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1.
Drug Alcohol Depend ; 219: 108486, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33421802

RESUMO

BACKGROUND: COVID-19 community mitigation measures (e.g., stay-at-home orders) may worsen mental health and substance use-related harms such as opioid use disorder and overdose and limit access to medications for these conditions. We used nationally-representative data to assess dispensing of select substance use and mental health medications during the pandemic in the U.S. METHODS: IQVIA Total Patient Tracker data were used to calculate U.S. monthly numbers of unique patients dispensed buprenorphine, extended-release (ER) intramuscular naltrexone, naloxone, selective serotonin or serotonin-norepinephrine reuptake inhibitors, benzodiazepines, and for comparison, HMG-CoA reductase inhibitors (statins) and angiotensin receptor blockers (ARBs) between January 2019-May 2020. Forecasted estimates of number of unique patients dispensed medications, generated by exponential smoothing statistical forecasting, were compared to actual numbers of patients by month to examine access during mitigation measures (March 2020-May 2020). RESULTS: Between March 2020-May 2020, numbers of unique patients dispensed buprenorphine and numbers dispensed naloxone were within forecasted estimates. Numbers dispensed ER intramuscular naltrexone were significantly below forecasted estimates in March 2020 (-1039; 95 %CI:-1528 to -550), April 2020 (-2139; 95 %CI:-2629 to -1650), and May 2020 (-2498; 95 %CI:-2987 to -2009). Numbers dispensed antidepressants and benzodiazepines were significantly above forecasted estimates in March 2020 (977,063; 95 %CI:351,384 to 1,602,743 and 450,074; 95 % CI:189,999 to 710,149 additional patients, respectively), but were within forecasted estimates in April 2020-May 2020. Dispensing patterns for statins and ARBs were similar to those for antidepressants and benzodiazepines. CONCLUSIONS: Ongoing concerns about the impact of the COVID-19 pandemic on substance use and mental health underscore the need for innovative strategies to facilitate continued access to treatment.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33443634

RESUMO

With the goal of expanding the diversity of tools available for controlling gene expression in cyanobacteria, the T7-RNA polymerase gene expression system from E. coli BL21(DE3) was adapted and systematically engineered for robust function Synechococcus sp. PCC 7002, a fast-growing saltwater strain. Expression of T7-RNA polymerase was controlled via LacI regulation, while functionality was optimized by both further tuning its expression level along with optimizing the translation initiation region of the expressed gene, in this case an enhanced YFP reporter. Under high CO2 conditions, the resulting system displayed a 60-fold dynamic range in expression levels. Furthermore, when maximally induced, T7-RNA polymerase-dependent protein production constituted up to two-thirds of total cellular protein content in Synechococcus sp. PCC 7002. Ultimately, however, this came at the cost of 40% reductions in both biomass and pigmentation levels. Taken together, the developed T7-RNA polymerase gene expression system is effective for controlling and achieving high-level expression of heterologous genes in Synechococcus sp. PCC 7002, making it a valuable tool for cyanobacterial research. KEY POINTS: • Promoter driving T7-RNA polymerase was optimized. • Up to 60-fold dynamic range in expression, depending on CO2 conditions. • Two-thirds of total protein is T7-RNA polymerase dependent.

3.
Am J Transplant ; 21(1): 307-313, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463950

RESUMO

Burnout among surgeons has been attributed to increased workload and decreased autonomy. Although prior studies have examined burnout among transplant surgeons, no studies have evaluated burnout in abdominal transplant surgery fellows. The objective of our study was to identify predictors of burnout and understand its impact on personal and patient care during fellowship. A survey was sent to all abdominal transplant surgery fellows in an American Society of Transplant Surgeons-accredited fellowship. The response rate was 59.2% (n = 77) and 22.7% (n = 17) of fellows met criteria for burnout. Fellows with lower grit scores were more likely to exhibit burnout compared with fellows with higher scores (3.6 vs 4.0, P = .026). Those with burnout were more likely to work >100 hours per week (58.8% vs 27.6%, P = .023), have severe work-related stress (58.8% vs 22.4%, P = .010), consider quitting fellowship (94.1% vs 20.7%, P < .001), or make a medical error (35.3% vs 5.2%, P = .003). This national analysis of abdominal transplant fellows found that burnout rates are relatively low, but few fellows engage in self-care. Personal and program-related factors attribute to burnout and it has unacceptable effects on patient care. Transplant societies and fellowship programs should develop interventions to give fellows tools to prevent and combat burnout.

4.
Nicotine Tob Res ; 22(Suppl 1): S96-S99, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320257

RESUMO

Implications In this commentary, we describe the evidence-based approach used to identify the primary cause of EVALI and to curb the 2019 outbreak. We also discuss future research opportunities and public health practice considerations to prevent a resurgence of EVALI.

5.
J Am Acad Orthop Surg Glob Res Rev ; 4(12): e20.00100, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33332853

RESUMO

INTRODUCTION: Wide-awake local anesthesia no tourniquet (WALANT) presents a nonstandard anesthetic approach initially described for use in hand surgery that has gained interest and utilization across a variety of orthopaedic procedures. In response to operating room resource constraints imposed by the COVID-19 pandemic, our orthopaedic service rapidly adopted and expanded its use of WALANT. METHODS: A retrospective review of 16 consecutive cases performed by 7 surgeons was conducted. Patient demographics, surgical details, and perioperative outcomes were assessed. The primary end point was WALANT failure, defined as intraoperative conversion to general anesthesia. RESULTS: No instances of WALANT failure requiring conversion to general anesthesia occurred. In recovery, one patient (6%) required narcotics for pain control, and the average postoperative pain numeric rating scale was 0.6. The maximum pain score experienced was 4 in the patient requiring postoperative narcotics. The average time in recovery was 42 minutes and ranged from 8 to 118 minutes. CONCLUSION: The WALANT technique was safely and effectively used in 16 cases across multiple orthopaedic subspecialties, including three procedures not previously described in the literature. WALANT techniques hold promise for use in future disaster scenarios and should be evaluated for potential incorporation into routine orthopaedic surgical care.


Assuntos
Anestesia Local/métodos , Salas Cirúrgicas/organização & administração , Procedimentos Ortopédicos , Adulto , Idoso , Anestésicos Locais/administração & dosagem , Epinefrina/administração & dosagem , Feminino , Hemostáticos/administração & dosagem , Humanos , Lidocaína/administração & dosagem , Masculino , Pessoa de Meia-Idade , Entorpecentes/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Pandemias , Estudos Retrospectivos , Vasoconstritores/administração & dosagem , Adulto Jovem
6.
Liver Transpl ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33306254

RESUMO

The incidence of hepatocellular carcinoma (HCC) is growing in the US, especially among the elderly. Older patients are increasingly getting transplanted for HCC, but the impact of advancing age on long-term post-transplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium (UMHTC) of 4980 patients. We divided the patients into 4 groups by age at transplantation- 18-64 (n = 4001), 65-69 (n = 683), 70-74 (n = 252) and ≥ 75 years (n = 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age over 50 years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (p = 0.004), and not HCC-related death (p = 0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients transplanted for HCC (n = 302). Patients older than 65 years had a higher incidence of de-novo cancer (18.1% vs 7.6%, p = 0.006) after transplantation and higher overall cancer-related mortality (14.3% vs 6.6%, p = 0.03). CONCLUSION: Even carefully selected elderly patients with HCC have significantly worse post-transplant survival, which are mostly driven by non-HCC related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve outcomes in elderly patients transplanted for HCC.

8.
Oncol Lett ; 20(6): 285, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33014163

RESUMO

An isolated third nerve palsy presenting as the primary manifestation of a lymphoma is rare, with only few cases having been described. The present study reports an unusual case of a healthy 67-year old male diagnosed with isolated right oculomotor nerve palsy (ONP), who was found to have an underlying B cell lymphoma. The patient's medical records were accessed upon consent. A thorough physical examination, including stroke and infections work-ups were performed. A chest computerized tomography (CT), brain magnetic resonance imaging and positron emission tomography (PET) scans and a mediastinal tissue biopsy, were performed as part of systematic diagnostic evaluations. The current report suggests that a PET fluorodeoxyglucose study or a CT scan of the chest, abdomen and pelvis (with contrast) may help in the early diagnosis of a cancer responsible for ONP, particularly if brain vessel imaging does not show a posterior cerebral artery aneurysm as a cause for the defect.

9.
Drug Alcohol Depend ; 216: 108323, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33032064

RESUMO

BACKGROUND: Emerging data indicate a resurgence of availability and harms of amphetamine-type stimulant (ATS) use. This study examined ATS overdose-involved emergency department (ED) visit trends and visit characteristics associated with ATS overdose. METHODS: Data from the Healthcare Cost and Utilization Project's (HCUP) 2010-2017 Nationwide Emergency Department Sample identified ATS overdose-involved visits. Predicted trend lines from 2010 to 2015 were fit using weighted logistic regression forany or only ATS-involved overdose using ICD-9-CM discharge diagnosis codes; percentage change from 2016 to 2017 used ICD-10-CM. Multivariable logistic regression examined characteristics in 2017 associated with only ATS-involved overdoses compared to drug overdoses not involving ATS. RESULTS: Every year from 2010 to 2015 the odds of any ATS overdose-involved ED visits increased 11 % (odds ratio [OR]: 1.11, 95 % CI: 1.09, 1.14) and 7 % for only ATS overdose-involved visits (OR: 1.07, 95 % CI: 1.04, 1.10). From 2016 to 2017, any and only ATS overdose-involved visit rates increased 19.1 % and 20.5 %, respectively (P < .05). In 2017, ATS overdose-involved visits (N = 42,428) accounted for 4.4 % of all drug overdose visits (N = 956,266). In adjusted regression models, characteristics more prevalent among patients with only ATS overdose included Western region; micropolitan and noncore urbanization levels; unintentional, undetermined, and assault intents; and cardiovascular effects. CONCLUSIONS: Our findings, coupled with the rising availability of ATS and related harms, underscore the expansion of current substance use and overdose prevention and response efforts to address stimulant use, particularly among groups at risk. Research to identify additional individual and community-level risk factors for increasing ATS overdose is warranted.

10.
Nutr Clin Pract ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002260

RESUMO

Pancreatic islet transplantation is a reliable approach for treating insulin-deficient diabetes. This established ß-cell replacement approach has shown considerable improvements in the last 2 decades. It has helped achieve metabolic homeostasis and safe outcomes for a subset of patients with type 1 diabetes and severe pancreatitis. Nutrition support, until recently, was considered as a secondary factor, merely identified as a means of providing all the necessary nutrients for such patients. However, new literature suggests that several factors, such as the route, timing, quantity, and composition of all the nutrients administered, have key disease-altering properties and are vital during the perioperative management of such patients. This review will highlight the benefits of performing the clinical islet transplantation on a subgroup of patients with type 1 diabetes and pancreatitis and summarize new data that identify the pivotal role of nutrition support as a critical intervention in their management.

11.
Br J Cancer ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33100327

RESUMO

BACKGROUND: The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS: Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors. RESULTS: Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5low) had a median OS of 18.5 (95% CI 11.76-21.32) months compared to 11.3 (95% CI 9.86-15.51) months in CCL5high; hazard ratio 1.95 (95% CI 1.04-8.65; p = 0.037). CONCLUSIONS: CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer. CLINICAL TRIAL REGISTRATION: The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008).

12.
Drug Alcohol Depend ; 217: 108297, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961454

RESUMO

BACKGROUND: Stimulant medications are commonly prescribed for the treatment of attention-deficit/hyperactivity disorder; however, they also have high potential for diversion and misuse. We estimated national stimulant dispensing trends from 2014 to 2019 and differences in dispensing by age, sex, state, prescriber specialty, payor type, patient copay, and stimulant type. METHODS: We calculated rates of stimulant dispensing using IQVIA National Prescription Audit (NPA) New to Brand, NPA Regional, and NPA Extended Insights data, which provide dispensing estimates from approximately 49,900 pharmacies representing 92 % of prescriptions dispensed in the United States. Average annual percent change (AAPC) from 2014 to 2019 was analyzed using Joinpoint regression. RESULTS: From 2014 to 2019, the national annual rate of stimulant dispensing increased significantly from 5.6 to 6.1 prescriptions per 100 persons. Rates differed by prescription stimulant type, with increases occurring among both amphetamine-type stimulants and long-acting stimulants. Rates among females (AAPC = 3.6 %; P = 0.001) and adults aged 20-39 years (AAPC=6.7 %; P = 0.002), 40-59 years (AAPC=9.7 %; P < 0.001), and ≥60 years (AAPC = 6.9 %; P = 0.001) increased significantly during the study period. Stimulant dispensing rates varied substantially across states, ranging from 1.0 per 100 in Hawaii to 13.6 per 100 in Alabama. CONCLUSIONS: National stimulant dispensing rates increased from 2014 to 2019, driven by notable increases among females and adults aged ≥20 years. These trends should be considered when prescribing stimulants given growing concerns over prescription stimulant diversion, misuse, and related health harms.

13.
J Infect Dis ; 222(Supplement_5): S346-S353, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32877553

RESUMO

BACKGROUND: Limited research exists on factors associated with human immunodeficiency virus (HIV) testing among people who inject drugs (PWID) in rural America. The purpose of this research is to identify factors associated with rural PWID in Appalachia having not been tested for HIV in the past year. METHODS: Cross-sectional data (n = 408) from a 2018 PWID population estimation study in West Virginia were used to examine factors associated with PWID having not been tested for HIV in the past year. RESULTS: Most participants identified as male (61%), white, non-Hispanic (84%), and reported having recently injected heroin (81%) and/or crystal methamphetamine (71%). Most (64%) reported having been tested for HIV in the past year, 17% reported having been tested but not in the past year, and 19% reported never having been tested. In multivariable analysis, not having been in a drug treatment program in the past year was associated with PWID not having been tested for HIV in the past year (adjusted prevalence ratio, 1.430; 95% confidence interval, 1.080-1.894). CONCLUSIONS: Drug treatment programs may be important venues for rural PWID to access HIV testing; however, testing services should be offered at multiple venues as most PWID had not engaged in drug treatment in the past year.

16.
MMWR Suppl ; 69(1): 38-46, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32817608

RESUMO

Adolescence is an important period of risk for substance use initiation and substance use-related adverse outcomes. To examine youth substance use trends and patterns, CDC analyzed data from the 2009-2019 Youth Risk Behavior Survey. This report presents estimated prevalence of current (i.e., previous 30-days) marijuana use, prescription opioid misuse, alcohol use, and binge drinking and lifetime prevalence of marijuana, synthetic marijuana, cocaine, methamphetamine, heroin, injection drug use, and prescription opioid misuse among U.S. high school students. Logistic regression and Joinpoint analyses were used to assess 2009-2019 trends. Prevalence of current and lifetime substance use by demographics, frequency of use, and prevalence of co-occurrence of selected substances among students reporting current prescription opioid misuse are estimated using 2019 data. Multivariable logistic regression analysis was used to determine demographic and substance use correlates of current prescription opioid misuse. Current alcohol, lifetime cocaine, methamphetamine, heroin, and injection drug use decreased during 2009-2019. Lifetime use of synthetic marijuana (also called synthetic cannabinoids) decreased during 2015-2019. Lifetime marijuana use increased during 2009-2013 and then decreased during 2013-2019. In 2019, 29.2% reported current alcohol use, 21.7% current marijuana use, 13.7% current binge drinking, and 7.2% current prescription opioid misuse. Substance use varied by sex, race/ethnicity, grade, and sexual minority status (lesbian, gay, or bisexual). Use of other substances, particularly current use of alcohol (59.4%) and marijuana (43.5%), was common among students currently misusing prescription opioids. Findings highlight opportunities for expanding evidence-based prevention policies, programs, and practices that aim to reduce risk factors and strengthen protective factors related to youth substance use, in conjunction with ongoing initiatives for combating the opioid crisis.


Assuntos
Alcoolismo/epidemiologia , Analgésicos Opioides/uso terapêutico , Uso Indevido de Medicamentos sob Prescrição/estatística & dados numéricos , Estudantes/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Feminino , Humanos , Masculino , Assunção de Riscos , Instituições Acadêmicas , Estudantes/estatística & dados numéricos , Inquéritos e Questionários , Estados Unidos/epidemiologia
17.
Lancet Respir Med ; 8(12): 1219-1232, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32763198

RESUMO

BACKGROUND: Since August, 2019, US public health officials have been investigating a national outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). A spectrum of histological patterns consistent with acute to subacute lung injury has been seen in biopsies; however, autopsy findings have not been systematically characterised. We describe the pathological findings in autopsy and biopsy tissues submitted to the US Centers for Disease Control and Prevention (CDC) for the evaluation of suspected EVALI. METHODS: Between Aug 1, 2019, and Nov 30, 2019, we examined lung biopsy (n=10 individuals) and autopsy (n=13 individuals) tissue samples received by the CDC, submitted by 16 US states, from individuals with: a history of e-cigarette, or vaping, product use; respiratory, gastrointestinal, or constitutional symptoms; and either pulmonary infiltrates or opacities on chest imaging, or sudden death from an undetermined cause. We also reviewed medical records, evaluated histopathology, and performed infectious disease testing when indicated by histopathology and clinical history. FINDINGS: 21 cases met surveillance case definitions for EVALI, with a further two cases of clinically suspected EVALI evaluated. All ten lung biopsies showed histological evidence of acute to subacute lung injury, including diffuse alveolar damage or organising pneumonia. These patterns were also seen in nine of 13 (69%) autopsy cases, most frequently diffuse alveolar damage (eight autopsies), but also acute and organising fibrinous pneumonia (one autopsy). Additional pulmonary pathology not necessarily consistent with EVALI was seen in the remaining autopsies, including bronchopneumonia, bronchoaspiration, and chronic interstitial lung disease. Three of the five autopsy cases with no evidence of, or a plausible alternative cause for acute lung injury, had been classified as confirmed or probable EVALI according to surveillance case definitions. INTERPRETATION: Acute to subacute lung injury patterns were seen in all ten biopsies and most autopsy lung tissues from individuals with suspected EVALI. Acute to subacute lung injury can have numerous causes; however, if it is identified in an individual with a history of e-cigarette, or vaping, product use, and no alternative cause is apparent, a diagnosis of EVALI should be strongly considered. A review of autopsy tissue pathology in suspected EVALI deaths can also identify alternative diagnoses, which can enhance the specificity of public health surveillance efforts. FUNDING: US Centers for Disease Control and Prevention.


Assuntos
Lesão Pulmonar Aguda/patologia , Vaping/patologia , Lesão Pulmonar Aguda/etiologia , Adulto , Autopsia , Biópsia , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Humanos , Pulmão/patologia , Masculino , Estados Unidos , Vaping/efeitos adversos
19.
Br J Cancer ; 123(5): 709-713, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641867

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.


Assuntos
Betacoronavirus , Consenso , Infecções por Coronavirus/epidemiologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Pneumonia Viral/epidemiologia , Guias de Prática Clínica como Assunto , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Incidência , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Quarentena/métodos , Risco , Reino Unido/epidemiologia
20.
Mol Ecol Resour ; 20(6): 1682-1696, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32619331

RESUMO

The rapid wide-scale spread of fall armyworm (Spodoptera frugiperda) has caused serious crop losses globally. However, differences in the genetic background of subpopulations and the mechanisms of rapid adaptation behind the invasion are still not well understood. Here we report the assembly of a 390.38-Mb chromosome-level genome of fall armyworm derived from south-central Africa using Pacific Bioscience (PacBio) and Hi-C sequencing technologies, with scaffold N50 of 12.9 Mb and containing 22,260 annotated protein-coding genes. Genome-wide resequencing of 103 samples and strain identification were conducted to reveal the genetic background of fall armyworm populations in China. Analysis of genes related to pesticide- and Bacillus thuringiensis (Bt) resistance showed that the risk of fall armyworm developing resistance to conventional pesticides is very high. Laboratory bioassay results showed that insects invading China carry resistance to organophosphate and pyrethroid pesticides, but are sensitive to genetically modified maize expressing the Bt toxin Cry1Ab in field experiments. Additionally, two mitochondrial fragments were found to be inserted into the nuclear genome, with the insertion event occurring after the differentiation of the two strains. This study represents a valuable advance toward improving management strategies for fall armyworm.

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