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1.
PLOS Glob Public Health ; 4(5): e0003270, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38781200

RESUMO

Chronic diseases such as HIV, hypertension, and diabetes increase the risk of severe coronavirus disease 2019 (COVID-19) and death. Thus, COVID-19 vaccine uptake data among these priority populations are needed to inform immunization programs. We assessed COVID-19 vaccine uptake among people living with HIV (PLWH) and those with hypertension/diabetes without HIV (PWoH) in Southwestern and Southcentral Uganda and determined factors influencing vaccination. We conducted a cross-sectional study from January to April 2023. We enrolled a random sample of participants aged 18 years and older seeking HIV, hypertension, or diabetes care at two regional referral hospitals (RRHs) in Mbarara and Masaka in Uganda. Using vaccination records abstraction and interviewer-administered questionnaires, we collected data on COVID-19 vaccine uptake, sociodemographic data, and reasons for non-uptake in unvaccinated persons. We compared COVID-19 vaccination uptake between PLWH and PWoH and applied modified Poisson regression to determine sociodemographic factors associated with vaccine uptake. The reasons for non-vaccine uptake were presented as percentages. Of the 1,376 enrolled participants, 65.6% were fully vaccinated against COVID-19. Vaccination coverage was 65% among PWLH versus 67% among PWoH. Higher education attainment and older age were associated with COVID vaccination. Participants with secondary education and those aged ≥50 years achieved >70% coverage. Fear of side effects was the most cited reason (67%) for non-vaccination among 330 unvaccinated participants, followed by vaccine mistrust (24.5%). People with chronic diseases in Southwestern Uganda had slightly lower than 70% COVID-19 vaccine coverage as recommended by WHO. Higher educational attainment and older age were linked to increased vaccine uptake. However, mistrust and fear of vaccine side effects were the main reasons for non-vaccination. To increase COVID-19 vaccine uptake, programs must reach those with lower educational attainment and younger age groups, and address the fear of vaccine side effects and mistrust among persons with underlying diseases in Uganda.

2.
Open Forum Infect Dis ; 11(4): ofae143, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38585183

RESUMO

Background: Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious antimalarial than sulfadoxine-pyrimethamine (SP); however, SP is associated with higher birthweight, suggesting that SP demonstrates "nonmalarial" effects. Chemoprevention of nonmalarial febrile illnesses (NMFIs) was explored as a possible mechanism. Methods: In this secondary analysis, we leveraged data from 654 pregnant Ugandan women without HIV infection who participated in a randomized controlled trial comparing monthly IPTp-SP with IPTp-DP. Women were enrolled between 12 and 20 gestational weeks and followed through delivery. NMFIs were measured by active and passive surveillance and defined by the absence of malaria parasitemia. We quantified associations among IPTp regimens, incident NMFIs, antibiotic prescriptions, and birthweight. Results: Mean "birthweight for gestational age" Z scores were 0.189 points (95% CI, .045-.333) higher in women randomized to IPTp-SP vs IPTp-DP. Women randomized to IPTp-SP had fewer incident NMFIs (incidence rate ratio, 0.74; 95% CI, .58-.95), mainly respiratory NMFIs (incidence rate ratio, 0.69; 95% CI, .48-1.00), vs IPTp-DP. Counterintuitively, respiratory NMFI incidence was positively correlated with birthweight in multigravidae. In total 75% of respiratory NMFIs were treated with antibiotics. Although overall antibiotic prescriptions were similar between arms, for each antibiotic prescribed, "birthweight for gestational age" Z scores increased by 0.038 points (95% CI, .001-.074). Conclusions: Monthly IPTp-SP was associated with reduced respiratory NMFI incidence, revealing a potential nonmalarial mechanism of SP and supporting current World Health Organization recommendations for IPTp-SP, even in areas with high-grade SP resistance. While maternal respiratory NMFIs are known risk factors of lower birthweight, most women in our study were presumptively treated with antibiotics, masking the potential benefit of SP on birthweight mediated through preventing respiratory NMFIs.

3.
Radiology ; 310(2): e223097, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38376404

RESUMO

Social determinants of health (SDOH) are conditions influencing individuals' health based on their environment of birth, living, working, and aging. Addressing SDOH is crucial for promoting health equity and reducing health outcome disparities. For conditions such as stroke and cancer screening where imaging is central to diagnosis and management, access to high-quality medical imaging is necessary. This article applies a previously described structural framework characterizing the impact of SDOH on patients who require imaging for their clinical indications. SDOH factors can be broadly categorized into five sectors: economic stability, education access and quality, neighborhood and built environment, social and community context, and health care access and quality. As patients navigate the health care system, they experience barriers at each step, which are significantly influenced by SDOH factors. Marginalized communities are prone to disparities due to the inability to complete the required diagnostic or screening imaging work-up. This article highlights SDOH that disproportionately affect marginalized communities, using stroke and cancer as examples of disease processes where imaging is needed for care. Potential strategies to mitigate these disparities include dedicating resources for clinical care coordinators, transportation, language assistance, and financial hardship subsidies. Last, various national and international health initiatives are tackling SDOH and fostering health equity.


Assuntos
Determinantes Sociais da Saúde , Acidente Vascular Cerebral , Humanos , Diagnóstico por Imagem , Envelhecimento , Acessibilidade aos Serviços de Saúde
4.
AJNR Am J Neuroradiol ; 45(4): 371-373, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38123951

RESUMO

In the fall of 2021, several experts in this space delivered a Webinar hosted by the American Society of Neuroradiology (ASNR) Diversity and Inclusion Committee, focused on expanding the understanding of bias in artificial intelligence, with a health equity lens, and provided key concepts for neuroradiologists to approach the evaluation of these tools. In this perspective, we distill key parts of this discussion, including understanding why this topic is important to neuroradiologists and lending insight on how neuroradiologists can develop a framework to assess health equity-related bias in artificial intelligence tools. In addition, we provide examples of clinical workflow implementation of these tools so that we can begin to see how artificial intelligence tools will impact discourse on equitable radiologic care. As continuous learners, we must be engaged in new and rapidly evolving technologies that emerge in our field. The Diversity and Inclusion Committee of the ASNR has addressed this subject matter through its programming content revolving around health equity in neuroradiologic advances.


Assuntos
Inteligência Artificial , Radiologia , Humanos , Radiologistas , Fluxo de Trabalho
5.
Can Fam Physician ; 69(5): 341-351, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37172994

RESUMO

OBJECTIVE: To examine the frequency, natural history, and outcomes of 3 subtypes of abdominal pain (general abdominal pain, epigastric pain, localized abdominal pain) among patients visiting Canadian family practices. DESIGN: Retrospective cohort study with a 4-year longitudinal analysis. SETTING: Southwestern Ontario. PARTICIPANTS: A total of 1790 eligible patients with International Classification of Primary Care codes for abdominal pain from 18 family physicians in 8 group practices. MAIN OUTCOME MEASURES: The symptom pathways, the length of an episode, and the number of visits. RESULTS: Abdominal pain accounted for 2.4% of the 15,149 patient visits and involved 14.0% of the 1790 eligible patients. The frequencies of each of the 3 subtypes were as follows: localized abdominal pain, 89 patients, 1.0% of visits, and 5.0% of patients; general abdominal pain, 79 patients, 0.8% of visits, and 4.4% of patients; and epigastric pain, 65 patients, 0.7% of visits, and 3.6% of patients. Those with epigastric pain received more medications, and patients with localized abdominal pain underwent more investigations. Three longitudinal outcome pathways were identified. Pathway 1, in which the symptom remains at the end of the visit with no diagnosis, was the most common among patients with all subtypes of abdominal symptoms at 52.8%, 54.4%, and 50.8% for localized, general, and epigastric pain, respectively, and the symptom episodes were relatively short. Less than 15% of patients followed pathway 2, in which a diagnosis is made and the symptom persists, and yet the episodes were long with 8.75 to 16.80 months' mean duration and 2.70 to 4.00 mean number of visits. Pathway 3, in which a diagnosis is made and there are no further visits for that symptom, occurred approximately one-third of the time, with about 1 visit over about 2 months. Prior chronic conditions were common across all 3 subtypes of abdominal pain ranging from 72.2% to 80.0%. Psychological symptoms consistently occurred at a rate of approximately one-third. CONCLUSION: The 3 subtypes of abdominal pain differed in clinically important ways. The most frequent pathway was that the symptom remained with no diagnosis, suggesting a need for clinical approaches and education programs for care of symptoms themselves, not merely in the service of coming to a diagnosis. The importance of prior chronic conditions and psychological conditions was highlighted by the results.


Assuntos
Registros Eletrônicos de Saúde , Medicina de Família e Comunidade , Humanos , Ontário/epidemiologia , Estudos Longitudinais , Estudos Retrospectivos , Dor Abdominal/epidemiologia , Dor Abdominal/etiologia , Dor Abdominal/diagnóstico , Doença Crônica
6.
AJR Am J Roentgenol ; 221(3): 302-308, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37095660

RESUMO

Artificial intelligence (AI) holds promise for helping patients access new and individualized health care pathways while increasing efficiencies for health care practitioners. Radiology has been at the forefront of this technology in medicine; many radiology practices are implementing and trialing AI-focused products. AI also holds great promise for reducing health disparities and promoting health equity. Radiology is ideally positioned to help reduce disparities given its central and critical role in patient care. The purposes of this article are to discuss the potential benefits and pitfalls of deploying AI algorithms in radiology, specifically highlighting the impact of AI on health equity; to explore ways to mitigate drivers of inequity; and to enhance pathways for creating better health care for all individuals, centering on a practical framework that helps radiologists address health equity during deployment of new tools.


Assuntos
Equidade em Saúde , Radiologia , Humanos , Inteligência Artificial , Radiologistas , Radiologia/métodos , Algoritmos
7.
Curr Probl Cardiol ; 48(8): 101190, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35346726

RESUMO

Homelessness is a major social determinant of health. We studied the clinical and economic profile of homeless young adults hospitalized with stroke. We studied the National Inpatient Sample database (2002-2017) to evaluate trends of stroke hospitalization, clinical outcomes, and health expenditure in homeless vs non-homeless young adults (<45 years). We identified 3134 homeless individuals out of 648,944 young adults. Homeless patients were more likely to be men, Black adults and had a higher prevalence of cardiometabolic risk factors and psychiatric disorders than non-homeless adults. Both homeless and non-homeless adults had a similar prevalence of ischemic and hemorrhagic stroke. Between 2002 and 2017, hospitalization rates per million increased for both non-homeless (295.8-416.8) and homeless adults (0.5-3.6) (P ≤ 0.01). Between 2003 and 2017, the decline in in-hospital mortality was limited to non-homeless adults (11%-9%), while it has increased in homeless adults (3%-11%) (P < 0.01). The prevalence of acute myocardial infarction (6.8% vs 3.3%, P < 0.01), and acute kidney injury (13.1% vs 9.4%, P < 0.01) was also higher in homeless vs. non-homeless adults. The length of stay and inflation-adjusted care cost were comparable between both study groups. Finally, a higher proportion of homeless patients left the hospital against medical advice than non-homeless adults. Homeless young stroke patients had significant comorbidities, increased hospitalization rates, and adverse clinical outcomes. Therefore, public health interventions should focus on multidisciplinary care to reduce health care disparities among young homeless adults.


Assuntos
Pessoas Mal Alojadas , Infarto do Miocárdio , Acidente Vascular Cerebral , Masculino , Humanos , Estados Unidos/epidemiologia , Adulto Jovem , Feminino , Hospitalização , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Infarto do Miocárdio/epidemiologia , Comorbidade
8.
J Natl Med Assoc ; 114(1): 69-77, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34986985

RESUMO

BACKGROUND: The exponential growth in CT utilization in emergency department (ED) until 2008 raised concerns regarding cost and radiation exposure. Head CT was one of the commonest studies. This led to mitigating efforts such as appropriate use guidelines, policy and payment reforms. The impact of these efforts is not fully understood. In addition, disparities in outcomes of acute conditions presenting to the ED is well known however recent trends in imaging utilization patterns and disparities are not well understood. In this study, we describe nationwide trends and disparities associated with head CT in ED settings between 2007 and 2014. METHODS: We analyzed 2007-2017 National Hospital Ambulatory Medical Care Survey (NHAMCS) with the primary goal to assess the rate and patterns of head CT imaging in ED. RESULTS: There were an estimated 117 million in 2007 and 139 million ED visits in 2017. There was a 4% increase in the any CT use in 2017 compared to 2007. No significant change in head CT utilization rate was seen. The 2007 head CT rate was 6.7% (95% CI: 6.1-7.3) compared to 7.7% (95% CI: 6.8-8.6) in 2017. Trauma, Headache and Dizziness are the top three indications for head CT use in the ED respectively. On adjusted analyses, significantly higher head CT utilization was seen in elderly, (age>65 yrs) and significantly lower utilization rate was seen in Non-Hispanic Black and Medicaid patients, and patients in rural locations. CONCLUSIONS: Previously reported exponential growth of CT use in ED is no longer seen. In particular, there was no significant change in ED head CT use between 2007 and 2017. Headache and Dizziness remain commonly used indications despite limited utility in most clinical scenarios, indicating continued need for appropriate use of imaging. There is significantly lower CT utilization in Non-Hispanic Black, Medicaid patients and those in rural locations, suggesting disparities in diagnostic work-up in marginalized and rural populations. This underscores the need for standardizing care regardless of race, insurance status and location.


Assuntos
Serviço Hospitalar de Emergência , Tomografia Computadorizada por Raios X , Idoso , Pesquisas sobre Atenção à Saúde , Hospitais , Humanos , Medicaid , Estados Unidos
9.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21265402

RESUMO

BackgroundRecent surges in coronavirus 2019 disease (COVID-19) is attributed to the emergence of more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs). However, the relative severity of SARS-CoV-2 VOCs in children is unknown. MethodsThis retrospective single-center cohort study was performed at the Ann & Robert H. Lurie Childrens Hospital of Chicago, academic free-standing childrens hospital. We included all children [≤] 18 years-old diagnosed with COVID-19 between October 15th, 2020 and August 31st, 2021 and whose SARS-CoV-2 isolate was sequenced using the Illumina platform. For each patient sample, we identified the SARS-CoV-2 lineage, which was assigned to one of the following groups: Non-VOC, alpha VOC, beta VOC, gamma VOC, or delta VOC. We measured frequency of 5 markers of COVID-19 severity: hospitalization; COVID-19 pharmacologic treatment; respiratory support; intensive care unit admission; and severe disease as classified by the COVID-19 World Health Organization (WHO) Clinical Progression Scale (severe disease; score [≥] 6). A series of logistic regression models were fitted to estimate odds of each severity marker with each VOC (in comparison to non-VOCs), adjusting for COVID-19 community incidence and demographic and clinical co-variates. ResultsDuring the study period, 2,025 patients tested positive for SARS-CoV-2; 1,422 (70.2%) had sufficient viral load to permit sequencing. Among the 499 (35.1%) patients whose isolate was sequenced, median (inter-quartile range) age was 7 (1,12) years; 256 (51.3%) isolates were a VOC: 96 (37.5%) alpha, 38 (14.8%) gamma, and 119 (46.5%) delta. After adjusting for age, Black race, Hispanic ethnicity, high-risk medical conditions, and COVID-19 community incidence, neither alpha nor delta was associated with severe COVID-19. Gamma was independently associated with hospitalization (OR 5.9, 95% CI 1.6-21.5, p=0.007), respiratory support (OR 8.3, 95% CI 1.5-56.3, p=0.02), and severe disease as classified by the WHO Clinical Progression Scale (OR 7.7, 95% CI 1.0-78.1, p=0.05). ConclusionsCompared to non-VOC COVID-19 infections, the gamma VOC, but not the alpha or delta VOCs, was associated with increased severity. These data suggest that recent increased in pediatric COVID-19 hospitalizations are related to increased delta COVID-19 incidence rather than increased delta virulence in children.

10.
BMJ Open ; 11(6): e048006, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155078

RESUMO

OBJECTIVE: To evaluate COVID-19 infection and mortality disparities in ethnic and racial subgroups in a state-wise manner across the USA. METHODS: Publicly available data from The COVID Tracking Project at The Atlantic were accessed between 9 September 2020 and 14 September 2020. For each state and the District of Columbia, % infection, % death, and % population proportion for subgroups of race (African American/black (AA/black), Asian, American Indian or Alaska Native (AI/AN), and white) and ethnicity (Hispanic/Latino, non-Hispanic) were recorded. Crude and normalised disparity estimates were generated for COVID-19 infection (CDI and NDI) and mortality (CDM and NDM), computed as absolute and relative difference between % infection or % mortality and % population proportion per state. Choropleth map display was created as thematic representation proportionate to CDI, NDI, CDM and NDM. RESULTS: The Hispanic population had a median of 158% higher COVID-19 infection relative to their % population proportion (median 158%, IQR 100%-200%). This was followed by AA, with 50% higher COVID-19 infection relative to their % population proportion (median 50%, IQR 25%-100%). The AA population had the most disproportionate mortality, with a median of 46% higher mortality than the % population proportion (median 46%, IQR 18%-66%). Disproportionate impact of COVID-19 was also seen in AI/AN and Asian populations, with 100% excess infections than the % population proportion seen in nine states for AI/AN and seven states for Asian populations. There was no disproportionate impact in the white population in any state. CONCLUSIONS: There are racial/ethnic disparities in COVID-19 infection/mortality, with distinct state-wise patterns across the USA based on racial/ethnic composition. There were missing and inconsistently reported racial/ethnic data in many states. This underscores the need for standardised reporting, attention to specific regional patterns, adequate resource allocation and addressing the underlying social determinants of health adversely affecting chronically marginalised groups.


Assuntos
COVID-19 , Etnicidade , Disparidades nos Níveis de Saúde , Hispânico ou Latino , Humanos , Grupos Raciais , SARS-CoV-2 , Estados Unidos/epidemiologia
11.
Sci Rep ; 11(1): 7612, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828176

RESUMO

Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addition, mRNA levels of CASP8 were higher in patients with recurrent prostate cancer when compared to patients with non-recurrent prostate cancer and high expression of CASP8 was associated with worse disease-free survival and overall survival in renal cancer. Together, our results suggest that CASP8 may potentially serve as a biomarker for high-risk prostate cancer and possibly renal cancer.


Assuntos
Caspase 8/genética , Neoplasias da Próstata/genética , Idoso , Biomarcadores Tumorais/sangue , Caspase 8/metabolismo , Intervalo Livre de Doença , Humanos , Imunoensaio/métodos , Imuno-Histoquímica/métodos , Testes Imunológicos/métodos , Masculino , Mesotelina , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Próstata/patologia , Antígeno Prostático Específico/sangue , Prostatectomia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Risco
12.
Front Psychol ; 11: 766, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411052

RESUMO

The author has been a grief therapist in private practice for almost 40 years. The largest percentage of his clients have been suicide loss survivors, and in this article, the author reflects on the "lessons learned" about how grief therapy with survivors is both the same as, and very different from, work with clients bereaved after other types of losses. After briefly reviewing some of the empirical literature about differences between suicide bereavement and grief after other modes of death, the author argues that perhaps the most distinguishing and difficult aspect of a suicide loss is the "perceived intentionality" of the death, and the related "perceived responsibility" for the death. The author goes on to identify a number of tasks of psychological reintegration after a suicide loss that can serve as a template for treatment goals for clinicians and clients alike. These include the cultivation of a very specific type of secure and nurturing therapeutic alliance; extensive psychoeducation about suicide, trauma, and grief; the need to help the client repair the psychological continuing bond with the deceased; and providing gentle support for the survivor in rebuilding an assumptive world that has been shattered by the suicide of a loved one. Finally, the article concludes with a discussion of the clinical implications of these differences for work with suicide loss survivors.

14.
Expert Opin Drug Saf ; 18(3): 231-240, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30714424

RESUMO

INTRODUCTION: Pharmacovigilance is essential to monitoring the safety profiles of authorized medicines. Compared with small-molecule drugs, biological drugs are more complex, more susceptible to structural variability due to manufacturing processes, and have the potential to induce immune-related reactions, underscoring the importance of safety monitoring for these products. Although highly similar to reference products, biosimilars are not expected to be structurally identical. For these reasons, proper reporting of potential adverse drug reactions (ADRs) using distinguishable names and batch numbers is essential for accurate tracing of all biological drugs. To address the need for robust pharmacovigilance, the European Parliament and Council of the European Union provided legislation regarding pharmacovigilance of biologics in 2010. AREAS COVERED: This narrative review examines the current state of pharmacovigilance for biologics in the European Union (EU) and discusses relevant information on pharmacovigilance of biosimilars, the current EU pharmacovigilance system, and areas that could be improved. EXPERT OPINION: Although steps have been taken to improve pharmacovigilance of biologics in the EU, several enhancements can still be made, including additional training for healthcare professionals on ADR reporting, the use of 2D barcodes that enhance traceability, and an open discussion of potentially missed opportunities in the pharmacovigilance of biosimilars.


Assuntos
Produtos Biológicos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Farmacovigilância , Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , União Europeia , Humanos
15.
MAbs ; 11(1): 94-105, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30570405

RESUMO

The increased interest in using monoclonal antibodies (mAbs) as a platform for biopharmaceuticals has led to the need for new analytical techniques that can precisely assess physicochemical properties of these large and very complex drugs for the purpose of correctly identifying quality attributes (QA). One QA, higher order structure (HOS), is unique to biopharmaceuticals and essential for establishing consistency in biopharmaceutical manufacturing, detecting process-related variations from manufacturing changes and establishing comparability between biologic products. To address this measurement challenge, two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) methods were introduced that allow for the precise atomic-level comparison of the HOS between two proteins, including mAbs. Here, an inter-laboratory comparison involving 26 industrial, government and academic laboratories worldwide was performed as a benchmark using the NISTmAb, from the National Institute of Standards and Technology (NIST), to facilitate the translation of the 2D-NMR method into routine use for biopharmaceutical product development. Two-dimensional 1H,15N and 1H,13C NMR spectra were acquired with harmonized experimental protocols on the unlabeled Fab domain and a uniformly enriched-15N, 20%-13C-enriched system suitability sample derived from the NISTmAb. Chemometric analyses from over 400 spectral maps acquired on 39 different NMR spectrometers ranging from 500 MHz to 900 MHz demonstrate spectral fingerprints that are fit-for-purpose for the assessment of HOS. The 2D-NMR method is shown to provide the measurement reliability needed to move the technique from an emerging technology to a harmonized, routine measurement that can be generally applied with great confidence to high precision assessments of the HOS of mAb-based biotherapeutics.


Assuntos
Anticorpos Monoclonais/química , Biofarmácia/normas , Laboratórios/normas , Espectroscopia de Ressonância Magnética/métodos , Humanos , Reprodutibilidade dos Testes
16.
PLoS One ; 13(5): e0196791, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29723257

RESUMO

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.


Assuntos
Analgésicos/isolamento & purificação , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Peptídeos/química , Bloqueadores dos Canais de Sódio/isolamento & purificação , Venenos de Aranha/química , Potenciais de Ação/efeitos dos fármacos , Substituição de Aminoácidos , Analgésicos/farmacologia , Animais , Capsaicina/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Gânglios Espinais/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Fibras Nervosas Amielínicas/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Técnicas de Patch-Clamp , Estimulação Física , Engenharia de Proteínas , Proteínas Recombinantes/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Tetrodotoxina/farmacologia
17.
Death Stud ; 42(3): 143-154, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29300139

RESUMO

The United States military began to experience a steady increase in suicide rates across all service branches at the inception of the wars in Afghanistan (2001) and Iraq (2003). As the number of suicide deaths increased, so did the number of affected survivors who seek postvention support. Unique issues that accompany suicide death may expose survivors to a more distressing and complicated grief process. Peer support has clinically been observed to be widely utilized by suicide loss survivors. This article explores unique issues accompanying military suicide loss, potential benefits of postvention peer-based support, clinical considerations, and future directions.


Assuntos
Luto , Família/psicologia , Militares/psicologia , Grupo Associado , Apoio Social , Suicídio/psicologia , Sobreviventes/psicologia , Adulto , Criança , Humanos , Estados Unidos
19.
Death Stud ; 41(10): 611-613, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28678684

RESUMO

This article provides an introduction to this special issue of Death Studies on suicide postvention. The articles in the issue are derived from a document released by the National Action Alliance for Suicide Prevention, titled Responding to Grief, Trauma, and Distress after Suicide: U.S. National Guidelines. The article provides data and a rationale for considering suicide as a serious public health issue in the USA and around the world, and the need for postvention after a suicide occurs. A brief description of each of the articles in the special issue then follows.


Assuntos
Saúde Pública , Suicídio/psicologia , Humanos
20.
Death Stud ; 41(10): 659-672, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28557576

RESUMO

The loss of a loved one to suicide can present difficult challenges for suicide loss survivors (people bereaved by suicide) as well as for clinicians who would seek to help them. Building on the recommendations in the new document Responding to Grief, Trauma, and Distress after a Suicide: U.S. National Guidelines, this article provides an overview of clinical work with suicide loss survivors. It includes discussions of the common themes of suicide bereavement, the psychological tasks for integration of a suicide loss, and the options for providing grief therapy after a suicide. The article will be of value to caregivers who work with suicide loss survivors in counseling or therapeutic context.


Assuntos
Luto , Aconselhamento/métodos , Psicoterapia/métodos , Suicídio/psicologia , Sobreviventes/psicologia , Humanos
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