodysplastic Syndromes.

Anemia is the most common form of cytopenia in patients with myelodysplastic syndromes (MDS), who require chronic red blood cell transfusions and may present high serum ferritin (SF) levels as a result of iron overload. To better understand the potential effects of high SF levels, we conducted a systematic literature review (SLR) to identify evidence on the relationship between SF levels and clinical, economic, or humanistic outcomes in adult patients with MDS. Of 267 references identified, 21 were included. No studies assessing SF levels and their relationship with humanistic or economic outcomes were identified. Increased SF levels were an indicator of worse overall survival and other worsened outcomes; however, the association was not consistently significant. SF levels were a significant prognostic factor for relapse incidence of MDS and showed a significant positive correlation with number of blood units transfused but were not associated with progression to acute myeloid leukemia or the time to transformation. Higher SF levels were also an indicator of a lower likelihood of leukemia-free survival, relapse-free survival, and event-free survival. The SLR suggests that SF levels are associated with clinical outcomes in MDS, with higher levels correlated with number of blood units transfused, frequently indicating worse outcomes.

Ascertaining cells' synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries.

Brain function depends on synaptic connections between specific neuron types, yet systematic descriptions of synaptic networks and their molecular properties are not readily available. Here, we introduce SBARRO (Synaptic Barcode Analysis by Retrograde Rabies ReadOut), a method that uses single-cell RNA sequencing to reveal directional, monosynaptic relationships based on the paths of a barcoded rabies virus from its "starter" postsynaptic cell to that cell's presynaptic partners. Thousands of these partner relationships can be ascertained in a single experiment, alongside genome-wide RNAs. We use SBARRO to describe synaptic networks formed by diverse mouse brain cell types in vitro, finding that different cell types have presynaptic networks with differences in average size and cell type composition. Patterns of RNA expression suggest that functioning synapses are critical for rabies virus uptake. By tracking individual rabies clones across cells, SBARRO offers new opportunities to map the synaptic organization of neural circuits.

Family Obligation Attitudes, Gender, and Migration.

This study focuses on attitudes related to fulfilling family obligations and their relationships to migration behavior. We hypothesize that men who highly value fulfilling family obligations will be more likely to migrate in order to fulfill material obligations while women who highly value fulfilling family obligations will be less likely to migrate in order to fulfill care obligations. The empirical analysis examines data from the Chitwan Valley Family Study, located in south-central Nepal. We test whether variation in how much individuals value putting family needs before individual needs and caring for their adult parents matter for whether they migrate at all and if so, to which specific destinations. Our results provide only moderate support for these hypotheses but uncover patterns in how these attitudes toward family obligations are related to migration destinations. Men with strong attitudes toward family obligations are more likely to migrate internationally but especially to nearby India, sacrificing some level of economic returns for proximity. For women, the effect of attitudes is consistent: putting family needs first is negatively related to migration, while caring for adult parents is positively related to migration to India but not domestic or other international destinations. The findings suggest that our conventional typology of gendered labor and gender expectations for masculine breadwinning and feminine care might too strictly dichotomize the reality of how people actually care and provide for their families, obfuscating how they negotiate these competing demands.

Fatalistic Beliefs and Migration Behaviors: A Study of Ideational Demography in Nepal.

We investigate influences of fatalistic beliefs on domestic and international migration in Nepal, positing that fatalistic beliefs may affect decisions to migrate and where to locate. Fatalism is the belief that human outcomes are preordained by forces outside of one's power and control. Because of its relationship with effort and innovation, fatalism may be an important factor in people's decision to migrate and destination choice. We expect that fatalistic beliefs encourage or discourage migration depending upon societal expectations to migrate and the relative ease of migration to different destinations. Our empirical analysis relies on migration histories of respondents from the Chitwan Valley Family Study. Results from multinomial logistic regression models provide evidence that fatalistic beliefs increase overall migration propensity and has both positive and negative destination-specific effects. Fatalistic beliefs increase Nepalis' odds of migrating to destinations that are, relatively speaking, easier to access, but decrease the odds of migrating to destinations with higher barriers to entry.

The parafibromin tumor suppressor protein is part of a human Paf1 complex.

Parafibromin, the product of the HRPT2 (hyperparathyroidism-jaw tumor syndrome 2) tumor suppressor gene, is the human homologue of yeast Cdc73, part of the yeast RNA polymerase II/Paf1 complex known to be important for histone modification and connections to posttranscriptional events. By purifying cellular parafibromin and characterizing its associated proteins, we have identified a human counterpart to the yeast Paf1 complex including homologs of Leo1, Paf1, and Ctr9. Like the yeast complex, the parafibromin complex associates with the nonphosphorylated and Ser2 and Ser5 phosphorylated forms of the RNA polymerase II large subunit. Immunofluorescence experiments show that parafibromin is a nuclear protein. In addition, cotransfection data suggest that parafibromin can interact with a histone methyltransferase complex that methylates histone H3 on lysine 4. Some mutant forms of parafibromin lack association with hPaf1 complex members and with the histone methyltransferase complex, suggesting that disruption of these complexes may correlate with the oncogenic process.

Phosphorylation of the menin tumor suppressor protein on serine 543 and serine 583.

Multiple endocrine neoplasia type 1 (MEN-1) is a heritable syndrome typified by tumors in multiple endocrine organs, including the pituitary, parathyroids, and pancreatic islets. MEN-1 is attributable to mutations in the MEN1 tumor-suppressor gene that encodes the menin protein. Recent studies have implicated menin in transcriptional regulation and in covalent histone modification; however, little is known about modifications of the menin protein. Here, we report that menin is subject to phosphorylation on serine residues, including Ser543 and Ser583. Phosphorylation-defective mutants of either or both of these residues retain the associated histone methyltransferase activity of menin, as well as binding to the trithorax complex members Ash2L, Rbbp5, and MLL2 and to RNA polymerase II. Chromatin immunoprecipitation experiments reveal that binding of menin to the Hoxc8 locus is not affected by phosphorylation on Ser543 or Ser583.

Improving fatigue and depression in individuals with multiple sclerosis using telephone-administered physical activity counseling.

OBJECTIVE: To evaluate the impact of a physical activity intervention consisting of telephone counseling with home-based monitoring to improve fatigue and depression in individuals with multiple sclerosis (MS). METHOD: Single-blind randomized controlled trial. Sixty-four individuals with MS received either telephone counseling (N = 31), or self-directed physical activity education (N = 33). The education condition (EC) consisted of advice to increase physical activity and a DVD with examples of in-home exercises for multiple physical ability levels. The telephone counseling condition (TC) included EC as well as mailed graphic feedback, 6 telephone counseling sessions using principles of motivational interviewing, and telehealth home monitoring to track progress on physical activity goals. Booster sessions were provided when participants indicated they did not meet their goals. Assessment was conducted at baseline, 3-month, and 6-month follow-up. RESULTS: TC participants reported significantly reduced fatigue (d = -.70), reduced depression (d = -.72) and increased physical activity (d = .92) relative to EC participants. Of individuals receiving TC, 33.3% experienced clinically significant improvement in fatigue (vs. 18.2% in EC) and 53.3% experienced clinically significant improvement in depression (vs. 9.1% in EC). Improvements in physical activity mediated improvements in fatigue with a similar trend for depression. TC was highly feasible (participants completed 99.5% of schedule telephone sessions) and well tolerated (100% rated it highly successful). CONCLUSION: Telephone-based counseling with home monitoring is a promising modality to improve physical activity and treat fatigue and depression.

Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). METHODS: We systematically searched the literature (1970-2013) and classified articles using 2004 American Academy of Neurology criteria. RESULTS: This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk ≥5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0-6.5) (1 Class II). Six weeks' worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0-8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2-6.5) (1 Class II).

Spasticity management in multiple sclerosis.

Spasticity is a prevalent and potentially disabling symptom common in individuals with multiple sclerosis. Adequate evaluation and management of spasticity requires a careful assessment of the patient's history to determine functional impact of spasticity and potential exacerbating factors, and physical examination to determine the extent of the condition and culpable muscles. A host of options for spasticity management are available: therapeutic exercise, physical modalities, complementary/alternative medicine interventions, oral medications, chemodenervation, and implantation of an intrathecal baclofen pump. Choice of treatment hinges on a combination of the extent of symptoms, patient preference, and availability of services.