Development of effective therapeutics for mitigating the COVID-19 pandemic is a pressing global need. Neutralizing antibodies are known to be effective antivirals, as they can be rapidly deployed to ...prevent disease progression and can accelerate patient recovery without the need for fully developed host immunity. Here, we report the generation and characterization of a series of chimeric antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Some of these antibodies exhibit exceptionally potent neutralization activities in vitro and in vivo, and the most potent of our antibodies target three distinct non-overlapping epitopes within the RBD. Cryo-electron microscopy analyses of two highly potent antibodies in complex with the SARS-CoV-2 spike protein suggested they may be particularly useful when combined in a cocktail therapy. The efficacy of this antibody cocktail was confirmed in SARS-CoV-2-infected mouse and hamster models as prophylactic and post-infection treatments. With the emergence of more contagious variants of SARS-CoV-2, cocktail antibody therapies hold great promise to control disease and prevent drug resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study aimed to evaluate the impact of preoperative double-J stent (DJ) in pyeloplasty patients on perioperative complications, recurrence, and quality of life (QoL).
Pyeloplasties due to ...ureteropelvic junction obstructions between January 2010 and December 2020 were consecutively identified. A standardized follow-up questionnaire was used. Tabulation was made according to preoperative DJ versus no DJ. Subgroup analyses addressed primary robotic pyeloplasties.
Of 95 pyeloplasty patients, 62% received a preoperative DJ. Patients with preoperative DJ exhibited higher rates of Clavien-Dindo (CD) 2 (22 vs. 11%) complications, but not of CD3 (8.5 vs. 8.3%, p = 0.5). After a median follow-up of 61 months, 9 patients exhibited a recurrence, of whom 7 had a preoperative DJ. In QoL assessment, comparable findings were made between patients with and without preoperative DJ. In robotic pyeloplasty patients (n = 73), patients with preoperative DJ (58%, n = 42) experienced higher CD3 complication rates, compared to patients without preoperative DJ (12 vs. 6.5%). Moreover, higher rates of recurrences were observed in preoperative DJ patients (12 vs. 3.2%).
In a contemporary pyeloplasty cohort, the midterm success rate was good with 91%. Our findings suggest that preoperative DJ is associated with higher recurrence rates. However, QoL did not differ between patients with and without preoperative DJ.
Study Type – Therapy (case series) Level of Evidence 4
What's known on the subject? and What does the study add?
This international collaboration started in 2008 based upon the possible application ...of the ‘predictiveness curves’ (multinomial logistic regression method) developed at the Fred Hutchinson Cancer Research Center (FHCRC) to the internationally recognized Partin Tables for staging prostate cancer. Dr. Ying Huang, a biostatistician at the FHCRC, applied the ‘predictiveness curve’ statistical modeling concept to the Partin Tables and then created a new Partin Nomogram using total PSA (tPSA) as a continuous variable.
The new ‘2010 Partin Nomogram’ stage risk prediction capacity among the total cohort and the individual patients is based on the ‘predictiveness curves’ using the method developed in Huang et al.16. For each pathological stage, we calculated ‘the risk’ for each subject in the cohort based on the risk model and made a quantile plot based on the estimated risks. If one considers a point on the ‘predictiveness curve’ with an x‐coordinate of value v, then the value of its y‐coordinate, which we name R(v), is the 100 × vth percentile of risk in the study cohort. On the other hand, for a particular point on the curve with y‐coordinate p, the value of its x‐coordinate, which we name R−1(p), corresponds to the percentage of subjects in the study cohort with risk ≤pi.e. the cumulative distribution function (CDF) of risk at p. It is likely that this CDF of risk will be useful for clinicians and patients (see Fig. 2 in the article). Dr. Huang has also written an operational R‐program to calculate patient's risk and next we intend to develop a user friendly computer program based upon this program to allow the easy use by patients and physicians of the 2010 Partin Nomogram and the corresponding predictiveness curves for patient‐specific pathological stage outcome prediction.
OBJECTIVES
• To develop a ‘2010 Partin Nomogram’ with total prostate‐specific antigen (tPSA) as a continuous biomarker, in light of the fact that the current 2007 Partin Tables restrict the application of tPSA as a non‐continuous biomarker by creating ‘groups’ for risk stratification with tPSA levels (ng/mL) of 0–2.5, 2.6–4.0, 4.1–6.0, 6.1–10.0 and >10.0.
• To use a ‘predictiveness curve’ to calculate the percentile risk of a patient among the cohort.
PATIENTS AND METHODS
• In all, 5730 and 1646 patients were treated with radical prostatectomy (without neoadjuvant therapy) between 2000 and 2005 at the Johns Hopkins Hospital (JHH) and University Clinic Hamburg‐Eppendorf (UCHE), respectively.
• Multinomial logistic regression analysis was performed to create a model for predicting the risk of the four non‐ordered pathological stages, i.e. organ‐confined disease (OC), extraprostatic extension (EPE), and seminal vesicle (SV+) and lymph node (LN+) involvement.
• Patient‐specific risk was modelled as a function of the B‐spline basis of tPSA (with knots at the first, second and third quartiles), clinical stage (T1c, T2a, and T2b/T2c) and biopsy Gleason score (5–6, 3 + 4 = 7, 4 + 3 = 7, 8–10).
RESULTS
• The ‘2010 Partin Nomogram’ calculates patient‐specific absolute risk for all four pathological outcomes (OC, EPE, SV+, LN+) given a patient’s preoperative clinical stage, tPSA and biopsy Gleason score.
• While having similar performance in terms of calibration and discriminatory power, this new model provides a more accurate prediction of patients’ pathological stage than the 2007 Partin Tables model.
• The use of ‘predictiveness curves’ has also made it possible to obtain the percentile risk of a patient among the cohort and to gauge the impact of risk thresholds for making decisions regarding radical prostatectomy.
CONCLUSION
• The ‘2010 Partin Nomogram’ using tPSA as a continuous biomarker together with the corresponding ‘predictiveness curve’ will help clinicians and patients to make improved treatment decisions.
Abstract Biliary atresia (BA) is a neonatal biliary system disease closely associated with viral infection and bile duct inflammation. Silver nanoparticles (AgNps) have previously revealed antiviral ...and anti-inflammatory properties. In this study, we have investigated the effects of AgNps in the treatment of the Rhesus rotavirus inoculation induced BA in mice. The morphology, liver histopathology, clinical biochemistry examination, inflammatory cells were analyzed in BA mice. Results indicated that AgNps could significantly increase the survival rate of BA mice, reduce jaundice and weight lost and the liver enzymes and bilirubin metabolism clinical parameters were closed to the normal levels. Diminished numbers of NK cells were observed by flow cytometry analysis and immunohistochemical staining. Furthermore, the viral load was reduced and transcripts for TGF-β mRNA were augmented after AgNps treatment. Collectively, our results suggest that AgNps treatment has beneficial effects on the BA mouse model partially through upregulation of TGF-β.
To study the effect of corticosteroids in the treatment of severe acute respiratory syndrome (SARS).
A retrospective cohort of 78 consecutive adult SARS patients admitted to a regional hospital in ...Hong Kong between March and May 2003 was analysed to study the effectiveness of corticosteroid. They were categorized according to whether or not corticosteroid therapy was given, and compared in terms of demographic characteristics, comorbidities, peak lactate dehydrogenase (LDH) levels and clinical outcomes. Established adverse prognostic factors including old age, comorbidities and high LDH levels were used as covariates in multiple logistic regressions to adjust for their confounding effect on adverse outcomes.
Among 78 patients, 66 patients (84.6%) received corticosteroid. The LDH level was similar in both groups. The corticosteroid group had more adverse outcomes (37.9% vs. 16.7%) despite younger age and less comorbidity. In multivariate analysis, corticosteroid treatment was associated with a 20.7-fold increase in risk of either ICU admission or mortality, independent of age and disease severity.
Despite more favourable baseline characteristics and similar peak LDH levels, SARS patients given corticosteroid had more adverse outcomes.
Introduction:
MRI-targeted biopsy (TB) increases overall prostate-cancer (PCa) detection-rates and decreases the risk of insignificant PCa detection. However, the impact of these findings on the ...definite pathology after radical prostatectomy (RP) is under debate.
Materials and Methods:
Between 01/2014 and 12/2018, 366 patients undergoing prostate biopsy and RP were retrospectively analyzed. The correlation between biopsy Gleason-score (highest Gleason-score in a core) and the RP Gleason-score in patients undergoing systematic biopsy (SB-group) (
n
= 221) or TB+SB (TB-group,
n
= 145) was tested using the ISUP Gleason-group grading (GGG, scale 1–5). Sub analyses focused on biopsy GGG 1 and GGG ≥ 2.
Results:
Proportions of biopsy GGG 1–5 in the SB-group and TB-group were 24.4, 37.6, 19, 10.9, 8.1% and 13.8, 43.4, 24.2, 13.8, 4.8%, respectively (
p
= 0.07). Biopsy and pathologic GGG were concordant in 108 of 221 (48.9%) in SB- and 74 of 145 (51.1%) in TB-group (
p
= 0.8). Gleason upgrading was recorded in 33.5 and 31.7% in SB- vs. TB-group (
p
= 0.8). Patients with biopsy GGG 1 undergoing RP showed an upgrading in 68.5%(37/54) in SB- and 75%(15/20) in TB-group (
p
= 0.8). In patients with biopsy GGG ≥ 2 concordance increased for both biopsy approaches (54.5 vs. 55.2% for SB- vs. TB-group,
p
= 0.9).
Discussion:
Irrespective of differences in PCa detection-rates between TB- and SB-groups, no significant differences in GGG concordance and upgrading between patients of both groups undergoing biopsy, followed by RP, were recorded. Concordance rates increased in men with biopsy GGG ≥ 2. TB seems to detect more patients with PCa without a difference in concordance with final pathology.
•Low risk Mexican-American patients do not differ from their Caucasians counterparts.•Favorable intermediate risk Mexican-American patients exhibit higher rate of upgrading.•Low rate of upstaging was ...recorded in Mexican-American and Caucasian active surveillance candidates.•The literature on Mexican-American prostate cancer patients is sparse.
We compared upgrading and upstaging rates in low risk and favorable intermediate risk prostate cancer (CaP) patients according to racial and/or ethnic group: Mexican-Americans and Caucasians.
Within Surveillance, Epidemiology and End Results database (2010–2015), we identified low risk and favorable intermediate risk CaP patients according to National Comprehensive Cancer Network guidelines. Descriptives and logistic regression models were used. Furthermore, a subgroup analysis was performed to test the association between Mexican-American vs. Caucasian racial and/or ethnic groups and upgrading either to Gleason-Grade Group (GGG II) or to GGG III, IV or V, in low risk or favorable intermediate risk CaP patients, respectively.
We identified 673 (2.6%) Mexican-American and 24,959 (97.4%) Caucasian CaP patients. Of those, 14,789 were low risk (434 2.9% Mexican-Americans vs. 14,355 97.1% Caucasians) and 10,834 were favorable intermediate risk (239 2.2% Mexican-Americans vs. 10,604 97.8% Caucasians). In low risk CaP patients, Mexican-American vs. Caucasian racial and/or ethnic group did not result in either upgrading or upstaging differences. However, in favorable intermediate risk CaP patients, upgrading rate was higher in Mexican-Americans than in Caucasians (31.4 vs. 25.5%, OR 1.33, P = 0.044), but no difference was recorded for upstaging. When comparisons focused on upgrading to GGG III, IV or V, higher rate was recorded in Mexican-American relative to Caucasian favorable intermediate risk CaP patients (20.4 vs. 15.4%, OR 1.41, P = 0.034).
Low risk Mexican-American CaP patients do not differ from low risk Caucasian CaP patients. However, favorable intermediate risk Mexican-American CaP patients exhibit higher rates of upgrading than their Caucasian counterparts. This information should be considered at treatment decision making.
OBJECTIVE
To assess the association between surgical volume (SV) and the rate of positive surgical margins (PSM) after radical prostatectomy (RP) in a large single‐institution European cohort of ...patients.
PATIENTS AND METHODS
In all, 2402 men had a RP by a group of 11 surgeons, all of whom were trained by the surgeon with the highest SV; all surgeons used the same surgical technique. Variables assessed before RP were prostate‐specific antigen (PSA) level, clinical stage and biopsy Gleason sum; variables assessed after RP were PSA level, extracapsular extension, seminal vesicle invasion, lymph node invasion and pathological Gleason sum. These were used to predict the rate of PSM in models before or after RP. Multivariate models were complemented with SV to test its independent and multivariate statistical significance and to quantify its impact on the model’s overall (and 200 bootstrap‐corrected) predictive accuracy.
RESULTS
The mean (range) SV was 201 (1–1293) RPs; the mean (median, range) rate of PSM was 20.2 (21.4, 0–32.9)%. In multivariate models, SV was a highly statistically significant independent predictor of PSM (P < 0.001) and increased the predictive accuracy in multivariate models both before (2.0%) and after RP (1.5%, both P < 0.001). However, when the surgeon with the highest SV, who contributed to 1293 cases, was removed from the analyses, the multivariate independent prediction and the gains in predictive accuracy related to adding SV, disappeared in the models both before (P = 0.9, accuracy gain 0.1%) and after (P = 0.4, accuracy gain − 0.3%) RP.
CONCLUSIONS
These results indicate that patients treated by surgeons with a very high volume can expect to have a significantly lower rate of PSM, after accounting for clinical and pathological case‐mix differences. However, SV is not a predictor of PSM when analyses are restricted to intermediate‐ and low‐volume surgeons.
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