Category: Statistics

Nat Commun. 2021 May 13;12(1):2781. doi: 10.1038/s41467-021-23043-w.

ABSTRACT

Elucidating metal oxide growth mechanisms is essential for precisely designing and fabricating nanostructured oxides with broad applications in energy and electronics. However, current epitaxial oxide growth methods are based on macroscopic empirical knowledge, lacking fundamental guidance at the nanoscale. Using correlated in situ environmental transmission electron microscopy, statistically-validated quantitative analysis, and density functional theory calculations, we show epitaxial Cu₂O nano-island growth on Cu is layer-by-layer along Cu₂O(110) planes, regardless of substrate orientation, contradicting classical models that predict multi-layer growth parallel to substrate surfaces. Growth kinetics show cubic relationships with time, indicating individual oxide monolayers follow Frank-van der Merwe growth whereas oxide islands follow Stranski-Krastanov growth. Cu sources for island growth transition from step edges to bulk substrates during oxidation, contrasting with classical corrosion theories which assume subsurface sources predominate. Our results resolve alternative epitaxial island growth mechanisms, improving the understanding of oxidation dynamics critical for advanced manufacturing at the nanoscale.

PMID:33986274 | DOI:10.1038/s41467-021-23043-w

NPJ Vaccines. 2021 May 13;6(1):69. doi: 10.1038/s41541-021-00329-0.

ABSTRACT

Fentanyl is a major contributor to the devastating increase in overdose deaths from substance use disorders (SUD). A vaccine targeting fentanyl could be a powerful immunotherapeutic. Here, we evaluated adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens. We tested adjuvants derived from the heat-labile toxin of E. coli including dmLT and LTA1 by intramuscular, sublingual or intranasal delivery. Our results show anti-fentanyl serum antibodies and antibody secreting cells in the bone-marrow after vaccination with highest levels observed with an adjuvant (alum, dmLT, or LTA1). Vaccine adjuvanted with LTA1 or dmLT elicited the highest levels of anti-fentanyl antibodies, whereas alum achieved highest levels against the carrier protein. Vaccination with sublingual dmLT or intranasal LTA1 provided the most robust blockade of fentanyl-induced analgesia and CNS penetration correlating strongly to anti-FEN IgA. In conclusion, this study demonstrates dmLT or LTA1 adjuvant as well as mucosal delivery may be attractive strategies for improving the efficacy of vaccines against SUD.

PMID:33986280 | DOI:10.1038/s41541-021-00329-0

J Am Acad Orthop Surg Glob Res Rev. 2021 Feb 2;5(2). doi: 10.5435/JAAOSGlobal-D-20-00172.

ABSTRACT

INTRODUCTION: State legalization and widespread marketing efforts have increased the accessibility and consumption of off-label, non-FDA-approved, cannabinoid (CBD) products. Although clinical evidence is largely absent for the treatment of musculoskeletal pain, patients are experimenting with these products in efforts to relieve joint pain. Assessment of the prevalence, perceived efficacy compared with other nonsurgical modalities, and usage patterns is warranted. The purpose of this study was to report the prevalence and perceived self-efficacy of CBD products in patients with symptomatic hip and/or knee osteoarthritis (OA).

METHODS: Two-hundred consecutive patients presenting with painful hip or knee OA were surveyed at their initial evaluation at a large academic center. Using Single Assessment Numeric Evaluation (SANE) scores, survey questions assessed perceived pain and effectiveness of CBD products, in addition to other nonsurgical treatment modalities. Chart review provided demographic factors. Descriptive statistics were used to characterize the data.

RESULTS: Of the 200 patients (80 hip OA, 108 knee OA, and 12 both), 66% were female, and average age was 67 years (range 36 to 89 years). Twenty-four percent (48/200) of patients endorsed use of CBD products before their presentation. The average presenting SANE score (range 0 to 100) for non-CBD users was 50.8 compared with 41.3 among CBD users (P = 0.012). Sixty percent of patients learned about CBD through friends, and 67% purchased CBD directly from a dispensary. Oral tinctures (43%) and topical applications (36%) were the most commonly used forms. In addition, 8% of participants in this study had tried marijuana for their pain.

CONCLUSION: A 24% incidence of CBD usage was found among patients presenting with hip or knee OA. No significant perceived benefit of CBD use seems to exist compared with its nonuse, as patients who used CBD reported significantly worse SANE and visual analogue scale scores than nonusers at baseline. Follow-up studies are warranted to assess these findings.

PMID:33986220 | DOI:10.5435/JAAOSGlobal-D-20-00172

Nat Commun. 2021 May 13;12(1):2785. doi: 10.1038/s41467-021-22856-z.

ABSTRACT

With the availability of cellular-resolution connectivity maps, connectomes, from the mammalian nervous system, it is in question how informative such massive connectomic data can be for the distinction of local circuit models in the mammalian cerebral cortex. Here, we investigated whether cellular-resolution connectomic data can in principle allow model discrimination for local circuit modules in layer 4 of mouse primary somatosensory cortex. We used approximate Bayesian model selection based on a set of simple connectome statistics to compute the posterior probability over proposed models given a to-be-measured connectome. We find that the distinction of the investigated local cortical models is faithfully possible based on purely structural connectomic data with an accuracy of more than 90%, and that such distinction is stable against substantial errors in the connectome measurement. Furthermore, mapping a fraction of only 10% of the local connectome is sufficient for connectome-based model distinction under realistic experimental constraints. Together, these results show for a concrete local circuit example that connectomic data allows model selection in the cerebral cortex and define the experimental strategy for obtaining such connectomic data.

PMID:33986261 | DOI:10.1038/s41467-021-22856-z

Science. 2021 May 14;372(6543):694. doi: 10.1126/science.abj0016.

NO ABSTRACT

PMID:33986172 | DOI:10.1126/science.abj0016

J Am Acad Orthop Surg Glob Res Rev. 2020 Dec 4;4(12):e20.00194. doi: 10.5435/JAAOSGlobal-D-20-00194.

ABSTRACT

BACKGROUND: Patient-reported outcome measures (PROMs) are critical and frequently used to assess clinical outcomes to support medical decision-making.

QUESTIONS/PURPOSE: The purpose of this meta-analysis was to compare differences in the modes of administration of PROMs within the field of orthopaedics to determine their impact on clinical outcome assessment.

PATIENTS AND METHODS: The PubMed database was used to conduct a review of literature from 1990 to 2018 with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. All articles comparing PROMs for orthopaedic procedures were included and classified by the mode of administration. Each specific survey was standardized to a scale of 0 to 100, and a repeated random effectsmodel meta-analysis was conducted to determine the mean effect of each mode of survey.

RESULTS: Eighteen studies were initially included in the study, with 10 ultimately used in the meta-analysis that encompassed 2384 separate patient survey encounters. Six of these studies demonstrated a statistically notable difference in PROM scores by mode of administration. The meta-analysis found that the standardized mean effect size for telephone-based surveys on a 100-point scale was 71.7 (SE 5.0) that was significantly higher (P , 0.0001) than survey scores obtained via online/tech based (65.3 [SE 0.70]) or self-administered/paper surveys (61.2 [SE 0.70]).

CONCLUSIONS: Overall, this study demonstrated that a documented difference exists in PROM quality depending on the mode of administration. PROM scores obtained via telephone (71.7) are 8.9% higher than scores obtained online (65.3, P , 0.0001), and 13.8% higher than scores obtained via self-administered on paper (61.8, P , 0.0001). Few studies have quantified statistically notable differences between PROM scores based solely on the mode of acquisition in orthopaedic.

PMID:33986216 | DOI:10.5435/JAAOSGlobal-D-20-00194

BMJ Open. 2021 May 13;11(5):e050105. doi: 10.1136/bmjopen-2021-050105.

ABSTRACT

INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units (ICUs). Using short-course antibiotics to treat VAP caused by Gram-negative non-fermenting bacteria has been reported to be associated with excess pneumonia recurrences. The “REducinG Antibiotic tReatment Duration for Ventilator-Associated Pneumonia” (REGARD-VAP) trial aims to provide evidence for using a set of reproducible clinical criteria to shorten antibiotic duration for individualised treatment duration of VAP.

METHODS AND ANALYSIS: This is a randomised controlled hierarchical non-inferiority-superiority trial being conducted in ICUs across Nepal, Thailand and Singapore. The primary outcome is a composite endpoint of death and pneumonia recurrence at day 60. Secondary outcomes include ventilator-associated events, multidrug-resistant organism infection or colonisation, total duration of antibiotic exposure, mechanical ventilation and hospitalisation. Adult patients who satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria are enrolled. Participants are assessed daily until fever subsides for >48 hours and have stable blood pressure, then randomised to a short duration treatment strategy or a standard-of-care duration arm. Antibiotics may be stopped as early as day 3 if respiratory cultures are negative, and day 5 if respiratory cultures are positive in the short-course arm. Participants receiving standard-of-care will receive antibiotics for at least 8 days. Study participants are followed for 60 days after enrolment. An estimated 460 patients will be required to achieve 80% power to determine non-inferiority with a margin of 12%. All outcomes are compared by absolute risk differences. The conclusion of non-inferiority, and subsequently superiority, will be based on unadjusted and adjusted analyses in both the intention-to-treat and per-protocol populations.

ETHICS AND DISSEMINATION: The study has received approvals from the Oxford Tropical Research Ethics Committee and the respective study sites. Results will be disseminated to patients, their caregivers, physicians, the funders, the critical care societies and other researchers.

TRIAL REGISTRATION NUMBER: NCT03382548.

PMID:33986070 | DOI:10.1136/bmjopen-2021-050105

J Immunother Cancer. 2021 May;9(5):e002254. doi: 10.1136/jitc-2020-002254.

ABSTRACT

BACKGROUND: Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.

METHODS: A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.

RESULTS: We found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.

CONCLUSION: Combining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

PMID:33986125 | DOI:10.1136/jitc-2020-002254

BMJ Open. 2021 May 13;11(5):e045888. doi: 10.1136/bmjopen-2020-045888.

ABSTRACT

OBJECTIVES: The benefits of minimally invasive surgery (MIS) for endometrial carcinoma (EC) are well established although the financial impact of robotic-assisted hysterectomy (RH) compared with laparoscopic hysterectomy (LH) is disputed.

DESIGN: Retrospective cohort study.

SETTING: English National Health Service hospitals 2011-2017/2018.

PARTICIPANTS: 35 304 women having a hysterectomy for EC identified from Hospital Episode Statistics.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the association between route of surgery on cost at intervention, 30, 90 and 365 days for women undergoing an open hysterectomy (OH) or MIS (LH/RH) for EC in England. The average marginal effect was calculated to compare RH versus OH and RH versus LH which adjusted for any differences in the characteristics of the surgical approaches. Secondary outcomes were to analyse costing data for each surgical approach by age, Charlson Comorbidity Index (CCI) and hospital MIS rate classification.

RESULTS: A total of 35 304 procedures were performed, 20 405 (57.8%) were MIS (LH: 18 604 and RH: 1801), 14 291 (40.5%) OH. Mean cost for LH was significantly less than RH, whereas RH was significantly less than OH at intervention, 30, 90 and 365 days (p<0.001). Over time, patients who underwent RH had increasing CCI scores and by the 2015/2016 year had a higher average CCI than LH. Comparing the cost of LH and RH against CCI score identified that the costs closely reflected the patients’ CCI. Increasing disparity was also seen between the MIS and OH costs with rising age. When exploring the association between provider volume, MIS rate and surgical costs, there was an association with the higher the MIS rate the lower the average cost.

CONCLUSIONS: Further research is needed to investigate costs in matched patient cohorts to determine the optimum surgical modality in different populations.

PMID:33986058 | DOI:10.1136/bmjopen-2020-045888

BMJ Open. 2021 May 13;11(5):e049877. doi: 10.1136/bmjopen-2021-049877.

ABSTRACT

INTRODUCTION: The outbreak of novel COVID-19 caught the world off guard in the first quarter of 2020. To stem the tide of this pandemic, there was acceleration of the development, testing and prelicensure approval for emergency use of some COVID-19 vaccine candidates. This led to raised public concern about their safety and efficacy, compounding the challenges of vaccine hesitancy. The onus of managing and administering these vaccines to a sceptical populace when they do become available rests mostly on the shoulders of healthcare workers (HCWs). Therefore, the vaccine confidence levels of HCWs become critical to the success of vaccination endeavours. This proposed study aims to estimate the level of vaccine confidence and the intention to receive a COVID-19 vaccine among future HCWs and their trainers at a specific university in Cape Town, South Africa, and to identify any vaccination concerns early for targeted intervention.

METHODS AND ANALYSIS: This proposed study is a cross-sectional survey study. An online questionnaire will be distributed to all current staff and students of the Faculty of Medicine Health Sciences of Stellenbosch University in Cape Town, South Africa. No sampling strategy will be employed. The survey questionnaire will consist of demographic questions (consisting of six items) and vaccine confidence questions (comprising six items in Likert scale format). Log binomial models will be employed to identify factors associated with vaccine confidence and intention. The strength of association will be assessed using the OR and its 95% CI. Statistical significance will be defined at a p value <0.05.

ETHICS AND DISSEMINATION: Ethics approval has been obtained for the study from Stellenbosch University (Human Research Ethics Committee reference number S19/01/014 (PhD)). The results will be shared with relevant health authorities, presented at conferences and published in a peer-reviewed journal.

PMID:33986069 | DOI:10.1136/bmjopen-2021-049877