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ABSTRACT: Social distancing protocols during the COVID-19 pandemic have resulted in a rapid expansion of telemedicine. It has allowed patients to save time and money on clinic visits, and physicians to communicate with patients who live remotely. Telemedicine has also been valuable in plastic surgery during initial consultations, transfers, and follow up visits. However, given the often-sensitive nature of plastic surgery, the professionalism and expectations of telemedicine have to be reviewed. A comprehensive literature search of the MEDLINE, PubMed, Google Scholar, EMBASE, and Cochrane Central Register of Controlled Trials was conducted for studies published through October 2020 with multiple search terms related to telemedicine and its use in plastic surgery. Data on the effectiveness, challenges, and professionalism of telemedicine were collected. Our review suggests that telemedicine can be an effective mode of communication in many realms of plastic surgery, including cleft care and craniofacial deformities. However, many plastic surgeons are unfamiliar with the existing platforms, and there are no clear guidelines on the most optimal platforms. Physicians have to recognize that patients might have low digital health literacy or may not even possess digital device for telemedicine. There also needs to be an overall improvement in patient education. Given that telemedicine use will continue to increase after the COVID-19 pandemic, regulations on Health Insurance Portability and Accountability Act-compliant platforms and specific guidelines on telemedicine visits, such as undressing, chaperones, privacy matters, need to be established while maintaining a professional relationship between the patient and the physician.
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COVID-19 , Cirurgiões , Cirurgia Plástica , Telemedicina , Humanos , Motivação , Pandemias , SARS-CoV-2RESUMO
Ankle arthrodesis (AA) provides reliable pain relief, good patient satisfaction scores, and improved overall function. However, this procedure has been associated with numerous complications and sequelae, such as pseudoarthrosis, malunion, gait abnormalities, increased demand on surrounding joints, and a long period of convalescence. Conversion to total ankle arthroplasty (TAA) is a potential option in the management of these complex and challenging situations. The purpose of this study is to investigate the outcomes of AA conversion to TAA. A systematic review of electronic databases was performed. Six studies involving 172 ankles met inclusion criteria. The weighted mean preoperative Visual Analogue Scale (VAS) score at the time of TAA conversion was 7.8 and the weighted mean postoperative VAS score at the time of final follow-up was 2.5. The weighted mean preoperative AOFAS score at the time of TAA conversion was 32 and the weighted mean postoperative AOFAS score at the time of final follow-up was 72.4. The rate of salvage tibiotalocalcaneal arthrodesis was 2.3% and rate of transtibial amputation was also 2.3% after attempted conversion from initial AA to TAA. Conversion of AA to TAA appears to be a viable option to improve patient outcomes and prevent extensive hindfoot arthrodesis and transtibial amputation. More prospective studies with consistent reporting of outcomes, complications, and revision rates with long-term follow-up are needed.
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Tornozelo , Artroplastia de Substituição do Tornozelo , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/cirurgia , Artrodese , Artroplastia de Substituição do Tornozelo/efeitos adversos , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Since the inception of the first surgical training system by Sir William Stewart Halsted, resident surgical skill development has been promulgated in teaching hospitals. Currently, the Council on Podiatric Medical Education does not mandate the availability of a cadaver lab as a residency curriculum requirement. The purpose of the present study is to assess the structure of the cadaver lab and availability in the current podiatric surgical training programs. A survey was sent electronically to 229 American Association of Colleges of Podiatric Medicine-approved residency programs, excluding OhioHealth, across all residency programs. A total of 173 (6.9%) residents from 74 (32.3%) residency programs completed the survey. This survey analyzed the characteristics and perception of the current state of cadaver lab in podiatric residency. The most reported type of cadaver labs available were medical company sponsored and hospital sponsored. Other hands-on training, including inanimate simulators (nâ¯=â¯24) and animal models (nâ¯=â¯5), was also reported. Overall, 87.9% of the surveyed residents found that cadaver lab is either extremely beneficial (57.8%) or somewhat beneficial (30.1%). The most important factors perceived in a successful cadaver lab were faculty instruction (nâ¯=â¯78), accessibility of lab (nâ¯=â¯46), and availability of instrumentation/hardware (nâ¯=â¯26). This qualitative survey is the first study to address the uniformity, perception, and potential value of the cadaver lab in a podiatric surgical residency.
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Educação de Pós-Graduação em Medicina/métodos , Internato e Residência/métodos , Procedimentos Ortopédicos/educação , Podiatria/educação , Cadáver , Currículo , Humanos , Estados UnidosRESUMO
BACKGROUND: Given findings that generally support the benefits of information and communication technology (ICT) for older adults' psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults. OBJECTIVE: To examine whether the association between ICT use and psychological adjustment (i.e., psychological distress and sense of community [SOC]) among older adults depends on their loneliness levels. METHODS: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older (56% female) was interviewed in 2017 on loneliness, frequency of ICT use (i.e., Internet and smart devices), psychological distress (6-item Kessler scale; K6), and SOC. RESULTS: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment (psychological distress and SOC); more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness. CONCLUSION: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account.
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Atitude Frente aos Computadores , Ajustamento Emocional , Tecnologia da Informação , Solidão/psicologia , Isolamento Social/psicologia , Estresse Psicológico , Idoso , Feminino , Hong Kong , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Smartphone , Estresse Psicológico/etiologia , Estresse Psicológico/psicologiaRESUMO
There is an increase in interest in the relationships between loneliness and psychosis. The notion of psychosis continuum implies that psychotic experiences extend from clinical populations with psychotic disorders to non-clinical populations. This meta-analytic review aimed to examine the respective associations of loneliness with positive and negative psychotic experiences along the psychosis continuum. A systematic database search was conducted and a total of 30 studies were included in the first meta-analysis and 15 studies were included in the second meta-analysis. There was a medium association between loneliness and positive psychotic experiences (r = 0.302, p < 0.001). In particular, the association between loneliness and paranoia was robust (r = 0.448, p < 0.001). The second meta-analysis revealed a medium association between loneliness and negative psychotic experiences (r = 0.347, p < 0.001). The associations between loneliness and both positive and negative psychotic experiences were found to be smaller among clinical than non-clinical samples. The above findings provided evidence for the associations between loneliness and the two core dimensions of psychotic experiences along the phenomenological continuum. Future research should examine the dynamics of these relationships in both clinical and non-clinical samples, preferably using a single-symptom approach.
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Solidão/psicologia , Transtornos Psicóticos/diagnóstico , Isolamento Social , HumanosRESUMO
Naviculocuneiform (NC) joint arthrodesis is an effective procedure to treat pain and provide stability to the medial column. Various forms of fixation have been described for NC arthrodesis. Despite this, the available literature is scant and questions remain regarding nonunion rate and contributory factors. A systematic review of the literature was undertaken to determine the rate of nonunion for NC joint arthrodesis. Seven studies involving 139 NC joint arthrodeses met inclusion criteria. The nonunion rate was 6.5% at a weighted mean follow-up of 73.2 months. There is insufficient evidence to provide a practice guideline based on the current literature. Adequately powered prospective clinical trials comparing well-matched patient groups with long-term follow-up are required to limit systematic error and enhance external validity. Specific outcomes measures should include union, functional assessment, complications, and cost-benefit analysis.
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Artrodese/efeitos adversos , Articulações Tarsianas/cirurgia , Humanos , Incidência , Ossos do Tarso/cirurgiaRESUMO
INTRODUCTION: There is an ongoing debate about whether negative affect are consequences or triggers of paranoid thinking. It has also been suggested that aberrant salience is central to the development of delusions. This study modelled the moment-to-moment relationships between negative affect, aberrant salience, and paranoia in acute inpatients with psychosis. METHODS: Participants with active paranoid delusions were assessed using clinical rating scales and experience sampling method (ESM) over 14 days. ESM data were analysed using time-lagged multilevel regression modelling. RESULTS: Both negative affect and aberrant salience predicted an increase in paranoia at the next time point. Conversely, the level of paranoia did not predict subsequent changes in negative affect or aberrant salience. Negative affect predicted an increase in aberrant salience at the next time point, and vice versa. CONCLUSIONS: Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom. Our results suggest both direct and indirect (via aberrant salience) pathways from negative affect to paranoia.
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Afeto , Delusões/psicologia , Transtornos Paranoides/psicologia , Transtornos Psicóticos/psicologia , Adulto , Ansiedade/diagnóstico , Ansiedade/psicologia , Delusões/diagnóstico , Depressão/diagnóstico , Depressão/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Transtornos Paranoides/diagnóstico , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnósticoRESUMO
OBJECTIVES: Information and communicative technology (ICT) use is a potential vehicle for improving the psychological well-being (PWB) of older people. We examined the roles of age, frailty, and social connectedness in the relationship between ICT use and PWB. METHOD: Telephone interviews were conducted in mid-2016 with 1201 participants aged 50 and above (55.7% female) residing in Hong Kong, China. The participants reported PWB, ICT use (frequency of using the Internet and smart devices), frailty status, contact with family, friends, and neighbors, self-rated health, subjective financial sufficiency, education level, and employment status. RESULTS: We found that the association between ICT and PWB was moderated by age: ICT was associated with PWB only among old-olds (75+), but not in other age groups. This moderation was mediated by contact with family, but not with friends or neighbors. The moderation was further qualified by frailty status: the ICT-by-age moderation was found only among frail, but not pre-frail or robust older adults. CONCLUSION: The findings suggest that ICT use can potentially enhance the PWB of older adults aged 75+ through facilitating their contact with family members. These benefits might be particularly salient for those who were frail. Improving ICT access and literacy among older adults may be promising.
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Envelhecimento/psicologia , Computadores de Mão/estatística & dados numéricos , Família/psicologia , Fragilidade/epidemiologia , Nível de Saúde , Internet/estatística & dados numéricos , Satisfação Pessoal , Rede Social , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Idoso Fragilizado , Amigos , Hong Kong , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hallux interphalangeal joint arthrodesis is an effective procedure to treat pain and provide stability and is often performed for intrinsic pain to the hallux interphalangeal joint. Additionally, this procedure is typically used in concert with the Jones tenosuspension. Although this as an accepted technique, the available data are scant, and questions remain regarding nonunion rates and contributory factors to poor healing. A systematic review of the reported data were undertaken to determine the rate of nonunion for hallux interphalangeal joint arthrodesis. Seven studies involving 313 hallux interphalangeal joint arthrodeses met the inclusion criteria. The nonunion rate was 28.3% at a weighted mean follow-up period of 8.4 months. The overall complication rate was 33.0%. Considering the increased rate of complications and nonunion rate for this commonly used procedure, additional prospective comparative analyses are needed regarding this topic to identify important patient demographic data and determine superior fixation constructs.
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Artrodese/efeitos adversos , Hallux , Articulação Metatarsofalângica/cirurgia , Complicações Pós-Operatórias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Adulto JovemRESUMO
Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment for ulcerative colitis and asthma. Model simulations revealed important differences between plasma and tissues, when evaluated for drug disposition and target suppression. Target concentrations at tissue sites and type (soluble vs membrane-bound), tissue-site binding, and binding affinity are all major determinants of BAb disposition and subsequently target suppression. For the presented case studies, higher doses and/or frequent dosing regimens are required to achieve 80 % target suppression in site specific tissue (the more relevant matrix) as compared to plasma. Site-specific target-mediated models may serve to guide the selection of first-in-human doses for new BAbs.
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Anticorpos Biespecíficos/farmacocinética , Simulação por Computador , Desenho de Fármacos , Modelos Biológicos , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/sangue , Anticorpos Biespecíficos/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Sítios de Ligação , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Especificidade de Órgãos , Valor Preditivo dos Testes , Ligação Proteica , Distribuição TecidualRESUMO
Practitioners of pharmacokinetic/pharmacodynamic modeling routinely employ various software packages that enable them to fit differential equation based mechanistic or empirical models to biological/pharmacological data. The availability and choice of different analytical tools, while enabling, can also pose a significant challenge in terms of both, implementation and transferability. A package has been developed that addresses these issues by creating a simple text-based format, which provides methods to reduce coding complexity and enables the modeler to describe the components of the model based on the underlying physiochemical processes. A Perl script builds the system for multiple formats (ADAPT, MATLAB, Berkeley Madonna, etc.), enabling analysis across several software packages and reducing the chance for transcription error. Workflows can then be built around this package, which can increase efficiency and model availability. As a proof of concept, tools are included that allow models constructed in this format to be run with MATLAB both at the scripting level and through a generic graphical application that can be compiled and run as a stand-alone application.
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Modelos Biológicos , Farmacocinética , Software , Interface Usuário-ComputadorRESUMO
Joint arthroplasty of the first metatarsophalangeal (MTP) joint is an accepted surgical option for patients with hallux rigidus. However, this procedure has been reported to have a high complication rate and unpredictable survivorship. Implant arthroplasty failure is a devastating complication that results in significant osseous defect with altered biomechanics of the foot. Commonly, salvage options are limited to arthrodesis with bone grafting. However, outcomes are rarely reported. The purpose of this study is to investigate the fusion rates of first metatarsophalangeal joint arthrodesis after conversion from failed implant arthroplasty. A systematic review of electronic databases to find reports of conversion arthrodesis after failed implant arthroplasty was performed. Six studies involving a total of 76 patients with a weighted mean age of 54.9 met the inclusion criteria. Out of the 6 included articles, the nonunion rate was 16.5% at a weighted mean follow-up of 48.1 months. The nonunion rate in the current report is higher than reported nonunion rates of primary arthrodesis. More prospective studies with consistent and standard outcome measures are needed to further determine the success rate of this salvage procedure.Levels of Evidence: 4, Systematic Review of Level 4 Studies.
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Artrodese , Hallux Rigidus , Articulação Metatarsofalângica , Humanos , Artrodese/métodos , Artroplastia/métodos , Hallux Rigidus/cirurgia , Incidência , Articulação Metatarsofalângica/cirurgia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia-inducible factor-2α inhibitor, recently approved in the United States for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other VHL disease-associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL-RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure-response (E-R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression-free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time-to-event analyses. Efficacy E-R was generally flat with non-significant positive trends with exposure. The safety E-R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure-dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit-risk assessment in VHL disease-associated neoplasms using E-R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit-risk profile of belzutifan 120 mg once daily dosing in patients with VHL-RCC for labeling and the overall development program.
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PURPOSE: The study aims to isolate and understand cytopathogenesis, ultrastructure, genomic characteristics and phylogenetic analysis of SARS-CoV-2 virus of B.1.210 lineage, that circulated in India during first wave of the pandemic. METHODS: Clinical specimen from an interstate traveller from Maharashtra to Karnataka, in May 2020, who was positive by RT PCR for SARS-CoV-2 infection was subjected to virus isolation and Whole Genome Sequencing. Vero cells were used to study cytopathogenesis and ultrastructural features by Transmission Electron Microscopy (TEM). Phylogenetic analysis of the whole genome sequences of several SARS-CoV-2 variants downloaded from GISAID was performed in comparison with the B.1.210 variant identified in this study. RESULTS: The virus was isolated in Vero cells and identified by immunofluorescence assay and RT PCR. The growth kinetics in infected Vero cells revealed a peak viral titre at 24 âh post-infection. Ultrastructural studies revealed distinct morphological changes with accumulation of membrane-bound vesicles containing pleomorphic virions in the cytoplasm, with single or multiple intranuclear filamentous inclusions and dilated rough endoplasmic reticulum with viral particles. Whole genome sequence of the clinical specimen as well as the isolated virus revealed the virus to be of lineage B.1.210 with the D614G mutation in the spike protein. Phylogenetic analysis of the whole genome sequence in comparison with other variants reported globally revealed that the isolated SARS-CoV-2 virus of lineage B.1.210 is closely related to the original Wuhan virus reference sequence. CONCLUSIONS: The SARS-CoV-2 variant B.1.210 virus isolated here showed ultrastructural features and cytopathogenesis similar to that of the virus reported during early phase of pandemic. Phylogenetic analysis showed that the isolated virus is closely related to the original Wuhan virus, thereby suggesting that the SARS-CoV-2 lineage B.1.210 that was circulating in India during the early phase of pandemic is likely to have evolved from the original Wuhan strain.
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COVID-19 , SARS-CoV-2 , Humanos , Chlorocebus aethiops , Animais , Pandemias , Filogenia , Células Vero , Índia , GenômicaRESUMO
Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM version 7.3, based on demographics/PK data from three clinical pharmacology (food effect, formulation bridging, and genotype/race effect) and two clinical studies (phase I dose escalation/expansion in patients with RCC and other solid tumors; phase II in patients with VHL). Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear two-compartment model with first-order absorption and elimination. For patients with VHL, the predicted geometric mean (% coefficient of variation) apparent clearance was 7.3 L/h (51%), apparent total volume of distribution was 130 L (35%), and half-life was 12.39 h (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model, dual UGT2B17 and CYP2C19 poor metabolizers (PMs) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in the overall population and subpopulations for belzutifan labeling.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Neoplasias Renais/tratamento farmacológico , Peso CorporalRESUMO
Brain infections are a major public health problem in India and other parts of the world, causing both mortality and lifelong disability. Even after a thorough investigation, many cases remain without an etiological diagnosis. Primate erythroparvovirus 1 (B19V) has been identified as a pathogen associated with undiagnosed meningoencephalitis in other settings, including the United Kingdom, France, and Latvia. Here, we reported 13/403 (3.2%) B19V PCR positive cases of meningoencephalitis in West Bengal, India. The positive samples were mostly from children (10/13, 76.92%) and presented as a spectrum consisting of acute encephalitis (7/13), acute meningoencephalitis (3/13), and meningitis (3/13). Of the 13 cases, 8/13 (61.5%) had no known etiology and 5/13 (38.5%) had a previous etiological diagnosis. The cases did not cluster in time or by location, suggesting sporadic occurrence rather than outbreaks. We were able to retrieve the complete B19V genomes from cerebrospinal fluid (CSF) in 12/13 cases. The sequences clustered into genotype 3b with complete genomes from Brazil, Ghana, and France, and partial genomes from India and Kyrgyzstan. This is the first report of B19V in cases of neurological infections from India. It highlights the need to evaluate the causal relationship between B19V with meningoencephalitis in the country. These were also the first complete genomes of genotype 3b from CSF and will be critical in the evaluation of the relationship between genotypes and disease. IMPORTANCE Cases of meningoencephalitis with no known etiology remain a major challenge to clinical management of brain infections across the world. In this study, we detected and characterized the whole-genome of primate erythroparvovirus 1 (B19V) in cases of meningoencephalitis in India. Our work highlighted the association between B19V and brain infections which has been reported in other countries. Our work also emphasized the need to examine the role of B19V in meningoencephalitis, specifically whether it caused or contributed to the disease together with other pathogens in India. Our study provided the first 12 genomes of B19V from cerebrospinal fluid. These genomes will contribute to an understanding of how the virus is changing across different locations and over time.
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Meningoencefalite , Infecções por Parvoviridae , Parvovirus B19 Humano , Parvovirus , Animais , DNA Viral/genética , Genômica , Genótipo , Índia/epidemiologia , Meningoencefalite/diagnóstico , Meningoencefalite/epidemiologia , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/epidemiologia , Parvovirus/genética , Parvovirus B19 Humano/genéticaRESUMO
PURPOSE: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab. PATIENTS AND METHODS: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated. RESULTS: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation. CONCLUSIONS: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.
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Neoplasias , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/genética , Critérios de Avaliação de Resposta em Tumores Sólidos , Microambiente TumoralRESUMO
Background: As the coronavirus disease 2019 (COVID-19) pandemic continues, the selection of genomic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with higher transmission, more severe disease, re-infection, and immune escape are a cause for concern. Such variants have been reported from the UK (B.1.1.7), South Africa (B.1.351) and, Brazil (P.1/B.1.1.28). We performed this study to track the importation, spread, and emergence of variants locally. Methods: We sequenced whole genomes of SARS-CoV-2 from international travellers (n=75) entering Karnataka, South India, between Dec 22, 2020 and Jan 31, 2021, and from positive cases in the city of Bengaluru (n=108), between Nov 22, 2020- Jan 22, 2021, as well as a local outbreak. We present the lineage distribution and analysis of these sequences. Results: Genomes from the study group into 34 lineages. Variant B.1.1.7 was introduced by international travel (24/73, 32.9%). Lineage B.1.36 and B.1 formed a major fraction of both imported (B.1.36: 20/73, 27.4%; B.1: 14/73, 19.2%), and circulating viruses (B.1.36: 45/103; 43.7%,. B.1: 26/103; 25.2%). The lineage B.1.36 was also associated with a local outbreak. We detected nine amino acid changes, previously associated with immune escape, spread across multiple lineages. The N440K change was detected in 45/162 (27.7%) of the sequences, 37 of these were in the B.1.36 lineage (37/65, 56.92%) Conclusions: Our data support the idea that variants of concern spread by travel. Viruses with amino acid replacements associated with immune escape are already circulating. It is critical to check transmission and monitor changes in SARS-CoV-2 locally.
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There is a lack of consensus in the literature regarding optimal treatment methods for Lisfranc injuries, and recent literature has emphasized the need to compare open reduction and internal fixation (ORIF) with primary arthrodesis (PA). The purpose of the current study is to compare reoperation and complication rates between ORIF and PA following Lisfranc injury in a private, outpatient, orthopaedic practice. A retrospective chart review was performed on patients undergoing operative intervention for Lisfranc injury between January 2009 and September 2015. A total of 196 patients met the inclusion criteria (130 ORIF, 66 PA), with a mean follow-up of 61.3 and 81.7 weeks, respectively. The ORIF group had a higher reoperation rate than the PA group, due to hardware removal. When hardware removals were excluded, the reoperation rate was similar. Postsurgical complications were compared between the 2 groups with no significant difference. In conclusion, ORIF and PA had similar complication rates. When hardware removals were excluded, the reoperation rates were similar, although hardware removals were more common in the ORIF group compared with the PA group.Levels of Evidence: Level III.
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Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by the mindset that higher dose provides higher efficacy. Examples of dose finding implemented by biopharmaceutical firms can change this mindset. The purpose of this article is to outline a pragmatic dose selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs). The approach was implemented for pembrolizumab. Selecting a recommended phase II dose (RP2D) with a novel mechanism of action is often challenging due to uncertain relationships between pharmacodynamics measurements and clinical end points. Additionally, phase I efficacy and safety data are generally inadequate for RP2D selection for IO mAbs. Here, the RP2D was estimated based on phase I (clinical study KN001 A and A2) pharmacokinetics data as the dose required for target saturation, which represents a surrogate for maximal pharmacological effect for antagonist mAbs. Due to limitations associated with collecting and analyzing tumor biopsies, characterizing intratumoral target engagement (TE) is challenging. To overcome this gap, a physiologically-based pharmacokinetic model was implemented to predict intratumoral TE. As tumors are spatially heterogeneous, TE was predicted in well-vascularized and poorly vascularized tumor regions. Additionally, impact of differences in target expression, for example, due to interindividual variability and cancer type, was simulated. Simulations showed that 200 mg every 3 weeks can achieve ≥ 90% TE in clinically relevant scenarios, resulting in the recommendation of 200 mg every 3 weeks as the RP2D. Randomized dose comparison studies (KN001 B2 and D) showing similar efficacy over a fivefold dose/exposure range confirmed the RP2D as the pivotal dose.