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Sperm cryopreservation maintains the diversities of porcine genetic resources and improves utilization efficiency of boar semen in artificial insemination practices. Freezability of boar semen presents remarkable differences among individuals. However, metabolic markers for boar semen freezability in both sperm and seminal plasma largely remain unknown. The present study thus aims to determine differences in metabolites of sperm and seminal plasma between poor (PF) and good (GF) freezability semen from a Chinese native pig and screen potential markers for semen freezability. A total of 72,048 metabolites in sperm and 66,551 metabolites in seminal plasma were identified by liquid chromatography-mass spectrometry, respectively. The proportion of lipid molecules among all metabolites in both sperm and seminal plasma was the maximum regardless of negative or positive mode. Furthermore, we identified 21 differentially expressed metabolites (DEMs) in sperm and 185 DEMs in seminal plasma between PF and GF group. Additionally, clustering analysis showed that DEMs in sperm and seminal plasma exhibited significant changes between PF and GF group. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEMs in sperm were mainly enriched in metabolic pathways of amino acids and caffeine. DEMs in seminal plasma were associated with AMPK and cAMP signaling pathways. Taken together, these results demonstrate that sperm and seminal plasma of native pigs present differential metabolome between PF and GF semen.

Chronic obstructive pulmonary disease (COPD) has been reported as a potential risk factor for developing herpes zoster (HZ). We aimed at comparing incidence rates of HZ between people with versus without COPD in the US. This retrospective cohort study used data from Optum's de-identified Clinformatics Data Mart database from 1/1/2013 through 12/31/2018. We identified two cohorts of people ≥40 years without prior HZ, HZ vaccination, postherpetic neuralgia (PHN) or HZ ophthalmicus: those with (COPD+) and those without (COPD-) a COPD diagnosis. Adjusted incidence rate ratios (aIRRs) of HZ and PHN were calculated using generalized linear models, controlling for the propensity score of being diagnosed with COPD and relevant demographic and clinical characteristics. People in the COPD+ cohort (n = 161 970) were considerably older, had more comorbidities and were more likely to use corticosteroids than those in the COPD- cohort (n = 9 643 522). The incidence rate of HZ was 5.7-fold higher in the COPD+ versus COPD- cohorts (13.0 vs. 2.3 per 1000 person-years [PY]; aIRR, 2.77; 95% confidence interval [CI], 2.69 to 2.85; P 0.001). The unadjusted incidence rate of PHN was 1.7-fold higher in the COPD+/HZ+ versus COPD-/HZ+ cohort (64.8 vs. 37.1 per 1000 PY), but not after adjustment (aIRR, 1.07; 95% CI, 0.79 to 1.45). HZ and PHN incidence rates increased with age. After adjustment, COPD+ adults had a 2.8-fold increased risk of developing HZ. These results may help to increase awareness about potential risk factors for HZ and highlight the need for vaccination among those at increased risk.

Patients with relapsed/refractory multiple myeloma (RRMM) resistant to multiple drug classes remain a high unmet need population. This longitudinal retrospective cohort study assessed real-world treatment patterns and outcomes in adults with RRMM. Patients who had three or more prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (double-exposed) were further categorized as refractory to a PI and an immunomodulatory agent (double-class refractory

The prevalence of chronic hepatitis B virus (HBV) infection is high in many countries; however, robust, real-world epidemiological data are lacking. This study describes the prevalence, characteristics, treatment patterns, and long-term clinical outcomes of patients with chronic HBV infection in the US, Germany, and Taiwan.This was a retrospective cohort analysis of three healthcare/insurance claims databases. Individuals were identified as patients with chronic HBV infection if their records contained HBV diagnostic codes from 1 January 2010 to 31 December 2012 (Germany and Taiwan) or 1 January 2013 (USA). Included patients were indexed on 1 January 2013. Patients' demographics, clinical characteristics, and healthcare utilisation were described. Treatment patterns and long-term clinical outcomes over follow-up (to 31 December 2016 or loss to follow-up) were estimated.The prevalence of chronic HBV infection was 0.10%, 0.17%, and 2.39% in the US, Germany, and Taiwan respectively. Prevalence was very low in children, increased rapidly in adulthood, and peaked in 50- 65 year olds before declining in the elderly. More US (16.6%) and German (15.4%) patients were HIV ± HCV coinfected than in Taiwan (4.1%). Baseline clinical characteristics and healthcare utilisation were broadly similar between countries. In total, 19.2%, 11.1%, and 5.9% of non-coinfected adult patients received treatment at index in the US, Germany, and Taiwan, respectively; most frequently with nucleos(t)ide analogue monotherapy (94.4%, 97.2%, 99.8% of treated patients, respectively) and rarely with interferons (0.27%, 1.63%, and 0.06%, respectively). Untreated Taiwanese patients were more likely to remain untreated than elsewhere, and treated Taiwanese patients were less likely to persist with therapy. Generally, the cumulative incidence of long-term clinical outcomes was lowest in Germany.This study provides a contemporary, real-world, intercontinental snapshot of chronic HBV infection. Long-term sequelae occurred in all populations, and treatment levels were low, suggesting an unmet need for (or access to) effective treatments.

Masked hypertension is difficult to identify and is associated with adverse outcomes. How and to what extent masked hypertension is related to overweight and obesity remain unclear. In participants with a clinic blood pressure (BP) 140/90 mmHg enrolled in a nationwide prospective registry in China, we performed ambulatory and home BP measurements and defined masked hypertension and masked uncontrolled hypertension as an elevated 24-h (≥130/80 mmHg), daytime (≥135/85 mmHg) or nighttime ambulatory BP (≥120/70 mmHg) or an elevated home BP (≥135/85 mmHg). Overweight and obesity were defined as a body mass index of 25.0-29.9 and ≥30.0 kg/m

Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm associated with poor overall survival (OS). This study (NCT04695431) compared clinical outcomes between patients with AdvSM treated with avapritinib in the Phase 1 EXPLORER (NCT0256198) and Phase 2 PATHFINDER (NCT03580655) trials (N = 176) and patients treated with best available therapy (BAT; N = 141). A multi-center, observational, retrospective chart review study was conducted at six study sites (four European, two American) to collect data from patients with AdvSM who received BAT; these data were pooled with data from EXPLORER and PATHFINDER. Comparisons between outcomes of OS, duration of treatment (DOT), and maximum reduction in serum tryptase were conducted between the treatment cohorts, with adjustment for key covariates. The results indicated that the avapritinib cohort had significantly better survival (adjusted hazard ratio (HR) (95% confidence interval (CI)): 0.48 (0.29, 0.79); p = 0.004) and significantly longer DOT (HR: 0.36 (0.26, 0.51); p p

Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of CLL patients treated with acalabrutinib vs ibrutinib to compare outcomes utilizing the Flatiron Health Database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1/1/2018-2/28/2021. The primary outcome of interest was time to treatment discontinuation (TTD). Average treatment effect among the treated weighting was used to balance key baseline characteristics between cohorts. Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional-hazards model was used to compare TTD between cohorts. Out of 2509 patients included in the analysis, 89.6% received ibrutinib and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% CI) TTD was not reached (NR; 25.1, NR) for the acalabrutinib cohort and was 23.4 months (18.1, 28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustments for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs. ibrutinib (HR 0.59; 0.43, 0.81; P = .001). In the largest available study comparing two BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs ibrutinib.

We have developed a simple time-bin phase encoding quantum key distribution system, using the optical injection locking technique. This setup incorporates both the merits of simplicity and stability in encoding, and the immunity to channel disturbance. We have demonstrated, to our knowledge, the longest field implementation of quantum key distribution over deployed aerial fiber with a distance of 87 km. During the 70-day field test, we achieved approximately a 1.0 kbps secure key rate with stable performance. Our work takes an important step toward widespread implementation of QKD systems in diverse and complex real-life scenarios.

Background Yersinia enterocolitica has been sporadically recovered from animals, foods, and human clinical samples in various regions of Ningxia, China. However, the ecological and molecular characteristics of Y. enterocolitica, as well as public health concerns about infection in the Ningxia Hui Autonomous Region, remain unclear. This study aims to analyze the ecological and molecular epidemiological characteristics of Y. enterocolitis in order to inform the public health intervention strategies for the contains of related diseases. Methods A total of 270 samples were collected for isolation [animals (n = 208), food (n = 49), and patients (n = 13)], then suspect colonies were isolated and identified by the API20E biochemical identification system, serological tests, biotyping tests, and 16S rRNA-PCR. Then, we used an ecological epidemiological approach combined with machine learning algorithms (general linear model, random forest model, and eXtreme Gradient Boosting) to explore the associations between ecological factors and the pathogenicity of Y. enterocolitis. Furthermore, average nucleotide identity (ANI) estimation, single nucleotide polymorphism (SNP), and core gene multilocus sequence typing (cgMLST) were applied to characterize the molecular profile of isolates based on whole genome sequencing. The statistical test used single-factor analysis, Chi-square tests, t-tests/ANOVA-tests, Wilcoxon rank-sum tests, and Kruskal–Wallis tests. Results A total of 270 isolates of Yersinia were identified from poultry and livestock (n = 191), food (n = 49), diarrhoea patients (n = 13), rats (n = 15), and hamsters (n = 2). The detection rates of samples from different hosts were statistically different (χ2 = 22.636, P Y. enterocolitica (n = 187) is a predominated species. Pathogenic isolates made up 52.4% (98/187), while non-pathogenic isolates made up 47.6% (89/187). Temperature and precipitation were strongly associated with the pathogenicity of the isolates (P Y. enterocolitica was located in the northern, northwestern, and southern of the Ningxia Hui Autonomous Region. The Y. enterocolitica isolates were classified into 54 sequence types (STs) and 125 cgMLST types (CTs), with 4/O:3 being the dominant bioserotype in Ningxia. The dominant STs and dominant CTs of pathogenic isolates in Ningxia were ST429 and HC100_2571, respectively. Conclusions The data indicated geographical variations in the distribution of STs and CTs of Y. enterocolitica isolates in Ningxia. Our work offered the first evidence that the pathogenicity of isolates was directly related to fluctuations in temperature and precipitation of the environment. CgMLST typing strategies showed that the isolates were transmitted to the population via pigs and food. Therefore, strengthening health surveillance on pig farms in high-risk areas and focusing on testing food of pig origin are optional strategies to prevent disease outbreaks.

PDF file, 27K, Growth inhibitory effect of KX-01 in combination with paclitaxel/doxorubicin demonstrated by combinational index in ER/PR/HER2- negative breast cancer cells.

PDF file, 388K, The body weights of mice were measured either once in a week or 10 days after treatment with vehicle, KX-01, PAX and KX-01 + PAX. Tumors obtained from tumor xenograft studies were fixed, paraffin embedded and sectioned. The slides were stained for H&E.

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Legends for all supplementary figures

PDF file, 341K, Alpha tubulin immunoifluorescence assay was performed in MDA-MB-231 cells treated with KX-01. Migration and invasion assay was performed in MDA-MB-231 cells on treatment with KX-01.

PDF file, 55K, Effect of KX-01 alone on MDA-MB-157 tumor xenograft and in combination with doxorubicin in both MDA-MB-231 and MDA-MB-157 xenografts in Nude mice.

Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate–targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01–treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERα promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERα expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen.Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ERα expression in ERα– breast tumors, a novel treatment strategy to treat triple-negative breast cancer. Mol Cancer Res; 15(11); 1491–502. ©2017 AACR.

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PDF file, 30K, Standard curve for number of human cells in mouse organs and quantification of micro-metastasis in KX-01 and doxorubicin combination treatment using real-time PCR for a human-specific α-satellite DNA sequence of the centromere region of human chromosome 17.

PDF file, 19K, KX-01 induces dose dependent apoptosis in dasatinib resistant MDA-MB-468 ER/PR/HER2-negative breast cancer cells.

Azithromycin is a common first-line antibiotic for respiratory infection; however, there is conflicting evidence regarding risk of cardiovascular death. We assessed cardiovascular and noncardiovascular mortality associated with azithromycin versus amoxicillin-clavulanate among US Veterans treated for nonear-nose-throat respiratory infection ("respiratory") or ear-nose-throat infection indication.Electronic health record data from the US Veterans Health Administration database were used to identify Veterans (30-74 years) with outpatient dispensings of oral azithromycin versus amoxicillin-clavulanate for respiratory or ear-nose-throat infection (January 01, 2000-December 31, 2014). Outcomes assessed were risk of cardiovascular death and noncardiovascular death within 1-5 and 6-10 days postdispensing. Inverse probability of treatment-weighted proportional hazards models and binomial regression models were used to estimate hazard ratios (HRs) and compute risk differences (RD) per million courses of therapy. Cardiac death (subset of cardiovascular death) was assessed in sensitivity analyses.There were 629 345 azithromycin and 168 429 amoxicillin-clavulanate dispensings for respiratory indications, 143 783 azithromycin, and 203 142 amoxicillin-clavulanate dispensings for ear-nose-throat indications. For respiratory indications, azithromycin was not associated with a significantly different risk of cardiovascular death versus amoxicillin-clavulanate within 1-5 days postdispensing (HR [95% confidence interval (CI)]: 1.12 [0.63, 2.00]; RD [95% CI]: 11 [-43, 64] deaths/million courses of therapy). No elevated risk for azithromycin was found for ear-nose-throat indications. Pooled results for both indications via meta-analysis showed no association between antibiotics and cardiovascular mortality. There was no significant difference in risk of noncardiovascular or cardiac death between antibiotics postdispensing.Azithromycin was not associated with elevated risk of cardiovascular or noncardiovascular death versus amoxicillin-clavulanate among US Veterans.

Purpose To assess clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN) in the USA. Methods NF1-PN patients aged 8–18 years (treatment-naïve or ≤ 1 month of selumetinib treatment) and their caregivers and caregivers of similar patients aged 2–7 years were recruited through the Children’s Tumor Foundation to participate in an online cross-sectional survey (December 2020–January 2021). Caregivers provided data on patients’ demographic and clinical characteristics and burden of debulking surgeries. Patients and caregivers provided self-reported or proxy responses to health-related quality of life (HRQoL) questions using validated instruments. Results Sixty-one patients and 82 caregivers responded to the survey. Median (range) age of patients was 11.5 (3–18) years, and 53.7% were female. Most were treatment-naïve (97.6%), with NF1-PN diagnosis for > 5 years (68.3%). Most patients (59.8%) had > 1 PN and 11.0% reporting > 5 PNs. Common NF1-PN symptoms included pain (64.6%), disfigurement (32.9%), and motor dysfunction (28.0%). Patients and caregiver proxies reported low overall HRQoL and reduced physical, emotional, social, and school functioning. Patients also reported considerable pain severity, interference, daily activity impairments, and movement difficulty. Few patients had received complete resections of their tumors (12.2%). 39.0% reported ≥ 1 debulking surgery, among whom, 15.6% had complications, and debulking surgery-related hospitalizations were common (53.1%). Conclusions The clinical and humanistic burden among pediatric NF1-PN patients is substantial. While debulking surgeries are used for symptom management, they are associated with considerable clinical sequelae. Results highlight a need for improved disease management strategies.

To obtain a nationally representative annualized estimate of the prevalence of pericarditis (inflammation of the pericardium) in the United States (US) in order to better understand the potential burden on the health care system. Three nationally representative datasets were used to estimate the annualized period prevalence and prevalence rate of pericarditis from 2007 to 2016: the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), and the Nationwide Inpatient Sample (NIS). Across all data sources, ICD-9/10 codes were used to identify healthcare encounters with ≥1 primary or secondary diagnosis related to pericarditis irrespective of duration or etiology. The prevalence of pericarditis in 2020 was extrapolated by multiplying the average annualized prevalence rate from 2007 to 2016 by the total US population as of March 2020. Data from NAMCS/NHAMCS (2007–2016) yielded an average annualized estimate of 125,209 patients with pericarditis, resulting in a pooled average annualized prevalence estimate of 40 patients with pericarditis per 100,000 persons. Data from NIS (2007–2016) yielded an average annualized estimate of 34,441 patients with pericarditis, resulting in a pooled average annualized prevalence estimate of 11 hospitalized patients with pericarditis per 100,000 persons. Extrapolation of these results based on the March 2020 population estimates from the US Census Bureau of 329,436,928 resulted in an estimated US prevalence of pericarditis to be approximately160,000. Despite certain methodologic limitations, our analysis of data from nationally representative sources support that pericarditis is a rare disease affecting substantially fewer than 200,000 persons in the US.

Supplementary Data from Real-World Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015–2020

Real-world evidence (RWE) has garnered great interest to support registration of new therapies and label expansions by the United States Food and Drug Administration (FDA). Currently, practical insights on the design and analysis of regulatory-grade RWE are lacking. This study aimed to analyze attributes of real-world studies in FDA's decision-making and characteristics of full versus accelerated approvals through a systematic review of oncology product approvals. Oncology approvals from 2015 to 2020 were reviewed from FDA.gov. Applications were screened for inclusion of RWE, and variables related to regulatory designations of the application, pivotal clinical trial, and real-world studies were extracted. FDA feedback was reviewed to identify takeaways and best practices for adequate RWE. Among 133 original and 573 supplemental approvals for oncology, 11 and 2, respectively, included RWE; none predated 2017. All real-world studies were retrospective in nature; the most common data source was chart review, and the most common primary endpoint was overall response rate, as in the pivotal trial. The FDA critiqued the lack of the following: a prespecified study protocol, inclusion/exclusion criteria matching to the trial, comparability of endpoint definitions, methods to minimize confounding and address unmeasured confounding, and plans to handle missing data. All full (versus accelerated) approvals shared the following characteristics: high magnitude of efficacy in the pivotal trial; designations of orphan disease, breakthrough therapy, and priority review; and no advisory committee meeting held. This study found that findings from external control real-world studies complemented efficacy data from single-arm trials in successful oncology product approvals.

In the absence of head-to-head comparisons across relapsed/refractory multiple myeloma (RRMM) treatments following the approval of the oral proteasome inhibitor ixazomib, in combination with lenalidomide and dexamethasone (IRd), we conducted an indirect comparison of the efficacy of IRd relative to several RRMM therapies using Bayesian fixed-effects network meta-analysis (NMA) models. Data for the NMA were obtained through a systematic literature review (conducted in June 2020), which identified randomized controlled trials (base case) and observational studies (extended network analysis) reporting overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). In the base case, IRd was associated with a significantly longer PFS than lenalidomide and dexamethasone (Rd), bortezomib monotherapy (V), dexamethasone (Dex), and pomalidomide and dexamethasone (Pom-dex), a significantly shorter PFS than daratumumab, lenalidomide, and dexamethasone (DRd), and a PFS comparable to elotuzumab, lenalidomide, and dexamethasone (ERd) and carfilzomib, lenalidomide, and dexamethasone (KRd). IRd was associated with a significantly longer OS than V, Dex, and Pom-dex, and an OS comparable to Rd, ERd, KRd, and DRd. The ORR of IRd was significantly higher than Rd, V, and Dex, significantly lower than KRd and DRd, and comparable to Pom-dex and ERd. The extended network analyses and sensitivity analyses were consistent with the base case. This NMA shows that IRd is relatively efficacious among RRMM treatments. Being an oral regimen, IRd is also convenient to manage. IRd could be a preferable treatment option for many patients with RRMM, particularly those seeking an efficacious and convenient therapeutic option.

Novel therapies improve clinical outcomes in chronic lymphocytic leukemia (CLL), although adverse event (AE) profiles differ. This study evaluated time and personnel costs of AE management among healthcare professionals (HCPs) treating patients with CLL with novel therapies. A non-interventional prospective survey was conducted over 2 months. Eligible HCPs reported the time per day spent performing AE management activities for CLL patients treated with acalabrutinib, ibrutinib, or venetoclax. Mean time and personnel costs (USD) per activity were summarized and used to estimate the total annual costs of AE management for an average-sized oncology practice. For an average-sized practice (28 HCPs with an average of 56 CLL patients), the mean annual personnel cost of AE management for CLL patients on novel agents was estimated at $115,733. The personnel cost associated with acalabrutinib ($20,912) was less than half that of ibrutinib ($53,801) and venetoclax ($41,884), potentially due to fewer severe AEs and less time spent by oncologists managing AEs compared to other HCP types. The substantial burden of AE management for patients with CLL may vary by treatment used. Acalabrutinib was associated with lower annual costs of AE management at an oncology practice level compared to ibrutinib and venetoclax.

Background Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting. Methods Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013–03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis. Results Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively. Conclusions This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.

The continuing rise in the incidence of multidrug-resistant organism infections has made combating this grave threat a national imperative. One of the most potent weapons in our arsenal against such organisms is the prudent use of antibiotics. Antimicrobial stewardship (AMS) programs aim to slow the development of antimicrobial resistance through judicious, monitored use of antibiotics. Traditionally, AMS programs have included pharmacists and physicians with training in AWS, infectious disease physicians, hospital leadership, microbiologists, and infection prevention professionals. Nurses are missing from AMS programs, especially intensive care nurses. Critical care nurses provide the majority of patient care to ICU patients and monitor the progress of the patient's condition. The ICU nurse is an obvious asset to the AMS programs. ICU nurses are well-educated autonomous professionals with a unique role in coordinating with the critical care team. Critical care nurses already perform numerous nursing tasks with AWS functions. This, together with their unique perspective makes them a valuable asset that has often been overlooked. Traditionally, perceived barriers have kept ICU nurses from joining AMS teams. By removing these barriers and engaging critical care nurses in the important work of AWS, we can strengthen our AMS team and achieve optimal outcomes for our patients.

Most fungal infections are common in humans. Pathogenic fungi are opportunistic but can cause fungal infection disease in patients with immunocompromised conditions, such as malignancy, chemotherapy, transplantation, acquired immunodeficiency syndrome, and usage of immunosuppressant drugs. Most invasive infections are caused by Aspergillus species, mucormycetes, Cryptococcus species, and Candida species. This article focuses on environmental fungi such as Aspergillus species and mucormycetes because the mode of transmission is different. The purpose of this article is to discuss invasive fungal infections (IFIs) caused by environmental fungi and to educate critical care nurses about infection control and risk mitigation to prevent IFIs.

Real-world evidence (RWE) has garnered great interest to support registration of new therapies and label expansions by the United States Food and Drug Administration (FDA). Currently, practical insights on the design and analysis of regulatory-grade RWE are lacking. This study aimed to analyze attributes of real-world studies in FDA's decision-making and characteristics of full versus accelerated approvals through a systematic review of oncology product approvals. Oncology approvals from 2015 to 2020 were reviewed from FDA.gov. Applications were screened for inclusion of RWE, and variables related to regulatory designations of the application, pivotal clinical trial, and real-world studies were extracted. FDA feedback was reviewed to identify takeaways and best practices for adequate RWE. Among 133 original and 573 supplemental approvals for oncology, 11 and 2, respectively, included RWE; none predated 2017. All real-world studies were retrospective in nature; the most common data source was chart review, and the most common primary endpoint was overall response rate, as in the pivotal trial. The FDA critiqued the lack of the following: a prespecified study protocol, inclusion/exclusion criteria matching to the trial, comparability of endpoint definitions, methods to minimize confounding and address unmeasured confounding, and plans to handle missing data. All full (versus accelerated) approvals shared the following characteristics: high magnitude of efficacy in the pivotal trial; designations of orphan disease, breakthrough therapy, and priority review; and no advisory committee meeting held. This study found that findings from external control real-world studies complemented efficacy data from single-arm trials in successful oncology product approvals.

Background Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist. Materials and Methods A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, real-world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second- or third-line were performed. Results One hundred twenty-six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value Conclusion Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second- or third-line suggests that early use of FTD/TPI may have clinical benefits. Implications for Practice In this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. This study offers insight into patients' treatment experience in real-world clinical settings.

Background Patients with inflammatory bowel disease (IBD) are at increased risk of herpes zoster (HZ). We evaluated the incidence of HZ in ulcerative colitis (UC) and Crohn’s disease (CD) patients and compared this with HZ incidence in a non-IBD population. Methods We conducted a retrospective cohort study (GSK study identifier: VEO-000043) of adults aged ≥18 years with UC and CD and without IBD who were identified from claims recorded in a US healthcare database between October 2015 and February 2020. Crude HZ incidence rates/1,000 person-years (PY) were calculated, and comparisons of HZ incidence rates between UC or CD and non-IBD cohorts were made using adjusted generalized linear models. Results The study population comprised a total of 29,928 UC, 25,959 CD, and 11,839,329 non-IBD patients. Crude overall HZ incidence rates were 13.64/1,000 PY (UC), 15.94/1,000 PY (CD), and 7.95/1,000 PY (non-IBD). UC and CD patients had increased HZ incidence rates, with adjusted incidence rate ratios of 1.35 (95% confidence interval [CI], 1.26–1.44) and 1.66 (95% CI, 1.56–1.77), respectively, compared with non-IBD patients. Stratified analysis indicated increased relative rates of HZ in progressively younger age strata in the UC and CD patients compared with non-IBD patients. HZ incidence rates were higher in UC and CD patients who had previously received thiopurines or methotrexate, TNF-inhibitors, or corticosteroids than in UC and CD patients who did not take those medicines. Conclusion UC and CD patients had increased HZ incidence rates compared with patients without IBD, demonstrating the importance of HZ prevention in IBD patients.

Digital measures of health status captured during daily life could greatly augment current in-clinic assessments for rheumatoid arthritis (RA), to enable better assessment of disease progression and impact. This work presents results from weaRAble-PRO, a 14-day observational study, which aimed to investigate how digital health technologies (DHT), such as smartphones and wearables, could augment patient reported outcomes (PRO) to identify RA status and severity in a study of 30 moderate-to-severe RA patients, compared to 30 matched healthy controls (HC). Sensor-based measures of health status, mobility, dexterity, fatigue, and other RA specific symptoms were extracted from daily iPhone guided tests (GT), as well as actigraphy and heart rate sensor data, which was passively recorded from patients’ Apple smartwatch continuously over the study duration. We subsequently developed a machine learning (ML) framework to distinguish RA status and to estimate RA severity. It was found that daily wearable sensor-outcomes robustly distinguished RA from HC participants (F1, 0.807). Furthermore, by day 7 of the study (half-way), a sufficient volume of data had been collected to reliably identify the characteristics of RA participants. In addition, we observed that the detection of RA severity levels could be improved by augmenting standard patient reported outcomes with sensor-based features (F1, 0.833) in comparison to using PRO assessments alone (F1, 0.759), and that the combination of modalities could reliability measure continuous RA severity, as determined by the clinician-assessed RAPID-3 score at baseline (r2, 0.692; RMSE, 1.33). The ability to measure the impact of disease on daily life—through objective and remote digital outcomes that are meaningful to patients—paves the way forward to enable the development of more patient-centric and personalised measurements for use in RA clinical trials.