Perspectives from patients with chronic lung disease on a telehealth-facilitated integrated palliative care model: a qualitative content analysis study.

BACKGROUND: Chronic lung disease affects nearly 37 million Americans and often results in significant quality of life impairment and healthcare burden. Despite guidelines calling for palliative care (PC) integration into pulmonary care as a vital part of chronic lung disease management, existing PC models have limited access and lack scalability. Use of telehealth to provide PC offers a potential solution to these barriers. This study explored perceptions of patients with chronic lung disease regarding a telehealth integrated palliative care (TIPC) model, with plans to use findings to inform development of an intervention protocol for future testing. METHODS: For this qualitative study, we conducted semi-structured interviews between June 2021- December 2021 with patients with advanced chronic lung disease. Interviews explored experiences with chronic lung disease, understanding of PC, and perceived acceptability of the proposed model along with anticipated facilitators and barriers of the TIPC model. We analyzed findings with a content analysis approach. RESULTS: We completed 20 interviews, with two that included both a patient and caregiver together due to patient preference. Perceptions were primarily related to three categories: burden of chronic lung disease, pre-conceived understanding of PC, and perspective on the proposed TIPC model. Analysis revealed a high level of disease burden related to chronic lung disease and its impact on day-to-day functioning. Although PC was not well understood, the TIPC model using a shared care planning approach via telehealth was seen by most as an acceptable addition to their chronic lung disease care. CONCLUSIONS: These findings emphasize the need for a patient-centered, shared care planning approach in chronic lung disease. The TIPC model may be one option that may be acceptable to individuals with chronic lung disease. Future work includes using findings to refine our TIPC model and conducting pilot testing to assess acceptability and utility of the model.

Designing for community engagement: user-friendly refugee wellness center planning process and concept, a health design case study.

BACKGROUND: Refugee and immigrant populations have diverse cultural factors that affect their access to health care and must be considered when building a new clinical space. Health design thinking can help a clinical team evaluate and consolidate these factors while maintaining close contact with architects, patients' community leaders, and hospital or institutional leadership. A diverse group of clinicians, medical students, community leaders and architects planned a clinic devoted to refugee and immigrant health, a first-of-its-kind for South Philadelphia. METHODS: The planning process and concept design of this wellness center is presented as a design case study to demonstrate how principles and methods of human-centered design were used to create a community clinic. Design thinking begins with empathizing with the end users' experiences before moving to ideation and prototyping of a solution. These steps were accomplished through focus groups, a design workshop, and iterations of the center's plan. RESULTS: Focus groups were thematically analyzed and generated two themes of access and resources and seven subthemes that informed the design workshop. A final floor plan of the wellness center was selected, incorporating priorities of all stakeholders and addressing issues of disease prevention, social determinants of health, and lifestyle-related illness that were relevant to the patient population. CONCLUSIONS: Design thinking methods are useful for health care organizations that must adapt to the needs of diverse stakeholders and especially populations that are underserved or displaced. While much has been written on the theory and stages of design thinking, this study is novel in describing this methodology from the beginning to the end of the process of planning a clinical space with input from the patient population. This study thus serves as a proof of concept of the application of design thinking in planning clinical spaces.

"I'm Going to Be Good to Me": Exploring the Role of Shame and Guilt in Patients With Type 2 Diabetes.

Objective: People with type 2 diabetes are likely to experience shame or guilt as they navigate through their disease. Previous research has shown that feelings of shame and guilt often exist within the clinician-patient relationship, often as a result of the complex care regimen required to achieve treatment goals. The purpose of this qualitative study was to explore patients' experiences of shame and guilt in type 2 diabetes management and the impact their clinicians have on these experiences. Methods: Semistructured interviews were used to explore patients' experiences with shame and guilt. Interviews were audio-recorded, transcribed, and coded using directed content analysis. Demographic data were also obtained. Results: We completed 20 interviews with people with type 2 diabetes (65% Black, 70% female). Participants exhibited feelings more consistent with guilt than with shame. All participants discussed how their clinicians affected these feelings. Patients who expressed feelings of guilt were able to recognize opportunities for behavior change without experiencing global devaluation, in which they linked their actions to an unchangeable aspect of their identity or personality, often describing their guilt as motivating of change. Unlike guilt, when patients experienced shame, they often exhibited global devaluation, in which they blamed their personality, experienced hopelessness, and increased maladaptive behaviors. Conclusion: Our findings highlight a notable difference between shame and guilt in the context of type 2 diabetes management. We believe that incorporation of an understanding of these nuances, along with ideal responses to both shame and guilt, will enhance clinicians' ability to provide high-quality patient-centered care to people with diabetes.

Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice.

A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) mediated by the PML-retinoic acid receptor α (RARα) oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by 2 point mutations (C62A/C65A) in the Pml RING domain. Although no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period. Additionally, we found that response to targeted therapy with all-trans retinoic acid in vivo was dependent on NB integrity. PML-RARα is recognized to be insufficient for development of APL, requiring acquisition of cooperating mutations. We therefore investigated whether NB disruption might be mutagenic. Compared with wild-type cells, primary PmlC62A/C65A cells exhibited increased sister-chromatid exchange and chromosome abnormalities. Moreover, functional assays showed impaired homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage. These data directly demonstrate that Pml NBs are critical for DNA damage responses, and suggest that Pml NB disruption is a central contributor to APL pathogenesis.

Assessment of Minimal Residual Disease in Standard-Risk AML.

BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.).

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells.

Germ cells and adult stem cells maintain tissue homeostasis through a finely tuned program of responses to both physiological and stress-related signals. PLZF (Promyelocytic Leukemia Zinc Finger protein), a member of the POK family of transcription factors, acts as an epigenetic regulator of stem cell maintenance in germ cells and haematopoietic stem cells. We identified L1 retrotransposons as the primary targets of PLZF. PLZF-mediated DNA methylation induces silencing of the full-length L1 gene and inhibits L1 retrotransposition. Furthermore, PLZF causes the formation of barrier-type boundaries by acting on inserted truncated L1 sequences in protein coding genes. Cell stress releases PLZF-mediated repression, resulting in L1 activation/retrotransposition and impaired spermatogenesis and myelopoiesis. These results reveal a novel mechanism of action by which, PLZF represses retrotransposons, safeguarding normal progenitor homeostasis.

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia.

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.

Interventions to decrease pain and anxiety in patients undergoing urodynamic testing: A randomized controlled trial.

AIMS: To determine if music (at 60 beats/min) or watching a pre-procedure educational video decreases pain and anxiety in women undergoing multichannel urodynamic testing compared to usual care. METHODS: Women undergoing multichannel urodynamic testing at a tertiary care center were randomized to one of three groups: usual care (UC), music (M), in which music was played throughout the urodynamic test, or video (V), in which subjects watched an informational video on the procedure prior to undergoing the test. Visual analog scales (VAS) were used to measure patient's pain and anxiety before and after the test. Demographic information was obtained and five-item Likert questionnaires were given to assess information seeking behavior, preparedness, embarrassment, and privacy. RESULTS: 98 subjects were included in this analysis. In the overall group, mean perceived pain on the pre-test VAS was significantly higher than the post-test VAS with pre-test mean (SD) 47(±30) and post-test mean (SD) 26(±23), P = 0.0001. Overall the anxiety pre-test VAS was significantly greater than post-test VAS with pre-test mean (SD) 46.9(±29) and post-test mean 17.9(±18), P = 0.0001. There were no differences in pain and anxiety scores between the two intervention groups and usual care. Patients who were randomized to usual care or the video arm felt more prepared for the test compared to patients who were randomized to the music arm, with (mean ± SD): usual care (42 ± 8), video (43 ± 9), music (37 ± 11), P = 0.002. CONCLUSIONS: Music and an educational video do not decrease pain or anxiety in subjects undergoing multichannel urodynamics compared to usual care. Neurourol. Urodynam. 35:975-979, 2016. © 2015 Wiley Periodicals, Inc.

The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.

Mutations in BRCA1 are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase. However, its regulation remains poorly understood. Here we report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO-conjugating enzyme Ubc9. PIAS SUMO E3 ligases co-localize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro SUMO modification of the BRCA1/BARD1 heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase (SRUbL). Further, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.

Laparoscopic repair of recurrent lateral enterocele and rectocele.

It is difficult to determine what types of procedures should be attempted in patients who have recurrent prolapse. We present a case of recurrent lateral enterocele and rectocele after the patient had undergone multiple surgeries for pelvic organ prolapse (POP), including a vaginal hysterectomy, bladder-neck suspension, anterior colporrhaphy, site-specific rectocele repair, apical mesh implant, iliococcygeus vault suspension, and transobturator suburethral sling procedure. With recurrence, the patient underwent robot-assisted laparoscopic sacral colpopexy, tension-free vaginal tape transobturator sling insertion, rectocele repair, and perineorrhaphy with cystoscopy. She then presented with defecatory outlet obstruction and constipation and subsequently was treated with a stapled transanal rectal resection. The patient returned with continued defecatory dysfunction and a recurrent lateral enterocele and rectocele. The recurrence was treated laparoscopically using a lightweight polypropylene mesh. The postoperative period was uneventful. Two years later, the patient reported decreased defecatory symptoms and no further symptomatic prolapse.

Histopathology of excised midurethral sling mesh.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to compare the histological characteristics of pathological specimens of excised midurethral sling mesh and surrounding vaginal tissue in patients who presented preoperatively with pain and/or exposure of mesh to patients who underwent mesh excision for voiding dysfunction without pain and/or erosion. METHODS: This is a retrospective case-control study of women who underwent excision of midurethral sling mesh between 2008 and 2013. Three groups were identified: (1) voiding dysfunction without pain or exposure (control group), (2) pain and/or mesh exposure, and (3) voiding dysfunction with pain and/or mesh exposure. All original pathological specimens were rereviewed by one pathologist blinded to indication for excision and the previous pathology report. Degree of inflammation and fibrosis were recorded based on a 4-point scale along with the presence of giant cell reaction. RESULTS: A total of 130 subjects met inclusion criteria: 60 (46.2 %) with voiding dysfunction only, 21 (16.2 %) with pain/erosion, and 49 (37.7 %) with both pain/exposure and voiding dysfunction. The voiding dysfunction only group was found to have significantly higher levels of inflammation, median grade 2 (1-3), compared to the other two groups with a p value of 0.007. There were no statistical differences in fibrosis and giant cell reaction between the three groups. CONCLUSIONS: Midurethral sling mesh excised for voiding dysfunction demonstrates elevated levels of inflammation compared to mesh that is excised for pain and/or exposure. The vaginal tissue fibrosis and giant cell reaction are similar in patients who undergo mesh excision for voiding dysfunction and pain, and/or mesh exposure.

Measuring Quality-weighted Hospital-Free Days in Acute Respiratory Failure: A Modified Delphi Study.

Rationale: Hospital-free days (HFDs), a measure of the number of days alive spent outside the hospital, is increasingly used as an endpoint in studies of patients with acute respiratory failure (ARF) or other critical and serious illnesses. Current approaches to measuring HFDs do not account for decrements in functional status or quality of life that ARF survivors and family members value. Objectives: To develop an acceptable approach to measure quality-weighted HFDs using patient-reported outcomes. Methods: We conducted a four-round modified Delphi process among ARF experts: those with lived or professional experience. Experts rated survivorship domains, instrument and data collection characteristics, and methods to translate responses into quality-weighted HFDs. The consensus threshold was that ⩾70% of respondents rated an item "totally acceptable" or "acceptable" and ⩽15% of respondents rated the item "totally unacceptable," "unacceptable," or "slightly unacceptable." Results: Fifty-seven experts participated in round 1. Response rates were 82-93% for subsequent rounds. Priority survivorship domains were physical function and health-related quality of life. Participants reached a consensus that data collection during ARF recovery should take less than 15 minutes per assessment, allow surrogate completion when patients are unable, and continue for at least 24 months of follow-up. Using the EuroQol-5 Dimensions (EQ-5D) questionnaire to quality weight HFDs met consensus criteria for acceptability. A majority of panelists preferred quality-weighted HFDs to unweighted HFDs or survival for use in future ARF studies. Conclusions: Quality-weighting HFDs using patient and/or surrogate responses to the EQ-5D captured stakeholder priorities and was acceptable to this Delphi panel.

Common postoperative pulmonary complications after hysterectomy for benign indications.

OBJECTIVE: The purpose of this study was to estimate the incidence of postoperative pulmonary complications after hysterectomy for benign indications. STUDY DESIGN: This was a retrospective cohort study of all women who underwent hysterectomy for benign indications at the Cleveland Clinic from Jan. 1, 2001, to Dec. 31, 2009. Exclusion criteria incorporated patients who underwent hysterectomy for premalignant or malignant conditions. Pulmonary complications were defined as postoperative pneumonia, respiratory failure, atelectasis, and pneumothorax based on International classification of diseases, ninth revision, codes. RESULTS: In the 9-year study period, 3226 women underwent hysterectomy for benign indications (abdominal, 38.4%; vaginal, 39.3%; laparoscopic, 22.3%). Ten of the 3226 women (0.3%; 95% confidence interval, 0.17-0.57%) who underwent hysterectomy were identified with postoperative pulmonary complications. Among the different types of hysterectomy, the incidence of pulmonary complications was not different (total abdominal hysterectomy, 0.9%; vaginal hysterectomy, 0.12%; laparoscopic hysterectomy, 0.9%; P = .8). CONCLUSION: The incidence of postoperative pulmonary complications after hysterectomy for benign indications is low.

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity.

The neighbor of Brca1 gene (Nbr1) functions as an autophagy receptor involved in targeting ubiquitinated proteins for degradation. It also has a dual role as a scaffold protein to regulate growth-factor receptor and downstream signaling pathways. We show that genetic truncation of murine Nbr1 leads to an age-dependent increase in bone mass and bone mineral density through increased osteoblast differentiation and activity. At 6 mo of age, despite normal body size, homozygous mutant animals (Nbr1(tr/tr)) have approximately 50% more bone than littermate controls. Truncated Nbr1 (trNbr1) co-localizes with p62, a structurally similar interacting scaffold protein, and the autophagosome marker LC3 in osteoblasts, but unlike the full-length protein, trNbr1 fails to complex with activated p38 MAPK. Nbr1(tr/tr) osteoblasts and osteoclasts show increased activation of p38 MAPK, and significantly, pharmacological inhibition of the p38 MAPK pathway in vitro abrogates the increased osteoblast differentiation of Nbr1(tr/tr) cells. Nbr1 truncation also leads to increased p62 protein expression. We show a role for Nbr1 in bone remodeling, where loss of function leads to perturbation of p62 levels and hyperactivation of p38 MAPK that favors osteoblastogenesis.

Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia.

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a "hotspot region" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15;17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.

Patient-Focused Websites Related to Postpartum Pelvic Floor Health: A DISCERN Quality Analysis.

OBJECTIVE: The aim of the study was to evaluate the quality of patient-focused websites addressing postpartum pelvic floor health. METHODS: The Google search engine was used to perform a search of the following 3 terms: (1) "postpartum pelvic floor (PPF)," (2) "postpartum leaking urine (PLU)," and (3) "postpartum leaking stool (PLS)." The top 20 results from each search term were evaluated using the DISCERN quality appraisal tool and Journal of the American Medical Association (JAMA) benchmark criteria by 2 independent researchers. Websites were also categorized by type. Cohen κ was performed to determine interrater reliability between reviewers. The Kruskal-Wallis test was used to evaluate the differences in DISCERN and JAMA criteria scores. RESULTS: The weighted mean κ between the investigators for each search term was κ = 0.47 (range = 0.163 [PPF] to 0.759 [PLU]), suggesting moderate agreement between reviewers. There was a significant difference in mean DISCERN scores between the terms, with "postpartum leaking urine" yielding the highest mean score. When comparing DISCERN scores by category, society- and government-sponsored websites (mean = 55 ± 13) scored significantly higher than other categories. Using JAMA criteria, mean scores ranged between 1.83 and 2.83/4, but there were no significant differences between websites. CONCLUSIONS: The overall quality of health information available on the internet regarding postpartum pelvic health is low. Higher-quality search results are found within society- and government-sponsored websites as well as under the search term "postpartum leaking urine." It is important for health care providers to guide their patients to websites with reliable information about postpartum pelvic floor recovery.

Short-Term Outcomes of Vaginal Hysterectomy at the Time of Robotic Sacrocolpopexy.

OBJECTIVE: With the introduction of robotic sacrocolpopexy (RSC) at our institution in 2008, we noted a reduction in residents' vaginal hysterectomy (VH) experience. In 2012, we made a transition to perform VH on all robotic sacrocolpopexies. Our objective was to report our short-term outcomes and adverse events. METHODS: In this case series, we evaluated women who underwent VH with concomitant RSC for stages II to IV pelvic organ prolapse between 2012 and 2017. In these cases, the vesicovaginal and rectovaginal spaces were developed transvaginally. Descriptive analysis including demographics, short-term outcomes, and adverse events are reported. RESULTS: In this group of 209 women, median (interquartile interval) duration of follow-up was 49 (26-60) weeks. The majority of the women were white (84.7%) and postmenopausal (80.9%), with a mean (SD) age of 59 (9) years. At a median follow-up time of 49 weeks, pelvic organ prolapse quantification revealed 20 patients (12.4%) with Ba or Bp greater or equal to 0 and 1.4% of patients required repeat prolapse surgery. Among 9 women (4.3%) with postoperative fever, 4 (1.9%) were treated for pelvic collection/abscess. Of 5 women (2.4%) who had venous thromboembolism, 3 (1.4%) were diagnosed with pulmonary embolism. There were 18 patients (8.6%) treated for urinary tract infection within 6 postoperative weeks. Mesh exposure was noted in 16 (7.7%) of the patients, and 11 (6.2%) required reoperation. CONCLUSIONS: Vaginal hysterectomy at the time of RSC may increase the risk of infection and mesh exposure compared with procedures without concomitant hysterectomy.

Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance.

Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.

Risk of deep venous thrombosis and pulmonary embolism in urogynecologic surgical patients.

OBJECTIVE: We sought to determine the incidence of symptomatic deep venous thrombosis and pulmonary embolism, collectively referred to as venous thromboembolic events (VTE), in patients undergoing urogynecologic surgery to guide development of a VTE prophylaxis policy for this patient population. STUDY DESIGN: We conducted a retrospective analysis of VTE incidence among women undergoing urogynecologic surgery over a 3-year period. All patients wore sequential compression devices intraoperatively through hospital discharge. RESULTS: Forty of 1104 patients (3.6%) undergoing urogynecologic surgery were evaluated with chest computed tomography, lower extremity ultrasound, or both for suspicion of VTE postoperatively. The overall rate of venous thromboembolism in this population was 0.3% (95% confidence interval, 0.1-0.8). CONCLUSION: Most women undergoing incontinence and reconstructive pelvic surgery are at a low risk for VTE. Sequential compression devices appear to provide adequate VTE prophylaxis in this patient population.