Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.

Human Papillomavirus Self-Sampling for Primary Cervical Cancer Screening in Under-Screened Women in Hong Kong during the COVID-19 Pandemic.

The aim of this study was to assess the effectiveness of HPV self-sampling for cervical cancer screening and the best means of service delivery, with a specific focus on under-screened women, particularly during the COVID-19 pandemic. Using three arms of service delivery (social media, school outreach and underserved outreach), we recruited under-screened women aged 30-65 years from two population groups: the general public and specific underserved communities, from whom self-sampled specimens and optional clinician-sampled cervical specimens were obtained for HPV testing. A total of 521 self-sampling kits were distributed, of which 321 were returned, giving an overall uptake rate of 61.6%. The response rate was higher in the face-to-face underserved outreach (65.5%) compared to social media (22.8%) and school outreach (18.2%). The concordance for HPV detection between self-sampled and clinician-sampled specimens was 90.2% [95% confidence interval (CI) 85.1-93.8%; Cohen's kappa 0.59 (95% CI 0.42-0.75)]. Overall, 89.2% of women were willing to have self-sampling again. In conclusion, HPV self-sampling is an effective method for cervical cancer screening and can be considered as an option, particularly in women who are reluctant or unable to attend regular screening. Various service deliveries could be considered to increase participation in cervical cancer screening.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

TLR7/8 agonist treatment induces an increase in bone marrow resident dendritic cells and hematopoietic progenitor expansion and mobilization.

There is accumulating evidence suggesting that toll-like receptor (TLR) signals play an important role in the regulation of hematopoietic stem/progenitor cells (HSPCs). TLR7/8 stimulation induces the myeloid differentiation of normal HSPCs and acute myeloid leukemia cells. However, the in vivo effect of TLR7/8 agonists on hematopoiesis is largely unknown. Here, we show that, similar to TLR4 and TLR2, treatment with the TLR7/8 agonist R848 induces an expansion of phenotypic hematopoietic stem cells (HSCs) with reduced repopulating potential and HSPC mobilization. In contrast to chronic TLR4 stimulation, treatment with R848 for 5 days did not induce a significant increase in myeloid-biased HSCs. Treatment with R848 results in a significant increase in classic dendritic cells (DCs) in the bone marrow, but a decrease in common dendritic cell progenitors and pre-DCs. Phenotypic analysis of DCs revealed that R848 treatment is associated with altered expression of certain chemokines, activation markers, and migratory receptors. Together, these data indicate that systemic administration of a TLR7/8 agonist has unique effects on hematopoiesis, including the expansion of DCs in the bone marrow, that might have clinical relevance to augment responses to certain immunotherapies, such as cancer vaccines and immune checkpoint blockade.

Nurse-led follow-up in survivorship care of gynaecological malignancies-A randomised controlled trial.

OBJECTIVE: To assess clinical and psychosocial outcomes of nurse-led follow-up in survivorship care of gynaecological malignancies. METHODS: Women with endometrial or ovarian cancer who were attending regular post-treatment follow-up at a tertiary referral centre were randomised into two groups-group-1: telephone follow-up by nurses and group-2: gynaecologists-led clinic follow-up. Women in group-1 were asked about their symptoms and quality of life (QoL) by nurses. Women in group-2 were followed up by gynaecologists and underwent symptom reviews and physical examinations. All ovarian cancer patients in both groups also had CA125 measured. All recruited women completed a QoL questionnaire (EORTC QLQ-C30), HADS-anxiety questionnaire and symptom checklist. RESULTS: 385 women (215 with endometrial and 170 with ovarian cancer) were randomised. There was no significant difference in the detection of recurrence according to the two follow-up protocols. However, women in the nurse-led arm scored higher on emotional (p = 0.023) and cognitive functioning (p = 0.012). Those in the gynaecologist-led arm scored higher on the HADS-anxiety scale (p = 0.001) and were more likely to report symptoms. CONCLUSIONS: Our results demonstrate a preliminary non-inferiority of nurse-led follow-up, with improved psychological morbidity and QoL. Thus, nurse-led follow-up can be considered an effective substitute for hospital-based care.

Costs Associated with the Treatment of Low Back Disorders: A Comparison of Surgeons and Physiatrists.

BACKGROUND: Spine care is costly and subject to wide variability. Defining costs and patterns of care for different specialties is critical to improving value. OBJECTIVE: Determine costs, utilization, and differences therein for nonoperative and operative specialists in treating low back disorders. We hypothesized costs associated with nonoperative specialists would be lower. DESIGN: Retrospective cohort. SETTING: Medicare Limited Data Set (5% sample), 2011 to 2014. PARTICIPANTS: A total of 170 011 patients saw a primary care provider for a low back disorder between 1 July 2011, and 1 January 2013. Excluding those seen for a low back disorder in the preceding 6 months, final cohorts totaled 11 829 patients subsequently evaluated by a physiatrist (specialist in physical medicine and rehabilitation; 3183 patients) or surgeon (orthopedic or neurosurgeon; 8646 patients) within the following 6 months. MAIN OUTCOME MEASURES: Total Medicare expenditures, spine-specific costs, spine surgical rates over 24 months. RESULTS: Cohorts had comparable demographics, initial diagnoses, and baseline mean per-member per-month (PMPM) total spending. Mean 2-year spine-specific spending was $3978 for the physiatrist cohort and $7387 for the surgeon cohort. Comparatively, the physiatrist cohort had lower total mean 2-year spine-specific spending (-$3409; 95% confidence interval [CI] -$3824 to -$2994), mean PMPM total spending (-$122/mo; CI -$184 to -$60), and surgical rate (7.8% vs. 18.9%, risk ratio [RR] = 0.41; CI 0.36-0.47). Surgery predominantly drove cost differential. Mean PMPM total spending for both cohorts remained elevated at 24 months compared to baseline mean spending (physiatrist: +$293; CI $447 to $138; surgeon: +$325; CI $425 to $225). CONCLUSIONS: Following a new episode of a low back disorder, substantial costs were seen for those subsequently evaluated by a physiatrist or surgeon. Costs were considerably lower for those first seen by a physiatrist. Patients in both cohorts displayed long-term increases in health care costs. Our data suggest that early engagement in nonoperative care, when appropriate, may improve value.

Gout Severity in Recipients of Kidney Transplant.

PURPOSE: This retrospective analysis of medical chart data was performed to compare severity and treatment of gout in patients with or without a history of kidney transplantation (KT). METHODS: Via an online survey, a panel of board-certified US nephrologists (N = 104) provided the following deidentified chart data for their 3 most recent patients with gout: age, sex, serum uric acid, numbers of swollen or tender joints, visible tophi, gout flare events (prior 12 months), gout drug treatment history, and KT history. The presence of "severe, uncontrolled gout" was defined as: serum uric acid ≥ 7.0 mg/dL, ≥1 tophi and ≥2 flares in the last 12 months, and history of xanthine oxidase inhibitor treatment. RESULTS: Twenty-five out of 312 (8.0%) gout patients had a history of KT. Univariate analysis found that patients with gout and history of kidney transplants had: greater prevalence of severe uncontrolled gout (27% vs 8%, P = .007) and tophi (36% vs 17%, P = .030), and higher rates of failure or physician perceived contraindication to allopurinol (44% vs 23%, P = .028). CONCLUSION: This study provides preliminary evidence that gout in patients with history of KT is more severe and poses greater challenges to pharmacologic management. Although gout has been linked to worse outcomes among kidney recipients in the literature, there are presently no publications on gout severity among patients with KT in comparison to other patients with gout. Further investigation of disease severity and appropriate, effective treatment options in recipients of kidney transplant with a diagnosis of gout, especially prior to the transplant, is warranted.

Risk factors for aquiring multidrug-resistant organisms in urinary tract infections: A systematic literature review.

BACKGROUND: This is the first review to analyze literature identifying risk factors for a multidrug-resistant urinary tract infection (MDR UTI). Risk factors for other infections involving multidrug-resistant organisms have been evaluated in other reviews, but they do not assess urinary tract infections. The purpose of this study is to collect currently published data to determine the most commonly and consistently identified risk factors for UTIs. MATERIAL AND METHODS: For this study, 3 independent researchers searched PubMed, Embase, and Cochrane database from 1966 to February 2016 for articles identifying risk factors for MDR UTI. RESULTS: A total of 25 studies including 31,284 patients with positive cultures provide evidence for 12 possible risk factors for MDR UTI . The most commonly identified risk factor was previous antibiotic usage as evidenced in 16 of the 20 studies that evaluated this possible risk factor. The time range utilized to define previous antibiotic usage ranged from 2 days to 365 days. Other risk factors with the strongest supporting data were urinary catheterization, previous hospitalization, and nursing home residence. CONCLUSION: We identified 12 different possible risk factors for a MDR UTI, however several risk factors have minimal or conflicting evidence. The definitions of the risk factors varied widely among the studies, and should be standardized for future studies.

Addressing the risk of bacterial contamination in platelets: a hospital economic perspective.

BACKGROUND: Bacterially contaminated platelets (PLTs) remain a serious risk. The Food and Drug Administration has issued draft guidance recommending hospitals implement secondary testing or transfuse PLTs that have been treated with pathogen reduction technology (PRT). The cost implications of these approaches are not well understood. STUDY DESIGN AND METHODS: We modeled incurred costs when hospitals acquire, process, and transfuse PLTs that are PRT treated with INTERCEPT (Cerus Corp.) or secondary tested with the PLT PGD Test (Verax Biomedical). RESULTS: Hospitals will spend $221.27 (30.0%) more per PRT-treated apheresis PLT unit administered compared to a Zika-tested apheresis PLT unit that is irradiated and PGD tested in hospital. This difference is reflected in PRT PLT units having: 1) a higher hospital purchase price ($100.00 additional charge compared to an untreated PLT); 2) lower therapeutic effectiveness than untreated PLTs among hematologic-oncologic patients, which contributes to additional transfusions ($96.05); or 3) fewer PLT storage days, which contributes to higher outdating cost from expired PLTs ($67.87). Only a small portion of the incremental costs for PRT-treated PLTs are offset by costs that may be avoided, including primary bacterial culture, secondary bacterial testing ($26.65), hospital irradiation ($8.50), Zika testing ($4.47), and other costs ($3.03). CONCLUSION: The significantly higher cost of PRT-treated PLTs over PGD-tested PLTs should interest stakeholders. For hospitals that outdate PLTs, savings associated with expiration extension to 7 days by adding PGD testing will likely be substantially greater than the cost of implementing PGD-testing. Our findings might usefully inform a hospital's decision to select a particular blood safety approach.

Persistence of dysphagia and odynophagia after mediastinal radiation and chemotherapy in patients with lung cancer or lymphoma.

Esophageal symptoms are common during radiation and chemotherapy. It is unclear how often these symptoms persist after therapy. We retrospectively reviewed medical records of 320 adults treated for nonmetastatic breast cancer (84), lung cancer (109), or Hodgkin and non-Hodgkin lymphoma (127) who were disease-free at 10-14 months after therapy. Treatment included chemotherapy with or without nonmediastinal radiation therapy (150 patients), chemotherapy plus sequential mediastinal radiation therapy (MRT) (48 patients), chemotherapy plus concurrent MRT (61 patients), or non-MRT only (61 patients). Proton pump inhibitor use was documented. All treatment groups had similar prevalence of the esophageal symptom of heartburn before therapy. Rates were higher during treatment in those who received MRT with or without chemotherapy, but declined by 10-14 months after treatment. However, low baseline rates of dysphagia (4%) and odynophagia (2%) increased significantly after combined chemotherapy and MRT to 72% for dysphagia and 62% for odynophagia (P < 0.01) during treatment and stayed significantly elevated over baseline with 27% of the patients having dysphagia and 11% having odynophagia at 10-14 months after treatment. The use of proton pump inhibitors by patients who had MRT with chemotherapy was significantly increased during and after treatment (P = 0.002). Dysphagia, odynophagia and the use of proton pump inhibitors were significantly more common both during and after treatment than before treatment in patients who received both chemotherapy and mediastinal radiation. Our data highlight the important challenge for clinicians of managing patients with lung cancer and lymphoma who have persistent esophageal problems, particularly dysphagia and odynophagia, at approximately 1 year after treatment.

Perceptions of medical errors in cancer care: an analysis of how the news media describe sentinel events.

OBJECTIVE: To analyze the print news media's coverage of sentinel events involving cancer patients. METHODS: Using LexisNexis, we identified English-language newspaper articles covering medical errors in cancer care between January 1, 2000, and December 31, 2010. Articles were coded for 3 major themes using a standardized abstraction instrument: narrative statements and point of view most prominently represented, attribution of blame, and orientation toward patient safety. We also abstracted country where the newspaper was published, type of error event, and extent of patient harm. RESULTS: We analyzed 64 articles from 37 print newspaper syndications that circulated in 6 countries/regions. Reports of medical errors rarely were framed from the point of view of a safety expert or the responsible clinician (13% and 3%, respectively) compared with the patient and legal points of view (both 30%). Articles held individual clinicians (41%) and hospital systems (28%) responsible for most errors. Four in 10 articles failed to present medical errors as "systems" problems. Article perspective varied considerably by country, with 53% of articles from the UK and 63% from Australia and New Zealand judged as negatively slanted compared with 14% in the United States and Canada. CONCLUSIONS: In reports of medical errors involving cancer patients, the news media regularly blame individual clinicians for mistakes and fail to present a systems-based understanding of these events.

Disparities in evaluation of patients with rectal bleeding 40 years and older.

BACKGROUND & AIMS: Rectal bleeding is associated with colorectal cancer. We characterized the evaluation of patients aged 40 years and older with rectal bleeding and identified characteristics associated with inadequate evaluation. METHODS: We conducted a retrospective review of records of outpatient visits that contained reports of rectal bleeding for patients aged 40 years and older (N = 480). We studied whether patient characteristics affected whether or not they received a colonoscopy examination within 90 days of presentation with rectal bleeding. Patient characteristics included demographics; family history of colon cancer and polyps; and histories of screening colonoscopies, physical examinations, referrals to specialists at the index visit, and communication of laboratory results. Data were collected from medical records, and patient income levels were estimated based on Zip codes. RESULTS: Nearly half of the patients presenting with rectal bleeding received colonoscopies (48.1%); 81.7% received the procedure within 90 days. A history of a colonoscopy examination was more likely to be reported in white patients compared with Hispanic or Asian patients (P = .012 and P = .006, respectively), and in high-income compared with low-income patients (P = .022). A family history was more likely to be documented among patients with private insurance than those with Medicaid or Medicare (P = .004). A rectal examination was performed more often for patients who were white or Asian, male, and with high or middle incomes, compared with those who were black, Hispanic, female, or with low incomes (P = .027). White patients were more likely to have their laboratory results communicated to them than black patients (P = .001). CONCLUSIONS: Sex, race, ethnicity, patient income, and insurance status were associated with disparities in evaluation of rectal bleeding. There is a need to standardize the evaluation of patients with rectal bleeding.

Multisite parent-centered risk assessment to reduce pediatric oral chemotherapy errors.

PURPOSE: Observational studies describe high rates of errors in home oral chemotherapy use in children. In hospitals, proactive risk assessment methods help front-line health care workers develop error prevention strategies. Our objective was to engage parents of children with cancer in a multisite study using proactive risk assessment methods to identify how errors occur at home and propose risk reduction strategies. METHODS: We recruited parents from three outpatient pediatric oncology clinics in the northeast and southeast United States to participate in failure mode and effects analyses (FMEA). An FMEA is a systematic team-based proactive risk assessment approach in understanding ways a process can fail and develop prevention strategies. Steps included diagram the process, brainstorm and prioritize failure modes (places where things go wrong), and propose risk reduction strategies. We focused on home oral chemotherapy administration after a change in dose because prior studies identified this area as high risk. RESULTS: Parent teams consisted of four parents at two of the sites and 10 at the third. Parents developed a 13-step process map, with two to 19 failure modes per step. The highest priority failure modes included miscommunication when receiving instructions from the clinician (caused by conflicting instructions or parent lapses) and unsafe chemotherapy handling at home. Recommended risk assessment strategies included novel uses of technology to improve parent access to information, clinicians, and other parents while at home. CONCLUSION: Parents of pediatric oncology patients readily participated in a proactive risk assessment method, identifying processes that pose a risk for medication errors involving home oral chemotherapy.

Medication errors in the home: a multisite study of children with cancer.

OBJECTIVE: As home medication use increases, medications previously managed by nurses are now managed by patients and their families. Our objective was to describe the types of errors occurring in the home medication management of children with cancer. METHODS: In a prospective observational study at 3 pediatric oncology clinics in the northeastern and southeastern United States, patients undergoing chemotherapy and their parents were recruited from November 2007 through April 2011. We reviewed medical records and checked prescription doses. A trained nurse visited the home, reviewed medication bottles, and observed administration. Two physicians independently made judgments regarding whether an error occurred and its severity. Overall rates of errors were weighted to account for clustering within sites. RESULTS: We reviewed 963 medications and observed 242 medication administrations in the homes of 92 patients. We found 72 medication errors. Four errors led to significant patient injury. An additional 40 errors had potential for injury: 2 were life-threatening, 13 were serious, and 25 were significant. Error rates varied between study sites (40-121 errors per 100 patients); the weighted overall rate was 70.2 errors per 100 patients (95% confidence interval [CI]: 58.9-81.6). The weighted rate of errors with injury was 3.6 (95% CI: 1.7-5.5) per 100 patients and with potential to injure the patient was 36.3 (95% CI: 29.3-43.3) per 100 patients. Nonchemotherapy medications were more often involved in an error than chemotherapy. CONCLUSIONS: Medication errors were common in this multisite study of outpatient pediatric cancer care. Rates of preventable medication-related injuries in this outpatient population were comparable or higher than those found in studies of hospitalized patients.

US Cancer Center Implementation of ASCO/Oncology Nursing Society Chemotherapy Administration Safety Standards.

PURPOSE: Because cancer chemotherapy is a high-risk intervention, ASCO and the Oncology Nursing Society (ONS) established in 2009 consensus- and evidence-based national standards for the safe administration of chemotherapy. We sought to assess the implementation status of the ASCO/ONS chemotherapy administration safety standards. METHODS: A written survey of chemotherapy practices was sent to National Cancer Institute-designated cancer centers. Implementation status of each of 31 chemotherapy administration safety standards was self-reported. RESULTS: Forty-four (80%) of 55 eligible centers responded. Although the majority of centers have fully implemented at least half of the standards, only four centers reported full implementation of all 31. Implementation varied by standard, with the poorest implementation of standards that addressed documentation of chemotherapy planning, agreed-on intervals for laboratory testing, and patient education and consent before initiation of oral or infusional chemotherapy. CONCLUSION: Given wide variation in the implementation of ASCO/ONS chemotherapy administration safety standards at US cancer centers, there are significant opportunities for improvement.