Background. The predominant strain during the 2013–2014 influenza season was 2009 pandemic influenza A(H1N1) virus (AH1N1pdm09). This vaccine-component has remained unchanged from 2009. Methods. The ...US Flu Vaccine Effectiveness Network enrolled subjects aged ≥6 months with medically attended acute respiratory illness (MAARI), including cough, with illness onset ≤7 days before enrollment. Influenza was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). We determined the effectiveness of trivalent or quadrivalent inactivated influenza vaccine (IIV) among subjects ages ≥6 months and the effectiveness of quadrivalent live attenuated influenza vaccine (LAIV4) among children aged 2–17 years, using a test-negative design. The effect of prior receipt of any A(H1N1)pdm09-containing vaccine since 2009 on the effectiveness of current-season vaccine was assessed. Results. We enrolled 5999 subjects; 5637 (94%) were analyzed; 18% had RT-PCR–confirmed A(H1N1)pdm09-related MAARI. Overall, the effectiveness of vaccine against A(H1N1)pdm09-related MAARI was 54% (95% confidence interval CI, 46%–61%). Among fully vaccinated children aged 2–17 years, the effectiveness of LAIV4 was 17% (95% CI, −39% to 51%) and the effectiveness of IIV was 60% (95% CI, 36%–74%). Subjects aged ≥9 years showed significant residual protection of any prior A(H1N1)pdm09-containing vaccine dose(s) received since 2009, as did children <9 years old considered fully vaccinated by prior season. Conclusions. During 2013–2014, IIV was significantly effective against A(H1N1)pdm09. Lack of LAIV4 effectiveness in children highlights the importance of continued annual monitoring of effectiveness of influenza vaccines in the United States.
Background. Each year, the US Influenza Vaccine Effectiveness Network examines the effectiveness of influenza vaccines in preventing medically attended acute respiratory illnesses caused by ...influenza. Methods. Patients with acute respiratory illnesses of ≤7 days' duration were enrolled at ambulatory care facilities in 5 communities. Specimens were collected and tested for influenza by real-time reverse-transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or immunization registries. Vaccine effectiveness was estimated in adjusted logistic regression models by comparing the vaccination coverage in those who tested positive for influenza with those who tested negative. Results. The 2011–2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval CI, 36–56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44–79) against type A (H1N1) pdm09 but only 39% (95% CI, 23–52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35–73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes. Conclusions. Vaccine effectiveness in the 2011–2012 season was modest overall, with lower effectiveness against the predominant A (H3N2) virus. This may be related to antigenic drift, but past history of vaccination might also play a role.
Background. During the 2012-2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza lineage viruses in the United States. Methods. Patients with acute cough illness for ≤7 ...days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as 100% × (1 - adjusted odds ratio) for vaccination in cases versus test-negative controls. Results. Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval CI, 43%-55%) overall, 39% (95% CI, 29%-47%) against influenza A(H3N2), 66% (95% CI, 58%-73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%-63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50-64 years (52%; 95% CI, 33%-65%) and persons aged 6 months-8 years (51%; 95% CI, 32%-64%) and lowest among persons aged ≥65 years (11%; 95% CI, -41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011-2012 vaccine 1 year earlier. Conclusions. The 2012-2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.
During the late Pleistocene, isolated lineages of hominins exchanged genes thus influencing genomic variation in humans in both the past and present. However, the dynamics of this genetic exchange ...and associated phenotypic consequences through time remain poorly understood. Gene exchange across divergent lineages can result in myriad outcomes arising from these dynamics and the environmental conditions under which it occurs. Here we draw from our collective research across various organisms, illustrating some of the ways in which gene exchange can structure genomic/phenotypic diversity within/among species. We present a range of examples relevant to questions about the evolution of hominins. These examples are not meant to be exhaustive, but rather illustrative of the diverse evolutionary causes/consequences of hybridization, highlighting potential drivers of human evolution in the context of hybridization including: influences on adaptive evolution, climate change, developmental systems, sex‐differences in behavior, Haldane's rule and the large X‐effect, and transgressive phenotypic variation.
During the COVID-19 pandemic, the US federal government required that skilled nursing facilities (SNFs) close to visitors and eliminate communal activities. Although these policies were intended to ...protect residents, they may have had unintended negative effects.
To assess health outcomes among SNFs with and without known COVID-19 cases.
This retrospective observational study used US Medicare claims and Minimum Data Set 3.0 for January through November in each year beginning in 2018 and ending in 2020 including 15 477 US SNFs with 2 985 864 resident-years.
January through November of calendar years 2018, 2019, and 2020. COVID-19 diagnoses were used to assign SNFs into 2 mutually exclusive groups with varying membership by month in 2020: active COVID-19 (≥1 COVID-19 diagnosis in the current or past month) or no-known COVID-19 (no observed diagnosis by that month).
Monthly rates of mortality, hospitalization, emergency department (ED) visits, and monthly changes in activities of daily living (ADLs), body weight, and depressive symptoms. Each SNF in 2018 and 2019 served as its own control for 2020.
In 2018-2019, mean monthly mortality was 2.2%, hospitalization 3.0%, and ED visit rate 2.9% overall. In 2020, among active COVID-19 SNFs compared with their own 2018-2019 baseline, mortality increased by 1.60% (95% CI, 1.58% to 1.62%), hospitalizations decreased by 0.10% (95% CI, -0.12% to -0.09%), and ED visit rates decreased by 0.57% (95% CI, -0.59% to -0.55%). Among no-known COVID-19 SNFs, mortality decreased by 0.15% (95% CI, -0.16% to -0.13%), hospitalizations by 0.83% (95% CI, -0.85% to -0.81%), and ED visits by 0.79% (95% CI, -0.81% to -0.77%). All changes were statistically significant. In 2018-2019, across all SNFs, residents required assistance with an additional 0.89 ADLs between January and November, and lost 1.9 lb; 27.1% had worsened depressive symptoms. In 2020, residents in active COVID-19 SNFs required assistance with an additional 0.36 ADLs (95% CI, 0.34 to 0.38), lost 3.1 lb (95% CI, -3.2 to -3.0 lb) more weight, and were 4.4% (95% CI, 4.1% to 4.7%) more likely to have worsened depressive symptoms, all statistically significant changes. In 2020, residents in no-known COVID-19 SNFs had no significant change in ADLs (-0.06 95% CI, -0.12 to 0.01), but lost 1.8 lb (95% CI, -2.1 to -1.5 lb) more weight and were 3.2% more likely (95% CI, 2.3% to 4.1%) to have worsened depressive symptoms, both statistically significant changes.
Among skilled nursing facilities in the US during the first year of the COVID-19 pandemic and prior to the availability of COVID-19 vaccination, mortality and functional decline significantly increased at facilities with active COVID-19 cases compared with the prepandemic period, while a modest statistically significant decrease in mortality was observed at facilities that had never had a known COVID-19 case. Weight loss and depressive symptoms significantly increased in skilled nursing facilities in the first year of the pandemic, regardless of COVID-19 status.
The Hybrid Origin of “Modern” Humans Ackermann, Rebecca Rogers; Mackay, Alex; Arnold, Michael L.
Evolutionary biology,
03/2016, Volume:
43, Issue:
1
Journal Article
Peer reviewed
Recent genomic research has shown that hybridization between substantially diverged lineages is the rule, not the exception, in human evolution. However, the importance of hybridization in shaping ...the genotype and phenotype of
Homo sapiens
remains debated. Here we argue that current evidence for hybridization in human evolution suggests not only that it was important, but that it was an essential creative force in the emergence of our variable, adaptable species. We then extend this argument to a reappraisal of the archaeological record, proposing that the exchange of cultural information between divergent groups may have facilitated the emergence of cultural innovation. We discuss the implications of this Divergence and Hybridization Model for considering the taxonomy of our lineage.
Despite advances in defining the critical molecular determinants for leukemia stem cell (LSC) generation and maintenance, little is known about the roles of microRNAs in LSC biology. Here, we ...identify microRNAs that are differentially expressed in LSC-enriched cell fractions (c-kit(+)) in a mouse model of MLL leukemia. Members of the miR-17 family were notably more abundant in LSCs compared with their normal counterpart granulocyte-macrophage progenitors and myeloblast precursors. Expression of miR-17 family microRNAs was substantially reduced concomitant with leukemia cell differentiation and loss of self-renewal, whereas forced expression of a polycistron construct encoding miR-17-19b miRNAs significantly shortened the latency for MLL leukemia development. Leukemias expressing increased levels of the miR-17-19b construct displayed a higher frequency of LSCs, more stringent block of differentiation, and enhanced proliferation associated with reduced expression of p21, a cyclin-dependent kinase inhibitor previously implicated as a direct target of miR-17 microRNAs. Knockdown of p21 in MLL-transformed cells phenocopied the overexpression of the miR-17 polycistron, including a significant decrease in leukemia latency, validating p21 as a biologically relevant and direct in vivo target of the miR-17 polycistron in MLL leukemia. Expression of c-myc, a crucial upstream regulator of the miR-17 polycistron, correlated with miR-17-92 levels, enhanced self-renewal, and LSC potential. Thus, microRNAs quantitatively regulate LSC self-renewal in MLL-associated leukemia in part by modulating the expression of p21, a known regulator of normal stem cell function.
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As ...JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
The Children's Oncology Group study AREN0534 aimed to improve event-free survival (EFS) and overall survival (OS) while preserving renal tissue by intensifying preoperative chemotherapy, completing ...definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response.
No prospective therapeutic clinic trials in children with bilateral Wilms tumors (BWT) exist. Historical outcomes for this group were poor and often involved prolonged chemotherapy; on NWTS-5, 4-year EFS for all children with BWT was 56%.
Patients were enrolled and imaging studies were centrally reviewed to assess for bilateral renal lesions. They were treated with 3-drug induction chemotherapy (vincristine, dactinomycin, and doxorubicin) for 6 or 12 weeks based on radiographic response followed by surgery and further chemotherapy determined by histology. Radiation therapy was provided for postchemotherapy stage III and IV disease.
One hundred eighty-nine of 208 patients were evaluable. Four-year EFS and OS were 82.1% (95% CI: 73.5%-90.8%) and 94.9% (95% CI: 90.1%-99.7%. Twenty-three patients relapsed and 7 had disease progression. After induction chemotherapy 163 of 189 (84.0%) underwent definitive surgical treatment in at least 1 kidney by 12 weeks and 39% retained parts of both kidneys. Surgical approaches included: unilateral total nephrectomy with contralateral partial nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral total nephrectomy (10.5%), unilateral partial nephrectomy (4%), and bilateral total nephrectomies (2.5%).
This treatment approach including standardized 3-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and histology-based postoperative therapy improved EFS and OS and preservation of renal parenchyma compared with historical outcomes for children with BWT.
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