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1.
Artigo em Inglês | MEDLINE | ID: mdl-33539968

RESUMO

PURPOSE: Data comparing moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) are lacking. We aim to compare late toxicity profiles of patients with early-stage prostate cancer treated with moderately hypofractionated PBT and IMRT. METHODS AND MATERIALS: This multi-institutional analysis included patients with low- or intermediate-risk biopsy-proven prostate adenocarcinoma from 7 tertiary referral centers treated from 1998 to 2018. All patients were treated with moderately hypofractionated radiation, defined as 250 to 300 cGy per daily fraction given for 4 to 6 weeks, and stratified by use of IMRT or PBT. Primary outcomes were late genitourinary (GU) and gastrointestinal (GI) toxicity. Adjusted toxicity rates were calculated using inverse probability of treatment weighting, accounting for race, National Comprehensive Cancer Network risk group, age, pretreatment International Prostate Symptom Score (GU only), and anticoagulant use (GI only). RESULTS: A total of 1850 patients were included: 1282 IMRT (median follow-up 80.0 months) and 568 PBT (median follow-up 43.9 months). Overall toxicity rates were low, with the majority of patients experiencing no late GU (56.6%, n = 1048) or late GI (74.4%, n = 1377) toxicity. No difference was seen in the rates of late toxicity between the groups, with late grade 3+ GU toxicity of 2.0% versus 3.9% (odds ratio [OR] 0.47; 95% confidence interval 0.17-1.28) and late grade 2+ GI toxicity of 14.6% versus 4.7% (OR 2.69; confidence interval 0.80-9.05) for the PBT and IMRT cohorts, respectively. On multivariable analysis, no factors were significantly predictive of GU toxicity, and only anticoagulant use was significantly predictive of GI toxicity (OR 1.90; P = .008). CONCLUSIONS: In this large, multi-institutional analysis of 1850 patients with early-stage prostate cancer, treatment with moderately hypofractionated IMRT and PBT resulted in low rates of toxicity. No difference was seen in late GI and GU toxicity between the modalities during long-term follow-up. Both treatments are safe and well tolerated.

3.
J Natl Compr Canc Netw ; 19(2): 134-143, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33545689

RESUMO

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

4.
Surg Endosc ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483847

RESUMO

BACKGROUND: The majority of patients undergoing bariatric surgery have hepatic steatosis. Liver biopsy is not technically difficult to perform at the time of metabolic and bariatric surgery (MBS), but there may be concerns for bleeding complications. The safety of liver biopsy (LBx) at the time of MBS has been studied in single institutional studies but has not been studied on a national level. METHODS: The MBSAQIP database for 2015-2018 was examined. The codes for Roux-en-Y gastric bypass (RYGB) of 43644 and sleeve gastrectomy (SG) 43775 were used along with 47000 (percutaneous liver biopsy), 47001 (percutaneous liver biopsy at time of other procedure), and 47379 (unlisted laparoscopic procedure, liver). Outcomes such as operative time, complications, and length of stay were examined. Propensity-matched analysis was performed to evaluate for adjusted associations. RESULTS: There were 546,532 patients that met our inclusion criteria. Of those, 21,367 (3.9%) underwent LBx. Only 5.5% (8012) of patients undergoing RYGB had a LBx and 3.3% (13,355) of SG patients. Patients who underwent a LBx had a longer operative time before (103 min vs 84 min, p < 0.001) and after propensity matching [regression coefficient (RC): 10.7 (8.87, 12.5)]. There was no increase in length of stay. There was an increased risk in mortality in the unadjusted analysis (prevalence ratio = 1.61, p = 0.02), but when propensity-matched analysis was done, there was no statistically significant difference between the two groups. Concerning bleeding or transfusion, there was no difference in bleeding or rates of transfusion (p= 0.22, p = 0.21). CONCLUSION: Liver biopsy at the time of MBS is safe. It adds operative time, but there is no increase in length of stay, bleeding complications, morbidity, or death.

5.
Liver Transpl ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33492761

RESUMO

The gut microbiome is altered in cirrhosis. Recent evidence has suggested a key role for the gut microbiota in the progression of cirrhosis and the development of hepatocellular carcinoma (HCC). We aimed to study differences in the microbial composition in cirrhotics with prior and future HCC in context of other complications (e.g. infections, hepatic encephalopathy). Two cohorts were recruited prospectively. Prior HCC: Outpatients with HCC within 2 years were age/sex/MELD-matched to those without HCC. Future HCC: Another cohort was followed for 2 years and divided into future HCC vs not after age/sex/MELD-matching and other complications were also recorded. Microbiota composition/predicted function: were analyzed with 16SrRNA Sequencing and PiCRUST and compared between (1) Prior HCC versus none (2) Future HCC versus none. Within future cohort, also between those who developed (a) HCC only versus without complications, (b) HCC only versus non-HCC complications only and (c) HCC+other complications versus non-HCC complications only. 142 men [76 total prior cohort (38 with/38 without HCC), 66 total future cohort (33 with/without future HCC)] were included. Groups had similar etiology, lactulose/rifaximin/PPI use, diabetes, and non-HCC complications. Microbial diversity was similar between prior HCC/not or future HCC/not. On DESeq2 higher Clostridium sensu stricto and Anaerotruncus were significantly associated with protection from HCC while the reverse was seen with Raoultella, and Haemophilus, regardless of prior/future HCC comparisons. Functions focused on urea cycle, bioenergetics, tryptophan, and toluene metabolism were different between groups. Rothia was specific for other complications. CONCLUSION: Despite age, sex and MELD-matching and accounting for other complications, gut microbiota composition and predicted function is different in men with cirrhosis with and without prior HCC and can be extended toward future HCC development.

6.
Genes (Basel) ; 12(1)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467186

RESUMO

The unique evolutionary dynamics and complex structure make the Y chromosome the most diverse and least understood region in the mammalian genome, despite its undisputable role in sex determination, development, and male fertility. Here we present the first contig-level annotated draft assembly for the alpaca (Vicugna pacos) Y chromosome based on hybrid assembly of short- and long-read sequence data of flow-sorted Y. The latter was also used for cDNA selection providing Y-enriched testis transcriptome for annotation. The final assembly of 8.22 Mb comprised 4.5 Mb of male specific Y (MSY) and 3.7 Mb of the pseudoautosomal region. In MSY, we annotated 15 X-degenerate genes and two novel transcripts, but no transposed sequences. Two MSY genes, HSFY and RBMY, are multicopy. The pseudoautosomal boundary is located between SHROOM2 and HSFY. Comparative analysis shows that the small and cytogenetically distinct alpaca Y shares most of MSY sequences with the larger dromedary and Bactrian camel Y chromosomes. Most of alpaca X-degenerate genes are also shared with other mammalian MSYs, though WWC3Y is Y-specific only in alpaca/camels and the horse. The partial alpaca Y assembly is a starting point for further expansion and will have applications in the study of camelid populations and male biology.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33444816

RESUMO

BACKGROUND AND AIMS: Bowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these neuron subtypes to facilitate development of novel therapeutic approaches to treat devastating enteric neuropathies, and to learn more about enteric nervous system function. METHODS: To identify subtype-specific genes, we performed single-nucleus RNA-seq on adult mouse and human colon myenteric plexus, and single-cell RNA-seq on E17.5 mouse ENS cells from whole bowel. We used immunohistochemistry, select mutant mice, and calcium imaging to validate and extend results. RESULTS: RNA-seq on 635 adult mouse colon myenteric neurons and 707 E17.5 neurons from whole bowel defined seven adult neuron subtypes, eight E17.5 neuron subtypes and hundreds of differentially expressed genes. Manually dissected human colon myenteric plexus yielded RNA-seq data from 48 neurons, 3798 glia, 5568 smooth muscle, 377 interstitial cells, and 2153 macrophages. Immunohistochemistry demonstrated differential expression for BNC2, PBX3, SATB1, RBFOX1, TBX2, and TBX3 in enteric neuron subtypes. Conditional Tbx3 loss reduced NOS1-expressing myenteric neurons. Differential Gfra1 and Gfra2 expression coupled with calcium imaging revealed that GDNF and neurturin acutely and differentially regulate activity of ∼50% of myenteric neurons with distinct effects on smooth muscle contractions. CONCLUSION: Single cell analyses defined genes differentially expressed in myenteric neuron subtypes and new roles for TBX3, GDNF and NRTN. These data facilitate molecular diagnostic studies and novel therapeutics for bowel motility disorders.

8.
Surg Obes Relat Dis ; 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33272856

RESUMO

BACKGROUND: Magnetic sphincter augmentation (MSA) has gained popularity as a treatment for gastroesophageal reflux disease (GERD). The role of MSA in treating GERD in metabolic and bariatric surgery (MBS) patients at the time of primary MBS is unknown. OBJECTIVE: To determine the short-term outcomes of MSA placed at the time of MBS. SETTING: National database, United States. METHODS: We queried the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database for MSA performed at time of the sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) for the years 2017-2018. A propensity adjusted analysis was performed to assess 30-day outcomes of patients who had MSA placed versus those who did not. RESULTS: There were 319,580 patients who underwent MBS in the study period. Twenty-four patients had MSA at time of surgery. These patients did not have a higher reported rate of preoperative GERD (P = .93). Six patients (25%) with MSA had a RYGB; the other 18 patients (75%) patients had SG (P < .001). Operative times were similar between the groups and there was no difference in length of stay. After propensity matched analysis (with 24 patients in each arm), patients who underwent an MSA had shorter discharge times (1.4 days [.8] versus 2.0 [.9], P = .012). CONCLUSION: MSA is safe in the short term in MBS. There is no difference in major morbidity or mortality and operative times are similar in MSA patients. The long-term efficacy of this practice is unknown.

9.
Elife ; 92020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33274714

RESUMO

Atlantic herring is widespread in North Atlantic and adjacent waters and is one of the most abundant vertebrates on earth. This species is well suited to explore genetic adaptation due to minute genetic differentiation at selectively neutral loci. Here we report hundreds of loci underlying ecological adaptation to different geographic areas and spawning conditions. Four of these represent megabase inversions confirmed by long read sequencing. The genetic architecture underlying ecological adaptation in herring deviates from expectation under a classical infinitesimal model for complex traits because of large shifts in allele frequencies at hundreds of loci under selection.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33268854

RESUMO

BACKGROUND: The optimal treatment for oligorecurrent prostate cancer (PCa) is a matter of debate. We aimed to assess oncologic outcomes of patients treated with metastasis-directed therapy (MDT) vs. androgen deprivation therapy (ADT) for oligorecurrent PCa. METHODS: We analyzed data from patients with oligorecurrent PCa treated with ADT (n = 121), salvage lymph node dissection (sLND) (n = 191) or external beam RT (EBRT) (n = 178). Radiological recurrence (RAR) was defined as a positive positron emission tomography imaging after MDT or ADT. Second-line systemic therapies (SST) were defined as any systemic therapy administered for progression. Oncologic outcomes were evaluated separately for patients with node-only or bone metastases. Kaplan-Meier method was used to assess time to RAR, SST, and cancer-specific mortality (CSM). Predictors of RAR, SST, and castration-resistant PCa (CRPCa) were assessed with Cox regression analyses. RESULTS: Overall, 74 (22.6%), 63 (19.2%), and 191 (58.2%) patients were treated with ADT, EBRT, and sLND for lymph node-only recurrence. Both sLND (HR 0.56, 95% CI 0.33-0.94) and EBRT (HR 0.46, 95% CI 0.25-0.85) were associated with better RAR than ADT. Similarly, sLND (HR 0.25, 95% CI 0.13-0.50) and EBRT (HR 0.41, 95% CI 0.19-0.87) were associated with longer SST, as compared with ADT. Similar results were found for CRPCa status. Oncologic outcomes were similar between sLND and EBRT. MDT was not associated with survival benefit in patients with bone metastases as compared with ADT. CONCLUSIONS: sLND and EBRT were associated with better RAR, SST, and CRPCa-free survival as compared with ADT in patients with oligometastatic PCa nodal recurrence. No difference in survival outcomes was observed between sLND and EBRT. MDT was not associated with survival benefit in patients with bone metastases, as compared with ADT.

11.
Eur Urol ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33309278

RESUMO

CONTEXT: Management of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity associated with any local salvage modality. OBJECTIVE: To quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low-dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy. EVIDENCE ACQUISITION: We performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities. EVIDENCE SYNTHESIS: A total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p < 0.01), with no other differences identified. CONCLUSIONS: Large differences in 5-yr outcomes were not uncovered when comparing all salvage treatment modalities against RP. Reirradiation with SBRT, HDR brachytherapy, or LDR brachytherapy appears to result in less severe GU toxicity than RP, and reirradiation with HDR brachytherapy yields less severe GI toxicity than RP. Prospective studies of local salvage for radiorecurrent disease are warranted. PATIENT SUMMARY: In a large study-level meta-analysis, we looked at treatment outcomes and toxicity for men treated with a number of salvage treatments for radiorecurrent prostate cancer. We conclude that relapse-free survival at 5 years is equivalent among salvage modalities, but reirradiation may lead to lower toxicity.

12.
Mil Med ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33201244

RESUMO

Corneal injury is a known risk for deployed troops worldwide. To the authors' knowledge, there has been no reported use of gamma-irradiated corneas in the setting of severe corneal trauma. Our report highlights the case of a 36-year-old active duty solider who sustained bilateral penetrating ocular trauma from a nearby ordnance explosion. We propose that ocular surgeons should consider utilizing gamma-irradiated corneas in (1) a situation where the corneal tissue is so damaged that it would be challenging to accomplish an adequate repair while providing the opportunity for future visual rehabilitation and (2) remote and/or deployed environments where storage of fresh donor tissue is limited. The long shelf life of gamma-irradiated corneas reduces the need for specialized storage equipment and the need for continuous resupply, both potentially leading to significant cost savings for the Military Health System.

13.
Cell Stem Cell ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33098807

RESUMO

The derivation of tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would have broad reaching implications for regenerative medicine. Here, we report the directed differentiation of human iPSCs into airway basal cells ("iBCs"), a population resembling the stem cell of the airway epithelium. Using a dual fluorescent reporter system (NKX2-1GFP;TP63tdTomato), we track and purify these cells as they first emerge as developmentally immature NKX2-1GFP+ lung progenitors and subsequently augment a TP63 program during proximal airway epithelial patterning. In response to primary basal cell medium, NKX2-1GFP+/TP63tdTomato+ cells display the molecular and functional phenotype of airway basal cells, including the capacity to self-renew or undergo multi-lineage differentiation in vitro and in tracheal xenografts in vivo. iBCs and their differentiated progeny model perturbations that characterize acquired and genetic airway diseases, including the mucus metaplasia of asthma, chloride channel dysfunction of cystic fibrosis, and ciliary defects of primary ciliary dyskinesia.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33127490

RESUMO

BACKGROUND: /Objectives:Definitive radiotherapy (RT), with or without concurrent chemotherapy, is an alternative to radical cystectomy for patients with localized, muscle-invasive bladder cancer (MIBC) who are either not surgical candidates or prefer organ preservation. We aim to synthesize an evidence-based guideline regarding the appropriate use of RT. METHODS: We performed a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) literature review using the PubMed and Embase databases. Based upon the literature review, critical management topics were identified and reformulated into consensus questions. An expert panel was assembled to address key areas of both consensus and controversy using the modified Delphi framework. RESULTS: A total of 761 articles were screened, of which 61 were published between 1975 to 2019 and included for full review. There were seven well-designed studies, 20 good quality studies, 28 quality studies with design limitations, and six references not suited as primary evidence. Adjuvant radiotherapy after cystectomy was not included due to lack of high-quality data or clinical utilization. An expert panel consisting of 14 radiation oncologists, one medical oncologist, and one urologist was assembled. We identified four clinical variants of MIBC: surgically fit patients who wish to pursue organ preservation, patients surgically unfit for cystectomy, patients medically unfit for cisplatin-based chemotherapy, and borderline cystectomy candidates based on age with unilateral hydronephrosis and normal renal function. We identified key areas of controversy, including use of definitive radiotherapy for patients with negative prognostic factors, appropriate radiotherapy dose, fractionation, fields and technique when used, and chemotherapy sequencing and choice of agent. CONCLUSIONS: There is limited level-one evidence to guide appropriate treatment of MIBC. Studies vary significantly with regards to patient selection, chemotherapy utilization, and radiotherapy technique. A consensus guideline on the appropriateness of RT for MIBC may aid practicing oncologists in bridging the gap between data and clinical practice.

15.
JAMA Oncol ; 6(12): 1912-1920, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33090219

RESUMO

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus. Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer. Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019. Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts. Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782). Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

16.
PLoS Genet ; 16(10): e1008926, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33090996

RESUMO

The domestic cat (Felis catus) numbers over 94 million in the USA alone, occupies households as a companion animal, and, like humans, suffers from cancer and common and rare diseases. However, genome-wide sequence variant information is limited for this species. To empower trait analyses, a new cat genome reference assembly was developed from PacBio long sequence reads that significantly improve sequence representation and assembly contiguity. The whole genome sequences of 54 domestic cats were aligned to the reference to identify single nucleotide variants (SNVs) and structural variants (SVs). Across all cats, 16 SNVs predicted to have deleterious impacts and in a singleton state were identified as high priority candidates for causative mutations. One candidate was a stop gain in the tumor suppressor FBXW7. The SNV is found in cats segregating for feline mediastinal lymphoma and is a candidate for inherited cancer susceptibility. SV analysis revealed a complex deletion coupled with a nearby potential duplication event that was shared privately across three unrelated cats with dwarfism and is found within a known dwarfism associated region on cat chromosome B1. This SV interrupted UDP-glucose 6-dehydrogenase (UGDH), a gene involved in the biosynthesis of glycosaminoglycans. Importantly, UGDH has not yet been associated with human dwarfism and should be screened in undiagnosed patients. The new high-quality cat genome reference and the compilation of sequence variation demonstrate the importance of these resources when searching for disease causative alleles in the domestic cat and for identification of feline biomedical models.

17.
Pathogens ; 9(11)2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33114123

RESUMO

Canine distemper virus (CDV) is a multi-host pathogen with variable clinical outcomes of infection across and within species. We used whole-genome sequencing (WGS) to search for viral markers correlated with clinical distemper in African lions. To identify candidate markers, we first documented single-nucleotide polymorphisms (SNPs) differentiating CDV strains associated with different clinical outcomes in lions in East Africa. We then conducted evolutionary analyses on WGS from all global CDV lineages to identify loci subject to selection. SNPs that both differentiated East African strains and were under selection were mapped to a phylogenetic tree representing global CDV diversity to assess if candidate markers correlated with documented outbreaks of clinical distemper in lions (n = 3). Of 54 SNPs differentiating East African strains, ten were under positive or episodic diversifying selection and 20 occurred in the clinical strain despite strong purifying selection at those loci. Candidate markers were in functional domains of the RNP complex (n = 19), the matrix protein (n = 4), on CDV glycoproteins (n = 5), and on the V protein (n = 1). We found mutations at two loci in common between sequences from three CDV outbreaks of clinical distemper in African lions; one in the signaling lymphocytic activation molecule receptor (SLAM)-binding region of the hemagglutinin protein and another in the catalytic center of phosphodiester bond formation on the large polymerase protein. These results suggest convergent evolution at these sites may have a functional role in clinical distemper outbreaks in African lions and uncover potential novel barriers to pathogenicity in this species.

18.
Curr Med Res Opin ; 36(12): 2047-2052, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33030383

RESUMO

OBJECTIVE: To examine opioid prescribing following cataract surgery among patients who did or did not receive Omidria (phenylephrine and ketorolac intraocular solution 1.0%/0.3%) referred to as "P/K". METHODS: The retrospective study compared adults over 65 without recent opioid use in the MarketScan databases who had a cataract-related surgical procedure between 1 January 2015 and 31 July 2019. Opioid prescription fills in the initial 2 and 7 days following surgery were compared between patients who did or did not receive P/K during surgery. RESULTS: We identified 218,672 older adults with cataract-related surgical procedures, of whom 5145 received P/K during surgery. Within 2 days of surgery, 0.50% of P/K patients and 0.68% of non-P/K patients received at least one opioid prescription. Pill counts in the first prescription post-surgery were lower for patients who received P/K than those who did not receive P/K (20 vs 45 respectively, p = .015). Findings were similar when a 7 day window was used. The reduction in opioids prescribed to patients who received P/K occurred despite the P/K-treated patients having a significantly higher incidence of preoperative comorbidities or risk factors for surgical complexity than patients who did not receive P/K (46.6% vs 31.3%, p < .001). CONCLUSIONS: Patients without recent opioid use who received P/K during cataract surgery, despite greater incidence of preoperative comorbidities and higher risk for surgical complexity, were prescribed fewer opioid pills following surgery than patients who did not receive P/K.

19.
J Cancer Res Ther ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-33063697

RESUMO

Objectives: The objective was to evaluate the diagnostic performance of surveillance11 C-choline positron emission tomography/computed tomography (PET/CT) for the detection of disease relapse in patients with a history of biochemically recurrent (BCR) prostate cancer (PCa) and prostate-specific antigen (PSA) ≤0.1 ng/ml. Materials and Methods: We included patients who had been treated for BCR PCa and had a surveillance11 C-choline PET/CT at serum PSA ≤0.1 ng/ml. Positive surveillance PET/CT was defined as a study that identified a new tracer-avid lesion or new tracer uptake in a previously treated lesion or both. Findings were confirmed against a composite radiologic-pathologic gold standard. Time to recurrence association analyses were performed for disease relapse risk with the use of Cox proportional hazards regression. Results: In total, 13 (12.1%) of the 107 patients had positive surveillance PET/CT scans, confirmed on pathologic assessment (n = 5) and subsequent imaging (n = 8). Among these 13 patients, ten had distant metastases, two had local recurrence, and one had both. Nine of the ten patients with metastases had oligometastatic disease defined as the presence of ≤3 metastases. Serum PSA became detectable again in only seven patients with positive surveillance PET/CT, after a mean interval from surveillance PET/CT of 292 days (range: 105-543 days). We identified an association of N stage with increased risk of recurrence (hazard ratio = 3.85; P = 0.036) although this was not significant after accounting for multiple testing. Conclusions: Surveillance11 C-choline PET/CT can detect early disease relapse at serum PSA ≤0.1 ng/ml in patients with a history of BCR PCa.

20.
JAMA Netw Open ; 3(10): e2024191, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026453

RESUMO

Importance: In late December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. Data on the routes of transmission to Los Angeles, California, the US West Coast epicenter for coronavirus disease 2019 (COVID-19), and subsequent community spread are limited. Objective: To determine the transmission routes of SARS-CoV-2 to Southern California and elucidate local community spread within the Los Angeles metropolitan area. Design, Setting, and Participants: This case series included 192 consecutive patients with reverse transcription-polymerase chain reaction (RT-PCR) test results positive for SARS-CoV-2 who were evaluated at Cedars-Sinai Medical Center in Los Angeles, California, from March 22 to April 15, 2020. Data analysis was performed from April to May 2020. Main Outcomes and Measures: SARS-CoV-2 viral genomes were sequenced. Los Angeles isolates were compared with genomes from global subsampling and from New York, New York; Washington state; and China to determine potential sources of viral dissemination. Demographic data and outcomes were collected. Results: The cohort included 192 patients (median [interquartile range] age, 59.5 [43-75] years; 110 [57.3%] men). The genetic characterization of SARS-CoV-2 isolates in the Los Angeles population pinpointed community transmission of 13 patients within a 3.81 km2 radius. Variation landscapes of this case series also revealed a cluster of 10 patients that contained 5 residents at a skilled nursing facility, 1 resident of a nearby skilled nursing facility, 3 health care workers, and a family member of a resident of one of the skilled nursing facilities. Person-to-person transmission was detected in a cluster of 5 patients who shared the same single-nucleotide variation in their SARS-CoV-2 genomes. High viral genomic diversity was identified: 20 Los Angeles isolates (15.0%) resembled SARS-CoV-2 genomes from Asia, while 109 Los Angeles isolates (82.0%) were similar to isolates originating from Europe. Analysis of other common respiratory viral pathogens did not reveal coinfection in the cohort. Conclusions and Relevance: These findings highlight the precision of detecting person-to-person transmission and accurate contact tracing directly through SARS-CoV-2 genome isolation and sequencing. Development and application of phylogenetic analyses from the Los Angeles population established connections between COVID-19 clusters locally and throughout the US.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/transmissão , Genoma Viral/genética , Pneumonia Viral/transmissão , Adulto , Idoso , Ásia , California/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Europa (Continente) , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Los Angeles/epidemiologia , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Pandemias , Filogenia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Análise de Sequência de RNA , Proteínas não Estruturais Virais/genética , Washington
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