Tag: pubmed

Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):e2020562118. doi: 10.1073/pnas.2020562118.

ABSTRACT

Intrinsically disordered proteins (IDPs) interact with globular proteins through a variety of mechanisms, resulting in the structurally heterogeneous ensembles known as fuzzy complexes. While there exists a reasonable comprehension on how IDP sequence determines the unbound IDP ensemble, little is known about what shapes the structural characteristics of IDPs bound to their targets. Using a statistical thermodynamic model, we show that the target-bound ensembles are determined by a simple code that combines the IDP sequence and the distribution of IDP-target interaction hotspots. These two parameters define the conformational space of target-bound IDPs and rationalize the observed structural heterogeneity of fuzzy complexes. The presented model successfully reproduces the dynamical signatures of target-bound IDPs from the NMR relaxation experiments as well as the changes of interaction affinity and the IDP helicity induced by mutations. The model explains how the target-bound IDP ensemble adapts to mutations in order to achieve an optimal balance between conformational freedom and interaction energy. Taken together, the presented sequence-ensemble relationship of fuzzy complexes explains the different manifestations of IDP disorder in folding-upon-binding processes.

PMID:34504009 | DOI:10.1073/pnas.2020562118

Eur Respir J. 2021 Sep 9:2101315. doi: 10.1183/13993003.01315-2021. Online ahead of print.

ABSTRACT

RATIONALE: Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child’s respiratory health.

METHODS: We performed an individual participant meta-analysis among 18 326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diet were estimated by energy-adjusted Dietary Inflammatory Index (E-DII^TM) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured by questionnaires and lung function by spirometry.

RESULTS: After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower FVC in children (Z-score difference (95% confidence interval (CI)): -0.05 (-0.08, -0.02), per IQR increase). No linear associations of the maternal E-DII or DASH score with child’s wheezing or asthma were observed. When exploratively examining the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low FEV₁/FVC (z-score <-1.64) (OR (95% CI) 1.20 (1.06, 1.36), 1.40 (1.06, 1.85), compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%.

CONCLUSION: Main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.

PMID:34503987 | DOI:10.1183/13993003.01315-2021

J Nucl Med. 2021 Sep 9:jnumed.121.262017. doi: 10.2967/jnumed.121.262017. Online ahead of print.

ABSTRACT

Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, has become a popular target for radionuclide-based theranostic applications in the advanced stages of prostate cancer. We conducted a meta-analysis of the therapeutic effects of PSMA-targeting alpha therapy [²²⁵Ac-PSMA radioligand therapy (RLT)] in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic search was performed using the keywords “mCRPC,” “²²⁵Ac-PSMA,” and “alpha therapy”. Therapeutic responses were analyzed as the pooled proportions of patients with more than 50% of prostate-specific antigen (PSA) decline and any PSA decline. Survival outcomes were analyzed by estimating summary survival curves for progression-free survival (PFS) and overall survival (OS). Adverse events were analyzed as the pooled proportions of patients with xerostomia and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia). Results: Nine studies with 263 patients were included in our meta-analysis. The pooled proportions of patients with more than 50% of PSA decline and any PSA decline were 60.99% [95% confidence interval (CI) = 54.92-66.83%] and 83.57% (95% CI = 78.62-87.77%), respectively. The estimated mean PFS and mean OS were 9.15 months (95% CI = 6.69-11.03 months) and 11.77 months (95% CI = 9.51-13.49 months), respectively. The pooled proportions of patients with adverse events were 62.81% (95% CI = 39.34-83.46%) for xerostomia, 14.39% (95% CI = 7.76-22.63%) for anemia, 4.12% (95% CI = 0.97-9.31%) for leukocytopenia, and 7.18% (95% CI = 2.70-13.57%) for thrombocytopenia. Conclusion: In our study, around 61% of patients had more than 50% of PSA decline and 84% of patients had any PSA decline after ²²⁵Ac-PSMA RLT. The common adverse events in ²²⁵Ac-PSMA RLT were xerostomia in 63% of patients and severe hematotoxicity in 4-14% of patients.

PMID:34503960 | DOI:10.2967/jnumed.121.262017

Eur Respir J. 2021 Sep 9:2100972. doi: 10.1183/13993003.00972-2021. Online ahead of print.

ABSTRACT

BACKGROUND: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and beta agonist (MABA), being developed for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD.

METHODS: This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol [UMEC/VI]; 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough FEV₁ on day 15. Secondary endpoints included: change from baseline in peak FEV₁; change from baseline in breathlessness, cough and sputum scale (BCSS); change from baseline in COPD assessment tool (CAT); adverse events; and pharmacokinetics.

RESULTS: Seventy-three participants were randomised. After 14 days, trough FEV₁ was significantly improved with navafenterol compared with placebo (least-squares [LS] mean difference 0.202 L; p<0.0001). There was no significant difference in FEV₁ between navafenterol and UMEC/VI (LS mean difference -0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period.

CONCLUSION: Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.

PMID:34503985 | DOI:10.1183/13993003.00972-2021

Clin Genitourin Cancer. 2021 Aug 14:S1558-7673(21)00159-2. doi: 10.1016/j.clgc.2021.08.002. Online ahead of print.

ABSTRACT

BACKGROUND: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue.

METHODS: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV.

RESULTS: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV.

CONCLUSION: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.

PMID:34503934 | DOI:10.1016/j.clgc.2021.08.002

AJNR Am J Neuroradiol. 2021 Sep 9. doi: 10.3174/ajnr.A7243. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Accurate differentiation of paragangliomas and schwannomas in the jugular foramen has important clinical implications because treatment strategies may vary but differentiation is not always straightforward with conventional imaging. Our aim was to evaluate the accuracy of both qualitative and quantitative metrics derived from dynamic contrast-enhanced MR imaging using golden-angle radial sparse parallel MR imaging to differentiate paragangliomas and schwannomas in the jugular foramen.

MATERIALS AND METHODS: A retrospective study of imaging data was performed on patients (n = 30) undergoing MR imaging for jugular foramen masses with the golden-angle radial sparse parallel MR imaging technique. Imaging data were postprocessed to obtain time-intensity curves and quantitative parameters. Data were normalized to the dural venous sinus for relevant parameters and analyzed for statistical significance using a Student t test. A univariate logistic model was created with a binary output, paraganglioma or schwannoma, using a wash-in rate as a variable. Additionally, lesions were clustered on the basis of the wash-in rate and washout rate using a 3-nearest neighbors method.

RESULTS: There were 22 paragangliomas and 8 schwannomas. All paragangliomas demonstrated a type 3 time-intensity curve, and all schwannomas demonstrated a type 1 time-intensity curve. There was a statistically significant difference between paragangliomas and schwannomas when comparing their values for area under the curve, peak enhancement, wash-in rate, and washout rate. A univariate logistic model with a binary output (paraganglioma or schwannoma) using wash-in rate as a variable was able to correctly predict all observed lesions (P < .001). All 30 lesions were classified correctly by using a 3-nearest neighbors method.

CONCLUSIONS: Paragangliomas at the jugular foramen can be reliably differentiated from schwannomas using golden-angle radial sparse parallel MR imaging-dynamic contrast-enhanced imaging when imaging characteristics cannot suffice.

PMID:34503944 | DOI:10.3174/ajnr.A7243

Clin Oncol (R Coll Radiol). 2021 Sep 7:S0936-6555(21)00326-5. doi: 10.1016/j.clon.2021.08.012. Online ahead of print.

ABSTRACT

AIMS: With interest in normal tissue sparing and dose-escalated radiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer, this study investigated the impact of motion-managed moderate deep inspiration breath hold (mDIBH) on normal tissue sparing and dose-escalation potential and compared this to planning with a four-dimensional motion-encompassing internal target volume or motion-compensating mid-ventilation approach.

MATERIALS AND METHODS: Twenty-one patients underwent four-dimensional and mDIBH planning computed tomography scans. Internal and mid-ventilation target volumes were generated on the four-dimensional scan, with mDIBH target volumes generated on the mDIBH scan. Isotoxic target dose-escalation guidelines were used to generate six plans per patient: three with a target dose cap and three without. Target dose-escalation potential, normal tissue complication probability and differences in pre-specified dose-volume metrics were evaluated for the three motion-management techniques.

RESULTS: The mean total lung volume was significantly greater with mDIBH compared with four-dimensional scans. Lung dose (mean and V_{21 Gy}) and mean heart dose were significantly reduced with mDIBH in comparison with four-dimensional-based approaches, and this translated to a significant reduction in heart and lung normal tissue complication probability with mDIBH. In 20/21 patients, the trial target prescription dose cap of 79.2 Gy was achievable with all motion-management techniques.

CONCLUSION: mDIBH aids lung and heart dose sparing in isotoxic dose-escalated radiotherapy compared with four-dimensional planning techniques. Given concerns about lung and cardiac toxicity, particularly in an era of consolidation immunotherapy, reduced normal tissue doses may be advantageous for treatment tolerance and outcome.

PMID:34503896 | DOI:10.1016/j.clon.2021.08.012

Chin J Traumatol. 2021 Aug 11:S1008-1275(21)00128-0. doi: 10.1016/j.cjtee.2021.08.004. Online ahead of print.

ABSTRACT

PURPOSE: Treatment of distal tibia fractures poses significant challenge to orthopedic surgeon because of poor blood supply and paucity of soft tissue coverage. There is considerable controversy regarding the superior option of treatment for distal tibia fracture between the minimally invasive percutaneous plate osteosynthesis (MIPPO) technique and intramedullary interlocking (IMIL) nailing for extra-articular distal tibia fractures. The aim of our study is to compare the functional outcome between the two treatment methods.

METHODS: This was the prospective comparative study of 100 patients with distal third tibia fractures divided into two groups. First group of patients were treated with MIPPO technique while second group of patients were managed by IMIL nailing. Patients were followed up in outpatient department to assess the functional outcomes, malunion, delayed union, nonunion, superficial and deep infection between the two groups. Statistical analyses were performed using the SPSS software (version 16.0).

RESULTS: Average mal-union in MIPPO group was 5 (3-7) ± 1.41 vs. 10.22 (8-14) ± 2.04° in IMIL group (p = 0.001). Similarly postoperative knee pain in IMIL group was 10% vs. 2% in MIPPO group (p = 0.001). In terms of superficial infection and nonunion, the results were 8% vs. 4% and 2% vs. 6% for the MIPPO and IMIL group, respectively (p = 0.001).

CONCLUSION: Both procedures have shown the reliable method of fixation for distal extra-articular tibia fractures preserving the soft tissue, bony vascularity and fracture hematoma that provide a favourable biological environment for fracture healing. Considering the results of the study, we have slightly more preference for the MIPPO technique.

PMID:34503904 | DOI:10.1016/j.cjtee.2021.08.004

Eval Program Plann. 2021 Sep 3:101997. doi: 10.1016/j.evalprogplan.2021.101997. Online ahead of print.

ABSTRACT

BACKGROUND: Between September 2015 and 2018, The Michigan Department of Health and Human Services (MDHHS) focused its Project PrIDE efforts on increasing PrEP awareness through a media campaign, and community engagement in. Wayne County, MI. A strained relationship between MDHHS and community has created barriers to sustained and effective community engagement. The local evaluation (LE) was developed to determine the barriers and facilitators to engagement in program activities.

METHODS: To understand the process and the factors that impacted the project’s goal, a mixed methods participatory evaluation approach was utilized. Data collection included quantitative data from meeting surveys, qualitative data from focus groups, and a photovoice project. Analysis and synthesis included descriptive statistics and deductive thematic coding.

RESULTS: CAB engagement increased collaboration, enhanced feasibility and utility, appropriateness, sustainability of activities, and increased transparency between MDHHS and CAB. Thematic coding identified Barriers and facilitators to engagement with PrEP activites included restrictive funding, comprehensive services delivery and CAB feedback underutilized and resulting in ineffective campaign messages.

CONCLUSIONS: Although a strained relationship was evident in the beginning, encouraging interagency collaboration in the development, implementation, and utilization of program and evaluation activities, resulted in the improvement of relationships between the community and MDHHS.

PMID:34503853 | DOI:10.1016/j.evalprogplan.2021.101997

Am J Orthod Dentofacial Orthop. 2021 Sep 6:S0889-5406(21)00371-1. doi: 10.1016/j.ajodo.2020.10.027. Online ahead of print.

ABSTRACT

INTRODUCTION: Orthodontic residents face challenges unparalleled to their predecessors, including competitive marketplaces, rising debt burdens, and changing demographics that have contributed to the shift in initial career choice from owner to employee. We aim to understand factors important to orthodontists at different career stages and the impact on job satisfaction through a sequential mixed methodology study.

METHODS: Semistructured interviews were conducted with 25 orthodontic residents and practitioners. A survey was developed from qualitative findings that explored career decision-making of orthodontic residents and practicing orthodontists, with descriptive and bivariate statistical analyses (n = 343 orthodontists and 185 residents).

RESULTS: Graduating orthodontic residents are choosing employment over ownership as their initial job, prioritizing high income to offset the educational debt. The majority of residents report thinking about their debt very often to all of the time and find it very to extremely stressful. Current residents have long-term goals of ownership, whereas practicing doctors of both genders became owners at equal frequencies. However, on average, women earn $119,000 less per year and report being the primary family caretaker more often than men.

CONCLUSIONS: Excellent patient care, work-life balance, and sufficient income are the most important drivers for career choices and job satisfaction for orthodontists of all ages. Despite debt, most residents and working orthodontists report a high level of job satisfaction and would recommend the field of orthodontics to others.

PMID:34503861 | DOI:10.1016/j.ajodo.2020.10.027