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The inextricable link between global environmental change and human health has gained attention as we witness increasingly catastrophic weather events and widespread environmental degradation wrought by pollution and biodiversity loss and respond to an ongoing COVID pandemic of zoonotic origins [1,2]. In 2014, Richard Horton et al. called for a collective manifesto to transform public health to planetary health [3], which drew a range of responses [4-6]. Planetary health was defined as the health of human civilisation and the state of the natural systems on which it depends [3]. Soon after that, the 2015 report of the Rockefeller Foundation – Lancet Commission on planetary health clearly indicated that we have been mortgaging the health of future generations to realise short-term economic and development gains in the present [7]. Human civilisation has largely flourished by unsustainably exploiting nature's resources, but now confronts substantial health risks from the degradation of nature's life support systems as a direct result of human activities. Health risks from large-scale environmental changes such as climatic change, ocean acidification, land degradation, water scarcity, overexploitation of fisheries, and biodiversity loss pose serious challenges to global health and are likely to increase over the coming decades because of growing populations, accelerating demand for resources (such as land, food, and energy), and inappropriate use of technology (such as the nuclear armament race). The World Health Organization (WHO) recently estimated that more than 13 million deaths annually occur due to avoidable environmental causes, including climate change, air pollution, and other exposures [8]. © 2022 THE AUTHOR(S)
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Background: Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging coronavirus that is endemic in dromedary camels. Kenya's >3 million camels have high seroprevalence of antibodies against MERS-CoV, with scant evidence of human infection, possibly due to a lower zoonotic potential of Clade C viruses, predominantly found in African camels. Methods: Between April 2018-March 2020, we followed camels aged 0-24 months from 33 camel-keeping homesteads within 50Km of Marsabit town through collecting deep nasal swabs and documenting signs of illness in camels every two weeks. Swabs were screened for MERS-CoV by reverse transcriptase (RT)-polymerase chain reaction (PCR) testing and virus isolation performed on PCR positive samples with cycle threshold (CT) <20. Both the isolates and swab samples (CT <30) were subjected to whole genome sequencing. Human camel handlers were also swabbed and screened for symptoms monthly and samples tested for MERS-CoV by RT-PCR. Results: Among 243 calves, 68 illnesses were recorded in 58 camels (53.9%);50/68 (73.5%) of illnesses were recorded in 2019, and 39 (57.3%) were respiratory symptoms (nasal discharge, hyperlacrimation and coughing). A total of 124/4,702 camel swabs (2.6%) from 83 (34.2%) calves in 15 (45.5%) enrolled compounds were positive for MERS-CoV RNA. Cases were detected between May-September 2019 with three infection peaks, a similar period when three (1.1%) human PCR-positive but asymptomatic cases were detected among 262 persons handling these herds. Sequencing of camel specimens revealed a Clade C2 virus with identical 12 nucleotide deletion at the 3' end of OFR3 region and one nucleotide insertion at the 5' region but lacked the signature ORF4b deletions of other Clade C viruses. Interpretation: We found high levels of transmission of distinct Clade C MERS-CoV among camels in Northern Kenya, with likely spillover infection to humans. These findings update our understanding of MERS-CoV epidemiology in this region.
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Background. Human-to-feline and airborne transmission among cats of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been described, though documented feline-to-human transmission has not been reported. In October 2020, all 3 Malayan tigers at a Tennessee AZA accredited zoo were diagnosed with symptomatic SARS-CoV-2 infection. We investigated to determine source and prevent further transmission. Methods. Tiger nasal swab specimens were tested at the National Veterinary Services Laboratories (NVSL). An environmental assessment at the zoo was completed. We interviewed 18 staff who interacted with the tigers during the 2 weeks before animal symptom onset. Confirmed human cases were defined as persons testing positive for SARS-CoV-2 by RT-PCR during September 28-October 29, with tiger interaction during their 14-day incubation period. Interviewed staff had repeat SARSCoV-2 RT-PCR and serum IgG testing on October 29. Tigers and staff testing positive had specimens sent to CDC for genomic sequencing. Tiger sequences were compared phylogenetically with 30 geographically associated human cases collected within 2 weeks of the outbreak and > 200 background sequences from TN. Results. NVSL confirmed SARS-CoV-2 infection in all 3 tigers. Environmental assessment identified fencing between humans and animals allowing airflow and an open outdoor exhibit observation point above the habitat. Confirmed cases were identified in a tiger keeper and veterinary assistant;both developed symptoms after exposure to symptomatic tigers and one sample was genotyped. Staff did not report known contact with ill visitors. All staff were negative for SARS-CoV-2 IgG. The tigers and most temporally and geographically associated cases had genetic sequences in clade 20G and B.1.2. Tiger sequences were 3-6 single nucleotide polymorphisms different from the positive tiger keeper (Figure). Figure. Whole-genome phylogenetic analysis. Whole-genome phylogenetic analysis from a portion of clade 20G showing divergence estimates from SARS-CoV-2 Wuhan-Hu-1 reference genome with sequences from humans living in Tennessee and Malayan tigers sampled during the outbreak investigation in October 2020. Sequence analysis showed 3-6 single nucleotide polymorphisms (SNPs) differences between one human tiger keeper and all three tiger sequences. Differences are indicated by one-step edges (lines) between colored dots (individual SARS-CoV-2 sequenced infections). Numbers indicate unique sequences. Note not all analyzed sequences are shown in this figure. Conclusion. Using a One Health approach, we concluded the index tiger was likely infected via transmission from an ill visitor at an exhibit observation point or unidentified asymptomatic staff. Infection spread to the other 2 tigers and tigerto-human transmission to 2 staff is possible thereafter. The zoo was advised on infection control practices for humans and animals, and no additional cases were identified.
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Background. In December 2020, B.1.1.7 lineage of SARS-CoV-2 was first detected in the United States and has since become the dominant lineage. Previous investigations involving B.1.1.7 suggested higher rates of transmission relative to non-B.1.1.7 lineages. We conducted a household transmission investigation to determine the secondary infection rates (SIR) of B.1.1.7 and non-B.1.1.7 SARS-CoV-2 lineages. Methods. From January-April 2021, we enrolled members of households in San Diego County, CA, and Denver, CO metropolitan area (Tri-County), with a confirmed SARS-CoV-2 infection in a household member with illness onset date in the previous 10 days. CDC investigators visited households at enrollment and 14 days later at closeout to obtain demographic and clinical data and nasopharyngeal (NP) samples on all consenting household members. Interim visits, with collection of NP swabs, occurred if a participant became symptomatic during follow-up. NP samples were tested for SARS-CoV-2 using TaqPath™ RT-PCR test, where failure to amplify the spike protein results in S-Gene target failure (SGTF) may indicate B.1.1.7 lineage. Demographic characteristics and SIR were compared among SGTF and non-SGTF households using two-sided p-values with chi-square tests;95% confidence intervals (CI) were calculated with Wilson score intervals. Results. 552 persons from 151 households were enrolled. 91 (60%) households were classified as SGTF, 57 (38%) non-SGTF, and 3 (2%) indeterminant. SGTF and non-SGTF households had similar sex distribution (49% female and 52% female, respectively;P=0.54) and age (median 30 years, interquartile range (IQR 14-47) and 31 years (IQR 15-45), respectively). Hispanic people accounted for 24% and 32% of enrolled members of SGTF and non-SGTF households, respectively (p=0.04). At least one secondary case occurred in 61% of SGTF and 58% of non-SGTF households (P=0.66). SIR was 52% (95%[CI] 46%-59%) for SGTF and 45% (95% CI 37%-53%) for non-SGTF households (P=0.18). Conclusion. SIRs were high in both SGTF and non-SGTF households;our findings did not support an increase in SIR for SGTF relative to non-SGTF households in this setting. Sequence confirmed SARS-CoV-2 samples will provide further information on lineage specific SIRs.
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Background. Background. Understanding the viral load and potential infectivity of individuals in nursing homes (NH) with repeat positive SARS-CoV-2 tests ≥ 90 days after initial infection has important implications for safety related to transmission in this high-risk setting. Methods. Methods. We collected epidemiologic data by reviewing records of a convenience sample of NH residents and staff with respiratory specimens who had positive SARS-CoV-2 rRT-PCR test results from July 2020 through March 2021 and had a SARS-CoV-2 infection diagnosed ≥ 90 days prior. No fully vaccinated individuals were included. Each contributed one repeat positive specimen ≥ 90 days after initial, which was sent to CDC and retested using rRT-PCR. Specimens were assessed for replication-competent virus in cell culture if Cycle threshold (Ct) < 34 and sequenced if Ct < 30. Using Ct values as a proxy for viral RNA load, specimens were categorized as high (Ct < 30) or low (if Ct ≥ 30 or rRT-PCR negative at retesting). Continuous variables were compared using Wilcoxon signed-rank tests. Proportions were compared using Chi-squared or Fisher's exact tests. Results. Results. Of 64 unvaccinated individuals with specimens from 61 unique NHs, 14 (22%) were sent for culture and sequencing. Ten of 64 (16%) had a high viral RNA load, of which four (6%) were culture positive and none were known variants of interest or concern (Figure 1). Median days to repeat positive test result were 122 (Interquartile range (IQR): 103-229) and 201 (IQR: 139-254), respectively, for high versus low viral load specimens (p=0.13). More individuals with high viral loads (5/10, 50%) reported COVID-19 symptoms than with a low viral load (1/27, 4%, p=0.003). Most individuals (46/58, 79%) were tested following known or suspected exposures, with no significant differences between high and low viral load (p=0.18). Conclusion. In this study, nearly 1 in 6 NH residents and staff with repeat positive tests after 90 days demonstrated high viral RNA loads and viable virus, indicating possible infectivity. While individuals with high RNA viral load may be more likely to be symptomatic, distinguishing asymptomatic individuals who have high viral loads may be difficult with timing since initial infection, other test results, or exposure history alone.
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Background. Key pathologies in severe COVID-19 include immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Figure 1). Fostamatinib, an oral SYK inhibitor approved for chronic immune thrombocytopenia, has shown activity in vitro using plasma from patients with severe COVID-19, by abrogating the hyperimmune response triggered by anti-spike IgG;1 inhibiting hyperactivation in platelets;2 and blocking NETosis in neutrophils.3 R406, active metabolite of fostamatinib, protected against LPS-induced acute lung injury and thrombosis in mice.4,5 In clinical studies, fostamatinib reduced IL-6 in patients with rheumatoid arthritis.6 Therefore, a phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo plus standard of care (SOC) in 59 hospitalized COVID-19 patients (manuscript pending). We initiated a phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19. Methods. A double-blind, randomized, placebo-controlled, adaptive design, multi-center, Phase 3 study (NCT04629703) is underway to evaluate the safety and efficacy of fostamatinib in 308 adult patients with COVID-19 (Figure 2). Hospitalized patients without respiratory failure (with or without supplemental oxygen) were included. Patients with ARDS or using extracorporeal membrane oxygenation (ECMO) were excluded. Patients will receive fostamatinib 150 mg BID or placebo for 14 days;both arms receive SOC. The primary outcome will be progression to severe/critical disease (worsening in clinical status score on the 8-point ordinal scale) within 29 days of the first dose of study drug. Fostamatinib is investigational for COVID-19. Results. Blinded update of trial in progress as of 28 April 2021. 12 patients have been randomized in North and South America. The clinical status score at Baseline was 5 (Hospitalized, requiring supplemental oxygen) in all 12 patients. Five patients had 8 adverse events (AE) (Fig 3). One AE (PE) was serious and is resolving. No deaths have been reported. At least two patients have been discharged (Day 5, Day 13) with continued dosing at home. Conclusion. Fostamatinib has the potential to provide a treatment option for the hyperimmune complications of COVID-19.
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The outbreak of novel coronavirus pneumonia was the most serious global issue in 2020, that caused enormous impacts on various aspects of human society from public health to economic well-being. Our ecological environment also experienced transformation due to restricted human activities during the epidemic. The implementation of ‘Lockdowns’ and ‘Stay-at-Home’ policies reduced the pollution emissions from transport and commercial activities altering the urban environment. In this study, the spatial and temporal distribution and changes of the air quality and thermal environment in Wuhan City and New York City in 2020 were conducted and analyzed. Spatial data from these two cities were acquired, processed, interpolated and analyzed to identify hot spots and cold spots which were reasoned. The dynamics of air pollution and Urban Heat Island (UHI) effect was the prime object of investigation. The study discovered interesting patterns of changes in those two cities which we the early epicenters of the pandemic. © 2022, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
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Background: Warm antibody autoimmune hemolytic anemia (wAIHA) currently has no approved treatment options and is a rare, potentially serious disorder. The disease is characterized by red blood cell (RBC) phagocytosis in macrophages via a spleen tyrosine kinase (SYK) dependent signaling pathway. Fostamatinib, a potent oral SYK inhibitor, prevents SYK-dependent platelet phagocytosis in immune thrombocytopenia (ITP) and is an approved treatment for ITP. Fostamatinib may also prevent SYK dependent RBC phagocytosis in wAIHA. Aims: We conducted subgroup analyses of the phase 2, open-label study (NCT02612558) to better understand factors related to response to fostamatinib in patients with wAIHA. We also provide an update on the phase 3, randomized, double-blind, placebo-controlled, global study (NCT03764618) of fostamatinib for wAIHA including a Data Monitoring Committee (DMC) review of blinded data. Methods: Both studies enrolled (or are enrolling) adult patients with a diagnosis of primary/secondary wAIHA (documented by a positive direct antiglobulin test);baseline hemoglobin level ≤10 g/dL. Exclusion Criteria include (but are not limited to): presence of other forms of AIHA;uncontrolled hypertension. Hemoglobin (Hgb) response was defined as Hgb ≥10 g/dL with a ≥2 g/dL increase from baseline without rescue therapy. The Phase 2 study treated patients for up to 24 weeks at 150 mg BID. The phase 3 study is currently enrolling patients. During the 24-week study, eligible patients are randomized 1:1 to received fostamatinib or placebo. Randomization is stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of 100 mg BID is increased to 150 mg BID after 4 weeks if drug is tolerated. Two concurrent wAIHA therapies are permitted during the study. A steroid taper protocol is implemented in patients with a Hgb response, and rescue therapy is allowed as needed. Patients can rollover to an open-label extension study upon completion of the randomized phase. Results: In the phase 2 studies, 44% (11/25) of patients had a Hgb Response by Week 24. In total, 48% responded as there was one late responder at Week 30 (12/25). Common adverse events (AEs) were diarrhea and hypertension. In a subgroup analysis, patients with secondary wAIHA (4/5 [80%]) appeared to respond better than patients with primary wAIHA (7/19 [37%]). Patients who received fostamatinib as second-line therapy (one prior wAIHA treatment) (6/9 [67%]) appeared to respond better than those who received fostamatinib as third-or-laterline therapy (>1 prior treatment) (5/15 [33%]). Female patients (8/14 [57%]) appeared to respond better than male patients (3/10 [30%]). Small sample sizes make it difficult to draw conclusions. Patient enrollment in the phase 3 study began last year. The study will enroll approximately 90 patients at 103 sites in 22 countries. As of January 11, 2021, 62 of 99 sites are open to screening (subject to local COVID-19 regulations), and 64 of 90 patients (71%) have been randomized. The DMC Review of data in 43 patients is shown in the table below. Summary/Conclusion: Fostamatinib markedly improved Hgb levels in 48% of 25 evaluable patients with wAIHA in phase 2 studies. The AEs observed in the phase 2 study are consistent with the fostamatinib safety database of >3500 patients across different diseases. The subgroup analyses in the phase 2 study were consistent with response rates in the larger ITP studies with regard to improved response rates with earlier line fostamatinib use. The results of the larger phase 3 study may help identify factors associated with better outcomes.
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Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: • Age ≥18;• Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);• failure of ≥1 prior treatment for wAIHA;• Haptoglobin <LLN (lower limit of normal) or total bilirubin >ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;• Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to <10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: • Presence of other forms of AIHA;• Uncontrolled or insufficiently controlled hypertension;• Neutrophil count <1,000/µL, • Platelet count <30,000/μL (unless patient has Evans syndrome);• Transaminase levels >1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy;duration of hemoglobin response;and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patien s have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. [Formula presented] Disclosures: Cooper: Amgen: Honoraria, Speakers Bureau;Novartis: Honoraria, Speakers Bureau. Numerof: Rigel: Current Employment, Current equity holder in publicly-traded company. Tong: Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter: Incyte: Consultancy, Honoraria;Genzyme: Consultancy, Honoraria;Immunovant: Consultancy, Honoraria;Momenta: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Dova: Consultancy, Honoraria;Merck Sharp Dohme: Consultancy, Honoraria;UCB: Consultancy, Honoraria;Up-To-Date: Consultancy, Honoraria, Patents & Royalties;Zafgen: Consultancy, Honoraria;Sanofi (Genzyme): Consultancy, Honoraria;Shionogi: Consultancy, Honoraria;Shire: Consultancy, Honoraria;Principia: Consultancy, Research Funding;Protalix Biotherapeutics: Consultancy;Shionogi: Consultancy;Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Daiichi Sankyo: Consultancy, Honoraria;Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Immunovant: Other: Travel Expenses, Research Funding;Caremark: Consultancy, Honoraria;CRICO: Consultancy, Honoraria;Kezar Life Sciences, Inc: Other, Research Funding;Principia Biopharma: Consultancy, Honoraria, Other, Research Funding;Protalex: Consultancy, Honoraria, Other, Research Funding;Rigel: Consultancy, Honoraria, Other, Research Funding;Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding;Protalex: Consultancy, Honoraria, Research Funding;Kyowa-Kirin: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Platelet Disorder Support Association: Consultancy, Honoraria.
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NATCHA Abstract: Bats are often consumed by some ethnic groups in Nigeria despite association of bats with many important emerging viruses. More than 300 bats representing eight species were captured during 2010–2011 in eight locations of northern Nigeria. Available fecal swabs (n = 95) were screened for the presence of arenaviruses, CoVs, paramyxoviruses (PMVs), reoviruses, rhabdoviruses, and influenza viruses using generic reverse transcription–polymerase chain reaction assays. Here, we document the detection of CoVs, PMVs, reoviruses, and rotaviruses (RVs) in Nigerian bats. The Nigerian bat CoVs are grouped within other bat SARS-CoV–like viruses identified from Ghana in a sister clade next to the human SARS-CoV clade. The phylogenetic analysis indicated a broad range of RVs present in Nigerian bats, some cluster with human RVs and some represent novel species. Our study adds that continuing global surveillance for viruses in bats to understand their origin, adaptation, and evolution is important to prevent and control future zoonotic disease outbreaks
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Content: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can have serious complications. In this disorder, autoantibodies bind to antigens on red blood cells leading to phagocytosis and destruction of the cells. This is mediated by Fcg receptors on macrophages through a spleen tyrosine kinase (SYK)-dependent pathway. Fostamatinib is a potent, oral SYK inhibitor approved for the treatment of chronic immune thrombocytopenia. Fostamatinib prevents platelet destruction by inhibition of platelet phagocytosis mediated through Fcg receptor and SYK in macrophages. Fostamatinib was evaluated for wAIHA in an open-label, multicenter, phase 2 study (NCT02612558). This study demonstrated markedly improved hemoglobin levels in 11 of 25 patients (44%) after fostamatinib treatment. Adverse events (AEs) were consistent with the safety database (>4000 patients across multiple diseases). Based on this phase 2 study, a randomized, double-blind, placebo-controlled, global phase 3 study (NCT03764618) was initiated in wAIHA patients to investigate the safety and efficacy of fostamatinib. The phase 3 study began enrolling patients at 103 sites in 22 countries (North America, Europe and Australia) in 2020 with a goal of enrolling approximately 90 patients. This is the first phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA. Inclusion criteria include: age ?18;documented diagnosis of primary or secondary wAIHA;failure of ?1 prior wAIHA treatment;haptoglobin below normal or total bilirubin above normal or lactate dehydrogenase above normal;and baseline hemoglobin ?9 g/dl or, if hemoglobin >9 g/dl and <10 g/dl, subject must be on permitted wAIHA treatment AND have anemia symptoms. Exclusion criteria include: other forms of AIHA;uncontrolled or poorly controlled hypertension;neutrophil count <1,000/ l;platelet count <30,000/?l (unless patient has Evans syndrome);and transaminase levels >1.5 x normal. Randomization of eligible patients will be 1:1 to fostamatinib or placebo for 24 weeks. Randomized patients will be stratified by concomitant steroid use and baseline anemia severity. Fostamatinib is started at 100 mg BID and increased to 150 mg BID at Week 4, if tolerated. The dose may be reduced for AEs. Patients may continue selected concurrent wAIHA therapies (maximum of 2) throughout the study. A steroid taper will be allowed in patients with a hemoglobin response. Rescue therapy will also be allowed. Patients who complete the study can rollover to an open-label extension. Efficacy endpoints will include hemoglobin response, ( ?10 g/dl with a ?2 g/dl increase from baseline without rescue therapy);duration of hemoglobin response;and the need for rescue therapy. Safety endpoints will be the recording of AEs. Patients will be evaluated in the clinic at two-week intervals. Using the Cochran Mantel Haenszel test at a two-sided significance level of 0.05, to detect a difference in response between the active and placebo groups with 80% power would require 90 subjects randomized 1:1. The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. As of 11 January 2021, 62 sites are open to screening (subject to local COVID-19 regulations), and 64 patients have been randomized.
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Objective To understand the sleep quality and psychological status of officers and soldiers in naval force stationed in Hubei, China during the coronavirus disease 2019 (COVID-19) epidemic, and to explore the influencing factors, so as to maintain the physical and mental health of officers and soldiers during the epidemic. Methods Pittsburgh sleep quality index (PSQI) scale, patient health questionnaire-9 (PHQ-9), generalized anxiety disorder-7 (GAD-7) and impact of event scale-revised (IES-R) were used to evaluate the sleep and psychological status of officers and soldiers in a naval force stationed in Hubei province. Results A total of 238 questionnaires were sent out, and 232 valid questionnaires were collected, with an effective rate of 97.5%. The median score of PSQI scale was 2.00 (1.00, 5.00), and poor and very poor sleep qualities accounted for 5.6% (13/232) and 0.9% (2/232), respectively. The median score of PHQ-9 was 0.00 (0.00, 2.00), and mild, moderate and severe depression accounted for 12.1% (28/232), 0.9% (2/232) and 0.4% (1/232), respectively. The median score of GAD-7 was 0.00 (0.00, 0.00), and mild anxiety was found in 7.8% (18/232) participants. The median score of IES-R was 1.00 (0.00, 5.00), and mild and moderate psychological stress accounted for 12.5% (29/232) and 1.3% (3/232), respectively. Conclusion The sleep quality and psychological status of the officers and soldiers from the naval force stationed in Hubei are generally good during the COVID-19 epidemic. A small proportion of them have mild psychosomatic disorders, such as poor sleep quality, depression, anxiety and psychological stress reaction. Psychological counseling and humanistic care should be given to better maintain the physical and mental health of naval forces and ensure their combat capability.