bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiological factors associated with recent HIV infection among newly-diagnosed cases in Singapore, 2013–2017
Authors: Ang Li Wei , Low Carmen , Wong Chen Seong , Boudville Irving Charles , Toh Matthias Paul Han Sim , Archuleta Sophia , Lee Vernon Jian Ming , Leo Yee Sin , Chow Angela , Lin Raymond Tzer-Pin
Published: March 2021

Background

Early diagnosis is crucial in securing optimal outcomes in the HIV care cascade. Recent HIV infection (RHI) serves as an indicator of early detection in the course of HIV infection. Surveillance of RHI is important in uncovering at-risk groups in which HIV transmission is ongoing. The study objectives are to estimate the proportion of RHI among persons newly-diagnosed in 2013–2017, and to elucidate epidemiological factors associated with RHI in Singapore.

Methods

As part of the National HIV Molecular Surveillance Programme, residual plasma samples of treatment-naïve HIV-1 positive individuals were tested using the biotinylated peptide-capture enzyme immunoassay with a cutoff of normalized optical density ≤ 0.8 for evidence of RHI. A recent infection testing algorithm was applied for the classification of RHI. We identified risk factors associated with RHI using logistic regression analyses.

Results

A total of 701 newly-diagnosed HIV-infected persons were included in the study. The median age at HIV diagnosis was 38 years (interquartile range, 28–51). The majority were men (94.2%), and sexual route was the predominant mode of HIV transmission (98.3%). Overall, 133/701 (19.0, 95% confidence interval [CI] 16.2–22.0%) were classified as RHI. The proportions of RHI in 2015 (31.1%) and 2017 (31.0%) were significantly higher than in 2014 (11.2%). A significantly higher proportion of men having sex with men (23.4, 95% CI 19.6–27.6%) had RHI compared with heterosexual men (11.1, 95% CI 7.6–15.9%). Independent factors associated with RHI were: age 15–24 years (adjusted odds ratio [aOR] 4.18, 95% CI 1.69–10.31) compared with ≥55 years; HIV diagnosis in 2015 (aOR 2.36, 95% CI 1.25–4.46) and 2017 (aOR 2.52, 95% CI 1.32–4.80) compared with 2013–2014; detection via voluntary testing (aOR 1.91, 95% CI 1.07–3.43) compared with medical care; and self-reported history of HIV test(s) prior to diagnosis (aOR 1.72, 95% CI 1.06–2.81).

Conclusion

Although there appears to be an increasing trend towards early diagnosis, persons with RHI remain a minority in Singapore. The strong associations observed between modifiable behaviors (voluntary testing and HIV testing history) and RHI highlight the importance of increasing the accessibility to HIV testing for at-risk groups.
Effects of body mass index and range of motion on intraoperative change in pelvic tilt during total hip arthroplasty using the direct anterior approach
Authors: Okamoto Masanori , Kawasaki Masashi , Okura Toshiaki , Seki Taisuke , Imagama Shiro
Published: March 2021

Background

Intraoperative pelvic tilt changes that occurs during total hip arthroplasty (THA) in the supine position affects cup placement and sometimes causes malalignment. The relationship between body mass index (BMI) and pelvic movement has been reported for some procedures, but not the direct anterior approach (DAA). The purpose of this study was to investigate intraoperative pelvic tilt changes that occurs during DAA.

Methods

In this single-center, retrospective study, we reviewed 200 hips that underwent primary THA via DAA in the supine position using an accelerometer-based navigation system. Intraoperative changes in pelvic tilt and axial rotation from the start of surgery to cup placement were assessed using the navigation system. Preoperative clinical factors that increased pelvic tilt and axial rotation toward the surgical side by > 10° were analyzed via univariate and multiple logistic regression analyses.

Results

The mean pelvic tilt value increased by 7.6° ± 3.8° (95% confidence interval [CI], 7.1–8.2; range, − 5.0–19.0) intraoperatively, and the axial rotation increased by 3.2° ± 2.7° (95% CI, 2.7–3.7; range, − 13.0–12.0). Univariate analysis revealed that the group with increased pelvic tilt showed significantly greater range of abduction and internal rotation, and significantly lower BMI than the group with no increased tilt. Pre-incisional pelvic tilt was significantly greater in the group with increased axial rotation than in the group with no increased rotation. On logistic regression analysis, BMI (odds ratio [OR], 0.889; 95% CI, 0.809–0.977; p = 0.014) and the range of internal rotation (OR, 1.310; 95% CI, 1.002–1.061; p = 0.038) were predictors of large increases in pelvic tilt. No predictors of large increases in axial rotation were identified.

Conclusion

Significant forward pelvic tilt was observed in patients with a low BMI values and high ranges of internal rotation via THA using the DAA. Findings indicated that surgeons should pay attention to intraoperative pelvic movements, which may help identify patients with significant pelvic tilt changes.
Three-dimensional evaluation of the effects of injectable platelet rich fibrin (i-PRF) on alveolar bone and root length during orthodontic treatment: a randomized split mouth trial
Authors: Zeitounlouian Talar S. , Zeno Kinan G. , Brad Bassel A. , Haddad Rania A.
Published: March 2021

Background

The role of injectable platelet rich fibrin (i-PRF) in orthodontic treatment has not been investigated with focus on its effect on dental and bony periodontal elements.

Objective

To evaluate the efficacy of i-PRF in bone preservation and prevention of root resorption.

Methods

A randomized split-mouth controlled trial included 21 patients aged 16–28 years (20.85 ± 3.85), who were treated for Class II malocclusion with the extraction of the maxillary first premolars. Right and left sides were randomly allocated to either experimental treated with i-PRF or control sides. After the leveling and alignment phase, the canines were retracted with 150gm forces. The i-PRF was prepared from the blood of each patient following a precise protocol, then injected immediately before canine retraction on the buccal and palatal aspects of the extraction sites. Localized maxillary cone beam computed tomography scans were taken before and after canine retraction to measure alveolar bone height and thickness and canine root length (indicative of root resorption), and the presence of dehiscence and fenestration. Paired sample t-tests and Wilcoxon signed rank tests were used to compare the changes between groups.

Results

No statistically significant differences in bone height, bone thickness were found between sides and between pre- and post-retraction period. However, root length was reduced post retraction but did not differ between sides. In both groups, postoperative dehiscence was observed buccally and palatally and fenestrations were recorded on only the buccal aspect.

Conclusions

I-PRF did not affect bone quality during canine retraction or prevent canine root resorption. I-PRF did not reduce the prevalence of dehiscence and fenestration.

Trial registration ClinicalTrials.gov (identifier number: NCT 03399760. 16/01/2018).
Inducing a sense of worthiness in patients: the basis of patient-centered palliative care for cancer patients in Iran
Authors: Aghaei Mir Hossein , Vanaki Zohreh , Mohammadi Eesa
Published: March 2021

Background

Patient-centered care is one of the main components in providing palliative care for cancer patients. This issue has been the subject of numerous studies and practices in nursing for many years. Few studies, however, have explored the perception of nurses about patient-centered treatments. This study aimed at exploring the perception of care-providers about offering patient-centered care to cancer patients.

Method

For attaining that aim, 18 care-providers were purposefully selected for an interview which allowed the researchers to explore the enriched experiences of these participants about offering patient-centered palliative care to cancer patients. After transcribing the recorded data, analysis was carried out based on Graneheim and Lundman’s method of content analysis. The research was qualitative in nature and conducted in 2019 in Iran.

Results

From content analysis, 3 main categories; considering patient’s spirituality, maintaining patient’s dignity during care, and reducing patient’s suffering, were found. The essence of these categories reflect on the care-providers’ consideration and effort in “inducing a sense of worthiness”in patients by providing patient-centered care. These categories also reflect on the perspective of care-providers about nurse- patient relationship for providing high qualified palliative care.

Conclusion

For providing patient-centered care inducing a sense of worthiness in patients, is the most fundamental component in providing palliative care to cancer patients. Therefore, by considering the structures and settings where the care is to be provided in the healthcare system, it is possible to direct the necessary educational, research, and administrative programs related to inducing a sense of worthiness in patients towards providing a more effective palliative care.
Improving l-threonine production in Escherichia coli by elimination of transporters ProP and ProVWX
Authors: Wang Shuaiwen , Fang Yu , Wang Zhen , Zhang Shuyan , Wang Liangjia , Guo Yong , Wang Xiaoyuan
Published: March 2021

Background

Betaine, an osmoprotective compatible solute, has been used to improve l-threonine production in engineered Escherichia colil-threonine producer. Betaine supplementation upregulates the expression of zwf encoding glucose-6-phosphate dehydrogenase, leading to the increase of NADPH, which is beneficial for l-threonine production. In E. coli, betaine can be taken through ProP encoded by proP or ProVWX encoded by proVWX. ProP is a H+-osmolyte symporter, whereas ProVWX is an ABC transporter. ProP and ProVWX mediate osmotic stress protection by transporting zwitterionic osmolytes, including glycine betaine. Betaine can also be synthesized in E. coli by enzymes encoded by betABIT. However, the influence of ProP, ProVWX and betABIT on l-threonine production in E. coli has not been investigated.

Results

In this study, the influence of ProP, ProVWX and betABIT on l-threonine production in E. coli has been investigated. Addition of betaine slightly improved the growth of the l-threonine producing E. coli strain TWF001 as well as the l-threonine production. Deletion of betABIT retarded the growth of TWF001 and slightly decreased the l-threonine production. However, deletion of proP or/and proVWX significantly increased the l-threonine production. When proP was deleted, the l-threonine production increased 33.3%; when proVWX was deleted, the l-threonine production increased 40.0%. When both proP and proVWX were deleted, the resulting strain TSW003 produced 23.5 g/l l-threonine after 36 h flask cultivation. The genes betABIT, proC, fadR, crr and ptsG were individually deleted from TSW003, and it was found that further absence of either crr (TWS008) or ptsG (TWS009) improved l-threonine production. TSW008 produced 24.9 g/l l-threonine after 36 h flask cultivation with a yield of 0.62 g/g glucose and a productivity of 0.69 g/l/h. TSW009 produced 26 g/l l-threonine after 48 h flask cultivation with a yield of 0.65 g/g glucose and a productivity of 0.54 g/l/h, which is 116% increase compared to the control TWF001.

Conclusions

In this study, l-threonine-producing E. coli strains TSW008 and TSW009 with high l-threonine productivity were developed by regulating the intracellular osmotic pressure. This strategy could be used to improve the production of other products in microorganisms.
Consequences of exposure to prenatal famine on estimated glomerular filtration rate and risk of chronic kidney disease among survivors of the great Ethiopian famine (1983–85): a historical cohort study
Authors: Abate Kalkidan Hassen , Abdulahi Misra , Abdulhay Fedlu , Arage Getachew , Mecha Mohammed , Yenuss Mohammed , Hassen Habtamu , Belachew Tefera
Published: March 2021

Background

The impact of an adverse prenatal environment such as famine exposure on the development of adulthood non-communicable chronic illnesses, including diabetes and hypertension has been well articulated in the recent past and supported by evidence. However, there exist few longitudinal studies conducted on the long term consequences of prenatal famine exposure on adulthood kidney function. Hence, we set out to examine whether prenatal exposure to the Ethiopian Great Famine (1983–1985) was associated with changes in estimated glomerular filtration rate (eGFR) and the risk of developing chronic kidney disease (CKD) later in adult life.

Methods

The study was conducted in 219 famine exposed and 222 non exposed cohorts in Raya Kobo district, North Wollo Zone, Northern Ethiopia. Estimated GFR was computed from standardized serum creatinine using the CKD Epidemiology Collaboration (CKD-EPI) equation. The definition of CKD includes those with an eGFR of less than 60 ml/min/1.73 m2 on at least in two occasions of 90 days apart (with or without markers of kidney damage). Linear and logistic regression analyses were employed to examine the independent effect of prenatal famine exposure on eGFR and CKD respectively.

Results

The mean (SD) serum creatinine of exposed and non-exposed groups were 0.78 (0.2) and 0.75 (0.2) respectively. The mean (SD) eGFR of exposed groups was 107.95 (27.49) while the non-exposed 114.48 (24.81) ml/min. In linear regression, the unadjusted model to examine the association between famine exposure and eGFR resulted in a significant negative beta coefficient (β = − 0.124: 95% CI: − 11.43, − 1.64). Adjusting the exposure for outstanding covariates of kidney health, including systolic blood pressure, fasting blood sugar and blood glucose did not alter the inverse relationship (β = −.114 95% CI: − 10.84, − 1.17). In the unadjusted bivariate logistic regression model, famine exposure resulted in nearly 2.7 times higher odds of developing CKD (OR: 2.68, 95% CI: 1.16, 6.2). The odds remained equivalent after adjusting for systolic blood pressure, fasting blood glucose and body mass index (OR = 2.61: 95% CI: 1.120, 6.09).

Conclusion

In the study setting, prenatal exposure to the Great Ethiopian Famine was associated with decreased eGFR and higher risk of developing CKD among survivors. These findings may imply that famine in early life may play a significant role in the development of kidney dysfunction in adulthood.
The relationship between depression and risk of metabolic syndrome: a meta‐analysis of observational studies
Authors: Moradi Yousef , Albatineh Ahmed N , Mahmoodi Hassan , Gheshlagh Reza Ghanei
Published: March 2021

Introduction

The link between metabolic syndrome and depression has always been controversial. Different studies that have examined the relationship between metabolic syndrome and depression have reported different results. Therefore, the goal of the present study was to examine the association between depression and MetS by meta-analysis.

Methods

Embase, Scopus, PubMed, and ISI were searched for publications in English from January 1990 to February 2020. Search included cohort and cross-sectional studies aimed at examining the association between depression and MetS. The risk of bias was assessed by Newcastle-Ottawa Scale. Heterogeneity and publication bias were tested, subgroup analysis and meta-regression were conducted.

Results

49 studies with total sample size 399,494 were analyzed. Results indicated the odds of MetS was higher in depressed compared to non-depressed individuals [OR: 1.48; 95 %CI: 1.33–1.64) vs. (OR: 1.38; 95 %CI: 1.17–1.64)]. For cross-sectional studies, depressed patients in Europe (OR = 1.35; 95 %CI: 1.47–1.99) were at higher odds of MetS compared to those in America and Asia. For cohort studies, depressed patients in America (OR = 1.46; 95 %CI: 1.16–1.84) were at higher odds of MetS than those in Europe. Cross-sectional studies indicated women with depression were at higher odds of MetS (OR = 1.95; 95 %CI: 1.38–2.74) compared to men. In both types of studies, the odds of MetS decreased with age.

Conclusions

Metabolic syndrome is more common in depressed compared to non-depressed individuals.
Population dynamics of some domestic mites in laboratory culture
Authors: Ammar A. M. , El Zayyat E. A. , Khayyal A. E. , Elleboudy N. A.
Published: March 2021

Background

Domestic mites are a primary source of allergens indoors all over the world. Extracts of mite allergens are important for diagnosing and treating mites allergy. The effective cultivation processes play a critical role in the final composition of mites' allergen extracts. In order to produce large amounts of antigens of domestic mites, culture techniques of domestic mites were studied. Domestic mites were isolated from collected dust samples and cultured on a fine-ground mixture of dust and sawdust (2:1). While dry yeast, wheat germ, and cornflour were used at a ratio of 2:1:1 for nutrition. Food was placed over a few centimeters of cement base that had been placed on the bottom of the rearing containers. The population growth rates were determined.

Results

Successful methods for mite cultures utilize high protein and carbohydrate foods, an average temperature of (25 ± 2) °C and relative humidity (80 ± 5) %. During a 14-week observation period of mites' culture, the peak in number was obtained after 8 weeks of the culture in Tyrophagus, 10 weeks in Dermatophagoides, and 12 weeks in Blomia; thereafter, the number decreased. Significant differences were found in the growth rates of Dermatophagoides (P = 0.02) and Blomia (P = 0.03) in between pure and mixed cultures.

Conclusions

The modifications made to the mixture of diet used for cultivation showed a high yield of domestic mites. Also, the cement layer also is an excellent way to make space for egg laying and prevent mites from escaping.
Prescribing patterns in patients with metastatic castrate-sensitive prostate cancer (mCSPC).
Authors: Mar Nataliya , Forsyth Michael
Published: March 2021

21

Background: Recent advances and approvals in mCSPC treatment offer improved outcomes. Docetaxel chemotherapy as well as novel hormonal therapies (NHT) including abiraterone, apalutamide and enzalumide are preferred regimens in addition to androgen deprivation therapy (ADT), with category 1 evidence supporting their use. Despite lack of consensus regarding use of first-generation anti-androgens (fgAI) aside from tumor flare prevention, they are still frequently prescribed. This multitude of options may lead to disparities in prescribing patterns. Methods: Retrospective analysis of pharmacy and medical claims data from the IQVIA database was performed. Patients were aged >18 years and had an ICD 9/10 diagnosis of metastatic prostate cancer (PCa) with >1 treatment claim. Patients on active therapy for another primary malignancy as well as those with <12 months of data pre- and <9 months post-first PCa-related event were excluded. Data was collected from 1/1/2015 to 6/30/2020. Treatment categories were classified as NHT, fgAI, chemotherapy, or ADT monotherapy. Results: National (N) and state of California (S) prescribing patterns are provided in Table. Nationally, Medicare reimbursed 16% NHT, 30% fgAI, 2% chemotherapy and 52% ADT, while third-party payers reimbursed 18% NHT, 20% fgAI, 3% chemotherapy and 59% ADT in 2020. State of California 2020 data yielded similar reimbursement patterns. In Southern California, academic centers prescribed 31% NHT, 23% fgAI and 46% ADT, while community-based practices prescribed 7% NHT, 36% fgAI and 57% ADT in 2020. In Southern California, community oncology practices prescribed 12% NHT, 40% fgAI, 2% chemotherapy and 44% ADT, while community urology practices prescribed 2% NHT, 38% fgAI, and 59% ADT in 2020. Data from 2015-2019 was similar. Conclusions: Although NHT utilization is increasing while chemotherapy utilization is declining, only a minority of mCSPC men received these therapies in 2020. Most of mCSPC men still receive ADT monotherapy or fgAI. Type of insurance carrier does not appear to affect prescribing patterns. Dramatic variations across treatment settings and different specialties exist, with academic centers prescribing more NHT than community-based practices and oncology practices prescribing more NHT than urology practices. These disparities should be addressed with provider education to standardize care delivery for mCSPC patients. [Table: see text]
Intraprostatic calcification and biochemical recurrence in men treated with Cs-131 prostate brachytherapy.
Authors: Schad Michael D , Rodríguez-López Joshua L , Patel Ankur , Houser Christopher J , Horne Zachary D , Benoit Ronald M , Smith Ryan P , Beriwal Sushil
Published: March 2021

237

Background: Vigneault et al. reported that baseline intraprostatic calcification (IC) was associated with a higher risk of biochemical recurrence (BCR) in men treated with I-125 prostate brachytherapy (PB). Cs-131 has different physical properties than I-125. We assessed whether baseline IC was associated with BCR in men treated with Cs-131 PB. Methods: We retrospectively reviewed the records of all low-risk (LR), favorable intermediate-risk (FIR), and unfavorable IR (UIR) prostate cancer patients treated with Cs-131 PB +/- external beam radiotherapy (EBRT) from 2/2011 to 7/2018 at our institution. Patients who received hormone therapy or those with < 24 months follow-up were excluded. Baseline IC status (defined as 1 or more ICs ≥ 5 mm) and characteristics were determined on post-PB CT scans. Baseline patient characteristics were compared via χ2, Mann–Whitney U, or Student’s t-test. Predictors of BCR (Phoenix definition) were analyzed via Cox proportional hazards model and Kaplan–Meier survival curves were generated. Results: Two hundred and sixteen LR, FIR, and UIR prostate cancer patients treated with Cs-131 PB +/- EBRT were included. Median follow up was 56.9 months (range 24.1–111.4 months). 76 patients (35.2%) had baseline IC and 140 patients (64.8%) did not. Baseline disease characteristics did not differ significantly between patients with vs. without ICs. In patients with baseline IC, the median number of ICs was 1 (range 1–3), median length of largest IC was 9.1 mm (range 5.0–33.1), and median peak density of largest IC was 884 Hounsfield units (range 283–1744). ICs were most commonly present in the midgland (88.2%) and central (97.4%) regions. On univariate Cox analysis of all baseline disease, treatment, and IC characteristics, only initial PSA (p = 0.016) and NCCN risk group (p = 0.047) were significant predictors of BCR, whereas baseline IC was not (p = 0.11). The 5-year BCR-free survival in patients with vs. without baseline IC was 97.7% vs. 93.8% (p = 0.40), respectively. Conclusions: In a cohort of LR and IR prostate cancer patients treated with Cs-131 PB, the rate of BCR in men with baseline IC was low and baseline IC was not associated with a higher risk of BCR.
Peri-operative morbidity and mortality in a modern series of patients treated with cytoreductive nephrectomy (CN) at five centers.
Authors: Esdaille Ashanda Rosetta Patrice , Karam Jose A. , Spiess Philippe E. , Raman Jay D. , Shapiro Daniel D. , Sharma Pranav , Sexton Wade J. , Zemp Logan , Bilotta Alyssa , Allen Glenn O. , Matin Surena F. , Wood Christopher G. , Abel Edwin J
Published: March 2021

268

Background: For metastatic renal cell cancer (mRCC) patients considering cytoreductive nephrectomy (CN), perioperative morbidity is important to discuss but few contemporary multi-institutional data are available. The objective of this study is to describe factors associated with perioperative outcomes in a modern multi-institutional cohort of patients treated with cytoreductive nephrectomy. Methods: Data for perioperative complications was recorded for patients treated with CN at 5 centers from 2005-2019. Postoperative complications within 90 days were categorized using Clavien- Dindo system. Univariate and multivariable analysis was used to evaluate for associations with complications and 90-day mortality. Factors evaluated included receipt of pre-surgical systemic therapy, ECOG performance status (PS), Charlson comorbidity index (CCI), concurrent IVC thrombectomy, age, and surgical approach (open vs. laparoscopic/robotic). Results: Perioperative outcomes were evaluated in 937 consecutive patients treated with CN at 5 institutions from 2005-2019. Median age at surgery was 61 years (IQR 53-68) and median tumor diameter was 9.8cm (IQR 7-12).Venous thrombus was present in 406/937 (43.3%) patients overall including 65/406 (16%) patients for whom IVC thrombus extended above the hepatic veins. Open and laparoscopic/robotic approach was used in 715 (76.3%) and 290 (23.4%) patients. The median ECOG PS was 1 (IQR 0-1) and median CCI was 1 (IQR 0-2). Pre-surgical systemic therapy was given to 243 (25.9%) patients prior to CN. The median length of hospital stay was 5 days (IQR 4-7) and 429 (34.6%) received blood transfusion. Median length of stay was 3.0 (IQR 2-4) for laparoscopic/robotic approach and 6 days (IQR 4-8) for patients with IVC thrombectomy. Hospital readmission within 30 days was identified in 112 (9.0%) patients. A total of 93/937 (9.9%) patients had major (≥Clavien 3) complications identified within 90 days postoperatively. On multivariable analysis, IVC thrombectomy was associated with higher risk of major complications OR 1.95 (95% CI 1.2-3.1), p = 0.006. Pre-surgical systemic therapy, ECOG PS, CCI, age and surgical approach were not associated with major complications (p = 0.09-0.85). Perioperative mortality was 12/937 (1.3%) at 30 days and 51/937 (6.7%) at 90 days. After multivariable analysis, pre-surgical systemic therapy, ECOG PS, CCI, age, and IVC thrombectomy were not associated with perioperative mortality (p = 0.1-0.85). Conclusions: Cytoreductive nephrectomy is associated with major complications for 10% of patients and 1% mortality at 30 days. Pre-surgical systemic therapy was not associated with increased risk of complications or mortality.
Radiomic features of renal cell carcinoma primary and metastatic sites as predictors of TERT and BAP1 mutations.
Authors: Meza Luis A , Filippov Aleksandr , Naim Sohaib , Dizman Nazli , Chehrazi-Raffle Alex , Philip Errol James , Maholtra Jasnoor , Muddasani Ramya , Chawla Neal Shiv , Wong Chi Wah , Salgia Sabrina , Karimi Misagh , Trent Jeffrey M. , Byron Sara Ann , Chaudhry Ammar , Pal Sumanta K.
Published: March 2021

282

Background: TERT and BAP1 mutations are associated with poor clinical outcome in patients (pts) with metastatic renal cell carcinoma (mRCC) (Dizman et al JITC 2020; Joseph et al J Urol 2016). In this study we explore radiogenomics as a non-invasive method to identify these alterations. Methods: Pts with mRCC who had genomic testing in the course of routine clinical care were included in the current analysis. Pts were assessed with the GEM Extra assay, a CAP-accredited, CLIA-certified test encompassing paired tumor-normal whole exome sequencing (WES) and tumor whole transcriptome sequencing (TGen; Phoenix, AZ). Pts underwent CT imaging; radiomic analysis was performed on the segmented metastatic and primary lesions. Features were independently correlated with TERT and BAP1 mutation status to generate Pearson correlation values (PCVs). Results: 92 pts (65:27 M: F) were included in the analysis; of these, the majority of pts (84%) had clear cell histology. Alterations in the TERT gene were seen in 12 pts. In these pts 1,325 radiomic features of the primary tissue were examined and 251 features correlated with a PCV ≥ |0.2|. Of these, 42 features were correlated with a PCV ≥ |0.3|. Highest correlation with TERT mutation was seen with Gray Level Cooccurrence Matrix (GLCM) and First Order Features (FOF). 9 pts had BAP1 mutation with 5 detected in primary tumor and 4 in metastatic sites. Analysis of primary tumor imaging yielded no significant associations between radiomic features and BAP1 mutation. However, out of approximately 1,500 radiomic features noted in metastatic sites, 111 features correlated with BAP1 mutation with a PCV ≥ 0.2. Of these, 15 features correlated with a PCV ≥ 0.3. The radiomic features with the highest correlation with BAP1mt were Gray Level Dependence Matrix (GLDM) and GLCM. Conclusions: By identifying a correlation between radiomic features of TERT mutation in primary tumors and BAP1 mutation in metastatic sites, our work may ultimately yield a non-invasive method of discerning mutational status in patents with mRCC. Efforts are ongoing to validate our findings within The Cancer Imaging Archive.
Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: The CheckMate 9ER trial.
Authors: Cella David , Choueiri Toni K. , Blum Steven I. , Ejzykowicz Flavia , Hamilton Melissa , Zhang Joshua , Ivanescu Cristina , Motzer Robert J.
Published: March 2021

285

Background: In the phase III, open-label CheckMate 9ER trial (NCT03141177), patients with aRCC were randomized 1:1 (stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk score, tumor programmed death ligand 1 expression, geographic region) to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328) for first-line treatment until disease progression or unacceptable toxicity (max N treatment, 2 years). N+C met primary and secondary efficacy endpoints by significantly improving progression-free survival, overall survival, and objective response rate versus S in aRCC patients with a clear cell component. Here, we present in-depth health-related quality of life (HRQoL) patient-reported outcome (PRO) results, including overall between-group comparisons of treatment groups and time to confirmed deterioration (TCD). Methods: PROs in all randomized patients were an exploratory endpoint assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and EQ-5D-3L instruments. PRO assessments at baseline, common on-treatment scheduled visits, and common follow-up visits for both arms were analyzed. Changes from baseline were assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors. TCD was calculated from Kaplan–Meier estimates and Cox proportional hazards models. Results: Median follow-up for overall survival was 18.1 months. PRO completion rates were > 90% at baseline, and ≥ 80% at all on-treatment assessments (≥ 10 patients) through week 91 in both arms. The overall least squares mean difference in change from baseline favored N+C over S in FKSI-19 (all domains) and in EQ-5D-3L. Patients treated with N+C experienced less treatment burden, with decreased risk of confirmed deterioration across most measurements versus S, including FKSI-19 total, disease-related symptoms (DRS), DRS-physical (DRS-P), DRS-emotional (DRS-E), functional well-being (FWB), and EQ-5D-3L visual analog scale (VAS) scores (Table). Conclusions: Patients reported statistically significant HRQoL benefits with N+C versus S. Treatment with N+C significantly reduced the risk of deterioration in HRQoL scores, including in disease-related symptoms of kidney cancer. These results suggest that the superior efficacy of N+C over S comes with the additional benefit of improved HRQoL. Clinical trial information: NCT03141177 . [Table: see text]
Analysis of plasma KIM-1 as a biomarker for recurrence risk after resection for localized renal cell carcinoma.
Authors: Xu Wenxin , Puligandla Maneka , Halbert Brian , Haas Naomi B. , Flaherty Keith , Uzzo Robert Guy , Dutcher Janice P. , DiPaola Robert S. , Sabbisetti Venkata , Bhatt Rupal Satish
Published: March 2021

342

Background: Recurrence is common after nephrectomy for renal cell carcinoma (RCC), but no circulating biomarkers are available to identify patients at highest risk of recurrence who may benefit from adjuvant therapy. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. Methods: Banked plasma samples were analyzed from the ECOG-ACRIN 2805 (ASSURE) trial evaluating adjuvant sunitinib, sorafenib, and placebo in resected high-risk RCC. KIM-1 levels were measured at trial enrollment 4-12 weeks post-nephrectomy (baseline) and on cycle 2 day 1 (C2D1) using a previously validated microbead assay. A lognormal accelerated failure time model was used to test for association between circulating KIM-1 and disease-free survival (DFS). Results: Plasma samples from 418 patients were analyzed. In univariable and multivariable analyses, higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms. This association remained independently significant after adjustment for Fuhrman grade, T-stage, N-stage, and tumor histology (survival time ratio 0.56 for 75th vs 25th percentile of KIM-1, 95% CI 0.42-0.73, p < 0.001). The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement. The addition of baseline KIM-1 improved the concordance of both the SSIGN and UISS prognostic models (SSIGN concordance 0.57 vs 0.43, p = 0.05; UISS concordance 0.60 vs 0.40, p = 0.0005). C2D1 KIM-1 was not an independent predictor for DFS after adjusting for baseline KIM-1. Conclusions: Elevated plasma KIM-1 level at post-nephrectomy baseline is associated with worse DFS in RCC. This is consistent with the hypothesis that post-nephrectomy plasma KIM-1 may be a biomarker for microscopic residual disease. The model was additionally adjusted for papillary and chromophobe histology, sex, and ECOG performance status. [Table: see text]
Social disparities in the diagnosis and management of bladder cancer.
Authors: Hasan Shaakir , Lazarev Stanislav , Garg Madhur , Press Robert H. , Chhabra Arpit , Choi Isabelle , Simone Charles B. , Gorovets Daniel , Mehta Keyur J.
Published: March 2021

403

Background: The socioeconomic characteristics associated with the diagnosis and management of bladder cancer are not well described. Methods: We utilized the National Cancer Database (NCDB) to stratify cases of urothelial cell carcinoma of the bladder by the National Comprehensive Cancer Network (NCCCN) guidelines: early (Tis, Ta, T1), muscle invasive (T2-T3, N0), locally advanced (T4, N1-3), and metastatic. We then used multivariate binomial and multinomial logistic regression analyses to identify demographic characteristics associated with stage at diagnosis and receipt of cancer-directed therapies. Hazard ratios (HR) are reported with 95% confidence intervals. Results: After exclusions, we identified 331,714 early, 72,154 muscle invasive, 15,579 locally advanced, and 15,161 metastatic cases. Relative to diagnosis at early stage, the two strongest independent predictors of diagnosis at muscle invasive, locally advanced, and metastatic disease included black race (HR = 1.19 [1.15-1.23], HR = 1.49 [1.40-1.59], HR = 1.66 [1.56-1.76], respectively), and female gender (HR = 1.21 [1.18-1.21], HR = 1.16 [1.12-1.20], and HR = 1.34 [1.29-1.38], respectively). Additional demographic factors associated with diagnosis at a more advanced stage on multivariable analysis included older age, treatment at an academic center (except for metastasis), Medicaid insurance, and patients from lower income/ less educated/more rural areas (all p < 0.01). The following demographic factors were less likely to receive cancer-directed therapies, signified by odds ratios, per multivariable binomial regression analysis: Additionalyl, female patients (HR = 1.03, 1.02-1.05) and black patients (HR = 1.13, 1.11-1.16) were the only demographic correlates of reduced survival in the entire cohort with multivariable cox regression analysis. Conclusions: In the largest study of its kind, we report that several socioeconomic, racial, and gender factors are associated with the diagnosis of bladder cancer at a later stage, as well as the use of less cancer-directed treatments. Further investigation is warranted to better characterize, and ultimately improve upon, health disparities in bladder cancer. Research Sponsor: None[Table: see text]
Post-hoc analysis of long-term outcomes in patients with CR, PR, or SD to pembrolizumab (pembro) or platinum-based chemotherapy (chemo) as 1L therapy for advanced urothelial carcinoma (UC) in KEYNOTE-361.
Authors: Loriot Yohann , Alva Ajjai Shivaram , Csőszi Tibor , Ozguroglu Mustafa , Matsubara Nobuaki , Geczi Lajos , Cheng Susanna Y. , Fradet Yves , Oudard Stephane , Vulsteke Christof , Morales-Barrera Rafael , Flechon Aude , Gunduz Seyda , Rodriguez-Vida Alejo , Mamtani Ronac , Yu Evan Y. , Liu Chih-Chin , Imai Kentaro , Homet Moreno Blanca , Powles Thomas
Published: March 2021

435

Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]
Heterogeneity in Nectin-4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin.
Authors: Chu Carissa , Sjöström Martin , Egusa Emily A , Gibb Ewan , Badura Michelle L , Koshkin Vadim S , Stohr Bradley A. , Meng Maxwell , Pruthi Raj , Friedlander Terence W. , Lotan Yair , Black Peter C. , Porten Sima P. , Feng Felix Y , Chou Jonathan
Published: March 2021

463

Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting Nectin-4 (encoded by the PVRL4/NECTIN4 gene ) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In the present study, we sought to 1) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and 2) determine if Nectin-4 expression mediates EV sensitivity or resistance. Methods: NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1912 total patients) were used to compare relative NECTIN4 expression across molecular subtypes. The outcome of the gene expression analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in multiple bladder cancer cell lines. NECTIN4 was stably over-expressed or knocked down in basal (TCCSUP and UMUC-3) and luminal (HT-1376, HT-1197 and UMUC-9) bladder cancer cell lines, respectively, and EV dose-response assays were performed, as measured by cell proliferation and clonogenic assays. Results: NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes (p < 0.001). NECTIN4 expression is positively correlated with the luminal markers GATA3, FOXA1, and PPARG across cohorts (Spearman’s rank correlation r = 0.57, p < 0.0001 for GATA3, r = 0.37, p < 0.0001 for FOXA1, and r = 0.56, p < 0.0001 for PPARG). NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 led to EV resistance, and EV-resistant cell lines expressed decreased levels of Nectin-4. Conclusions: Results of this pre-clinical study suggest that sensitivity to EV is mediated by expression of NECTIN4, which is significantly enriched in luminal subtypes of bladder cancer. Downregulation of NECTIN4 leads to resistance to EV. These findings have implications for biomarker development, patient selection and the inclusion of molecular subtyping in ongoing and future EV clinical trials. Further investigation into Nectin-4 loss as a mechanism of resistance in patients treated on EV is warranted.
A developmental lineage-based gene co-expression network for mouse pancreatic β-cells reveals a role for Zfp800 in pancreas development
Authors: Osipovich Anna B. , Dudek Karrie D. , Greenfest-Allen Emily , Cartailler Jean-Philippe , Manduchi Elisabetta , Potter Case Leah , Choi Eunyoung , Chapman Austin G. , Clayton Hannah W. , Gu Guoqiang , Stoeckert Christian J. , Magnuson Mark A.
Published: March 2021

To gain a deeper understanding of pancreatic β-cell development, we used iterative weighted gene correlation network analysis to calculate a gene co-expression network (GCN) from 11 temporally and genetically defined murine cell populations. The GCN, which contained 91 distinct modules, was then used to gain three new biological insights. First, we found that the clustered protocadherin genes are differentially expressed during pancreas development. Pcdhγ genes are preferentially expressed in pancreatic endoderm, Pcdhβ genes in nascent islets, and Pcdhα genes in mature β-cells. Second, after extracting sub-networks of transcriptional regulators for each developmental stage, we identified 81 zinc finger protein (ZFP) genes that are preferentially expressed during endocrine specification and β-cell maturation. Third, we used the GCN to select three ZFPs for further analysis by CRISPR mutagenesis of mice. Zfp800 null mice exhibited early postnatal lethality, and at E18.5 their pancreata exhibited a reduced number of pancreatic endocrine cells, alterations in exocrine cell morphology, and marked changes in expression of genes involved in protein translation, hormone secretion and developmental pathways in the pancreas. Together, our results suggest that developmentally oriented GCNs have utility for gaining new insights into gene regulation during organogenesis.
Development and Validation of a Nomogram Prognostic Model for Resected Limited-Stage Small Cell Lung Cancer Patients
Authors: Zeng Qingpeng , Li Jiagen , Tan Fengwei , Sun Nan , Mao Yousheng , Gao Yushun , Xue Qi , Gao Shugeng , Zhao Jun , He Jie
Published: March 2021

Background

In this study, we developed and validated nomograms for predicting the survival in surgically resected limited-stage small cell lung cancer (SCLC) patients.

Methods

The SCLC patients extracted from the Surveillance, Epidemiology, and End Results database between 2000 and 2014 were reviewed. Significant prognostic factors were identified and integrated to develop the nomogram using multivariable Cox regression. The model was then validated internally by bootstrap resampling, and externally using an independent SCLC cohort diagnosed between 2000 and 2015 at our institution. The prognostic performance was measured by the concordance index (C-index) and calibration curve.

Results

A total of 1006 resected limited-stage SCLC patients were included in the training cohort. Overall, 444 cases from our institution constituted the validation cohort. Seven prognostic factors were identified and entered into the nomogram construction. The C-indexes of this model in the training cohort were 0.723, 0.722, and 0.746 for predicting 1-, 3-, and 5-year overall survival (OS), respectively, and 0.816, 0.710, and 0.693, respectively, in the validation cohort. The calibration curve showed optimal agreement between nomogram-predicted survival and actual observed survival. Additionally, significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed. The proposed nomogram was then deployed into a website server for convenient application.

Conclusions

We developed and validated novel nomograms for individual prediction of survival for resected limited-stage SCLC patients. These models perform better than the previously widely used staging system and may offer clinicians instructions for strategy making and the design of clinical trials.
Environmental epidemiology and risk assessment
Authors: Hmara Ivan , Strel'nikov Viktor
Published: March 2021

The material presented in the textbook is based on modern ideas about environmental epidemiology as an interdisciplinary field of knowledge, the purpose of which is a multi — level study of the "environment-human health"system. Special attention is paid to the issues of risk assessment as an integral part of ecoepidemiological research. It corresponds to the program of the discipline "Environmental Epidemiology", approved by the Scientific and Methodological Council for Environmental Education of UMO Universities. For students in the field of training 05.03.06 "Ecology and nature management", as well as related biological, environmental and medical areas and specialists of the relevant work profiles.
Generally recognized principles and norms of international law: the concept and problems of application in the Russian Federation
Authors: Maksurov Aleksey
Published: March 2021

The monograph reflects the results of the author's research on the application of generally recognized principles and norms of international law in the Russian Federation, including taking into account the current changes in the Constitution of the Russian Federation. It will be useful for scientists and students (postgraduates) - lawyers, political scientists, sociologists, as well as practicing lawyers in all areas of law, specialists in the field of state and municipal law and management, international law.
Geographical expertise of Russia's economic development strategies
Authors: Blanuca Viktor
Published: March 2021

Thanks to the development of K. P. Kosmachev's ideas on the geographical expertise of the information base of the economic development projects of the territory, five new areas of expert geographical research are proposed. They are used to analyze the "Spatial Development Strategy of the Russian Federation for the period up to 2025", the "Digital Economy of the Russian Federation" program and the "National Strategy for the Development of Artificial Intelligence for the period up to 2030". Many contradictions are revealed and the latent meaning of each document is determined. The results obtained can be used to adjust existing and develop new strategies for Russia's economic development. It is intended for specialists, students and postgraduates.