The Impact of Obesity on Success of Immediate Lymphatic Reconstruction for Prevention of Breast Cancer-Related Lymphedema.

BACKGROUND: Breast cancer-related lymphedema (BRCL) is a potential sequela of high-risk breast cancer treatment. Preventive treatment with immediate lymphatic reconstruction (ILR) at the time of axillary lymph node dissection (ALND) has emerged as the standard of care; however, there is relatively little known about factors that may contribute to procedural failure. METHODS: A retrospectively maintained, institutional review board-approved study followed patients who underwent ILR at the time of ALND at our tertiary care center between May 2018 and May 2023. Patients who presented for at least one follow-up visit in our multidisciplinary lymphedema clinic met the criteria for inclusion. Patients who developed lymphedema despite ILR and potential contributing factors were further explored. RESULTS: 349 patients underwent ILR at our institution between May 2018 and May 2023. 341 of these patients have presented for follow-up in our multidisciplinary lymphedema clinic. 32 (9.4%) patients developed lymphedema despite ILR. This cohort was significantly more likely to be obese (56% vs 35%, P = 0.04). Multivariate logistic regression demonstrates increased odds of procedural failure in patients with a body mass index (BMI) ≥30 kg/m2 (odds ratio 2.6 [1.2-5.5], P = 0.01). CONCLUSION: These data comment upon our institutions outcomes following ILR. Patients who develop lymphedema despite ILR tend to have a higher BMI, with a significantly increased risk in patients with a BMI of 30 or greater. Consideration of these data is critical for preprocedural counseling and may support a BMI cutoff when considering candidacy for ILR going forward, as well as when optimizing failures for secondary lymphedema procedures.

Unrecognized sexual dysfunction in gay and bisexual men after prostate cancer treatment: the antecedents and impact of anodyspareunia.

BACKGROUND: Anodyspareunia may be an adverse outcome of prostate cancer (PCa) treatment for gay, bisexual, and other men who have sex with men (GBM). AIM: The aims of this study were to (1) describe the clinical symptoms of painful receptive anal intercourse (RAI) in GBM following PCa treatment, (2) estimate the prevalence of anodyspareunia, and (3) identify clinical and psychosocial correlates. METHODS: This was a secondary analysis of baseline and 24-month follow-up data from the Restore-2 randomized clinical trial of 401 GBM treated for PCa. The analytic sample included only those participants who attempted RAI during or since their PCa treatment (N = 195). OUTCOMES: Anodyspareunia was operationalized as moderate to severe pain during RAI for ≥6 months that resulted in mild to severe distress. Additional quality-of-life outcomes included the Expanded Prostate Cancer Index Composite (bowel function and bother subscales), the Brief Symptom Inventory-18, and the Functional Assessment of Cancer Therapy-Prostate. RESULTS: Overall 82 (42.1%) participants reported pain during RAI since completing PCa treatment. Of these, 45.1% experienced painful RAI sometimes or frequently, and 63.0% indicated that the pain was persistent. The pain at its worst was moderate to very severe for 79.0%. The experience of pain was at least mildly distressing for 63.5%. Painful RAI worsened for a third (33.4%) of participants after completing PCa treatment. Of the 82 GBM, 15.4% were classified as meeting criteria for anodyspareunia. Antecedents of anodyspareunia included a lifelong history of painful RAI and bowel dysfunction following PCa treatment. Those reporting symptoms of anodyspareunia were more likely to avoid RAI due to pain (adjusted odds ratio, 4.37), which was negatively associated with sexual satisfaction (mean difference, -2.77) and self-esteem (mean difference, -3.33). The model explained 37.2% of the variance in overall quality of life. CLINICAL IMPLICATIONS: Culturally responsive PCa care should include the assessment of anodyspareunia among GBM and explore treatment options. STRENGTHS AND LIMITATIONS: This is the largest study to date focused on anodyspareunia among GBM treated for PCa. Anodyspareunia was assessed with multiple items characterizing the intensity, duration, and distress related to painful RAI. The external validity of the findings is limited by the nonprobability sample. Furthermore, the cause-and-effect relationships between the reported associations cannot be established by the research design. CONCLUSIONS: Anodyspareunia should be considered a sexual dysfunction in GBM and investigated as an adverse outcome of PCa treatment.

Localized Hydrophobicity in Aqueous Zinc Electrolytes Improves Zinc Metal Reversibility.

The rechargeability of aqueous zinc metal batteries is plagued by parasitic reactions of the zinc metal anode and detrimental morphologies such as dendritic or dead zinc. To improve the zinc metal reversibility, hereby we report a new solution structure of aqueous electrolyte with hydroxyl-ion scavengers and hydrophobicity localized in solvent clusters. We show that although hydrophobicity sounds counterintuitive for an aqueous system, hydrophilic pockets may be encapsulated inside a hydrophobic outer layer, and a hydrophobic anode-electrolyte interface can be generated through the addition of a cation-philic, strongly anion-phobic, and OH--reactive diluent. The localized hydrophobicity enables less active water and less absorbed water on the Zn anode surface, which suppresses the parasitic water reduction; while the hydroxyl-ion-scavenging functionality further minimizes undesired passivation layer formation, thus leading to superior reversibility (an average Zn plating/stripping efficiency of 99.72% for 1000 cycles) and lifetime (80.6% capacity retention after 5000 cycles) of zinc batteries.

Creation and Psychometric Validation of the Sexual Minorities and Prostate Cancer Scale (SMACS) in Sexual Minority Patients-The Restore-2 Study.

BACKGROUND: Existing measures of sexual functioning in prostate cancer survivors focus primarily on erectile function and do not adequately measure the experiences of sexual minority men. AIM: To develop and psychometrically evaluate a new scale to measure sexual functioning among sexual minority men with prostate cancer. METHODS: Sexual minority prostate cancer patients (n = 401) completed an online battery of urinary and sexual functioning tests in 2019, including a new 37-item instrument about their sexual functioning post-treatment for prostate cancer. OUTCOMES: We used confirmatory factor analysis to determine the construct validity of a new scale including five subscales: a four-factor model for all participants (n = 401) evaluated Sexual Satisfaction, Sexual Confidence, Frequency of Sexual Problems, and Urinary Incontinence in Sex. A single-factor model completed only by participants who had attempted or desired receptive anal sex (n = 255) was evaluated in the fifth subscale: Problematic Receptive Anal Sex. To evaluate criterion validity, we calculated the intercorrelations between each Sexual Minorities and Prostate Cancer Scale (SMACS) subscale and four related scales: the Expanded Prostate Cancer Index Composite-50 (EPIC), the Functional Assessment of Cancer Therapy-Prostate, the Brief Symptom Inventory-18, and the International Consultation on incontinence questionnaire. Cronbach's alphas were calculated to measure internal consistency (ie, reliability). RESULTS: Cronbach's alpha values ranged from 0.64 to 0.89. Loadings (0.479-0.926) and model fit indices were strong (Root Mean Square Error of Approximation: 0.085, Standardized root mean squared residual: 0.063, comparative fit index: 0.927, Tucker-Lewis Index: 0.907). For criterion validity, Sexual Satisfaction, Sexual Confidence, and Frequency of Sexual Problems were moderately correlated with EPIC function and bother scores (r = 0.50-0.72) and Urinary incontinence in sex correlated moderately with EPIC Urinary Function and International Consultation on incontinence questionnaire scores (0.45-0.56). CLINICAL IMPLICATIONS: The SMACS can be used by clinicians and researchers to comprehensively measure sexual functioning in sexual minority men, in conjunction with existing scales. STRENGTHS AND LIMITATIONS: This new scale is validated in a large, geographically diverse cohort of sexual minority cancer survivors and fills an important gap in existing measures of sexual functioning. Limitations include a lack of a validation sample. CONCLUSION: The SMACS is a valid and reliable new scale that measures sexual minority men's experience of urinary incontinence in sex, problematic receptive anal sex, and sexual distress. Polter EJ, Kohli N, Rosser BRS, et al. Creation and Psychometric Validation of the Sexual Minorities and Prostate Cancer Scale (SMACS) in Sexual Minority Patients-The Restore-2 Study. J Sex Med 2022;19:529-540.

Recruiting an underserved, difficult to reach population into a cancer trial: Strategies from the Restore-2 Rehabilitation Trial for gay and bisexual prostate cancer patients.

BACKGROUND/AIMS: Sexual minorities are small and under-researched populations that are at disproportionate risk for cancer and poor cancer outcomes. Described as a "hidden population," the principal research challenge has been to develop effective methods to identify and recruit such cancer patients into cancer studies. Online recruitment strategies, as well as targeted clinic recruitment using patient-entered sexual orientation and gender identity data from electronic medical records have potential to transform recruitment, but studies testing the effects of how to recruit using these have not been published. METHODS: In 2019, we conducted a naturalistic, three-arm, stratified prospective study to compare three recruitment strategies: (a) clinic based recruitment of prostate cancer patients from gay health and urology clinics; (b) directly from the gay community; and (c) online recruitment (through cancer support, sex/dating, and social sites). For each strategy, we estimated time, workload, and direct costs involved. To study how recruitment strategy may affect sampling, we tested for retention rates, demographic and outcome differences across sites. Using these methods, we successfully recruited 401 gay and bisexual prostate cancer patients into a randomized, controlled, 24-month trial testing an online sexual and urinary rehabilitation curriculum tailored for this population. RESULTS: There were seven key results. First, it is possible to recruit substantial numbers of sexual minority men into prostate cancer studies provided online recruitment methods are used. Second, we observed big differences in dropout during study onboarding by recruitment source. Third, within online recruitment, the online sex/dating application (app) was the most successful and efficient, followed by the cancer support site, and then the social networking site. Fourth, while clinics were the cheapest source of recruitment, they were time intensive and low in yield. Fifth, the cancer support site and sex/dating app recruits differed by several characteristics, with the former being more rehabilitation-focused while the latter were younger and more sexually active. Sixth, we found almost no differences in outcomes across the three online recruitment sites. Seventh, because retention in online studies has been a concern, we confirm very low attrition at 3- and 6 months into the trial. CONCLUSION: For sexual minority cancer research, more research on how to use sexual orientation and gender identity electronic medical record data for clinic-based recruitment is needed. For other small or hard-to-reach populations, researchers should compare and publish online versus offline recruitment strategies.

The Sexual Functioning of Gay and Bisexual Men Following Prostate Cancer Treatment: Results from the Restore Study.

Prostate cancer is the second most common cancer in gay, bisexual, and other men who have sex with men (GBM). Few studies have assessed the effects of treatment on GBM's sexual behavior. For an online survey, 193 gay and bisexual men with prostate cancer were recruited from the North American's largest online cancer support group. Sexual functioning was measured using the Expanded Prostate Cancer Index Composite (EPIC) and a tailored Gay Sexual Functioning Inventory (GSFI). GBM have worse EPIC urinary and hormonal function and worse hormonal bother, but better sexual function and bother scores than published norms. In the GSFI, two-thirds of participants described their sexual functioning, post-treatment, as fair to poor. Only 22% reported erections sufficient for insertive anal sex. For receptive anal sex, one-third met criteria for anodyspareunia. Over half reported urination problems during sex or at orgasm. Erectile difficulties were common, severe, and a reason cited for not using condoms. Three men HIV seroconverted post-prostate cancer treatment. Differences in function and bother scores were observed by type of treatment, age, race/ethnicity, sexual orientation, but not relationship status. Sexual functioning significantly predicted long-term mental and physical health. GBM scored significantly worse on mental health and better on physical health than published norms. Sexual recovery after prostate cancer treatment is problematic for most GBM. Research to develop more effective sexual recovery, tailored to the needs of GBM treated for prostate cancer, is needed. Six implications for clinicians treating GBM with prostate cancer are identified.

Regenerative Injectable Therapies: Current Evidence.

Regenerative medicine is a growing field of musculoskeletal treatments that focuses on amplifying the body's natural healing properties to improve function and pain after injury. Regenerative treatments are applied locally at the site of injury and work though different mechanisms, some of which are unexplained at this time. Current evidence demonstrates benefit for certain regenerative treatments, but further standardization of treatments and additional studies are required to provide additional data to support specific regenerative treatments. This review seeks to explore the evidence and discuss appropriate use of the most common regenerative treatments including platelet-rich plasma, prolotherapy, autologous mesenchymal stem cells, human-derived allograft products, and saline.

Health-related quality of life by human immunodeficiency virus status in a cross-sectional survey of gay and bisexual prostate cancer survivors.

OBJECTIVE: Prostate cancer is the most common invasive cancer in gay and bisexual men (GBM). Despite the unique sexual and urinary concerns of this group, studies of prostate cancer rehabilitation have primarily focused on heterosexual men. GBM also have high prevalence of human immunodeficiency virus (HIV), which may be associated with lower health-related quality of life (HRQOL). We examined the association between HIV status and HRQOL in a cohort of GBM with prostate cancer. METHODS: Data from the Restore study, a cross-sectional online survey of GBM treated for prostate cancer, were used to examine this association. The Expanded Prostate Cancer Index Composite (EPIC) assessed function, bother, and summary measures in four domains: urinary, sexual, bowel, and hormone. Overall physical and mental HRQOL was assessed using the Short-Form Health Survey (SF-12). Multivariate analysis of variance and linear regression were used to evaluate the association between HIV status and HRQOL scores after adjustment for demographic and sexual characteristics. RESULTS: Of 192 participants, 24 (12.4%) reported an HIV diagnosis. After adjustment for covariates, HIV-positive status was associated with lower scores on the EPIC urinary (mean difference [MD]: -13.0, 95% CI, -21.4 to -4.6), sexual (MD: -12.5, 95% CI, -21.9 to -3.2), and bowel (MD: -5.9, 95% CI, -11.7 to -0.2) domains. No significant associations were observed between HIV status and other outcomes. CONCLUSIONS: HIV status may be associated with poorer urinary, sexual, and bowel HRQOL in GBM prostate cancer survivors.

A role for B cells in organic dust induced lung inflammation.

BACKGROUND: Agriculture organic dust exposures induce lung disease with lymphoid aggregates comprised of both T and B cells. The precise role of B cells in mediating lung inflammation is unknown, yet might be relevant given the emerging role of B cells in obstructive pulmonary disease and associated autoimmunity. METHODS: Using an established animal model, C57BL/6 wild-type (WT) and B-cell receptor (BCR) knock-out (KO) mice were repetitively treated with intranasal inhalation of swine confinement organic dust extract (ODE) daily for 3 weeks and lavage fluid, lung tissues, and serum were collected. RESULTS: ODE-induced neutrophil influx in lavage fluid was not reduced in BCR KO animals, but there was reduction in TNF-α, IL-6, CXCL1, and CXCL2 release. ODE-induced lymphoid aggregates failed to develop in BCR KO mice. There was a decrease in ODE-induced lung tissue CD11c+CD11b+ exudative macrophages and compensatory increase in CD8+ T cells in lavage fluid of BCR KO animals. Compared to saline, there was an expansion of conventional B2-, innate B1 (CD19+CD11b+CD5+/-)-, and memory (CD19+CD273+/-CD73+/-) B cells following ODE exposure in WT mice. Autoreactive responses including serum IgG anti-citrullinated protein antibody (ACPA) and anti-malondialdehyde-acetaldehyde (MAA) autoantibodies were increased in ODE treated WT mice as compared to saline control. B cells and serum immunoglobulins were not detected in BCR KO animals. CONCLUSIONS: Lung tissue staining for citrullinated and MAA modified proteins were increased in ODE-treated WT animals, but not BCR KO mice. These studies show that agriculture organic dust induced lung inflammation is dependent upon B cells, and dust exposure induces an autoreactive response.

ß2-Adrenergic agonists attenuate organic dust-induced lung inflammation.

Agricultural dust exposure results in significant lung inflammation, and individuals working in concentrated animal feeding operations (CAFOs) are at risk for chronic airway inflammatory diseases. Exposure of bronchial epithelial cells to aqueous extracts of hog CAFO dusts (HDE) leads to inflammatory cytokine production that is driven by protein kinase C (PKC) activation. cAMP-dependent protein kinase (PKA)-activating agents can inhibit PKC activation in epithelial cells, leading to reduced inflammatory cytokine production following HDE exposure. ß2-Adrenergic receptor agonists (ß2-agonists) activate PKA, and we hypothesized that ß2-agonists would beneficially impact HDE-induced adverse airway inflammatory consequences. Bronchial epithelial cells were cultured with the short-acting ß2-agonist salbutamol or the long-acting ß2-agonist salmeterol prior to stimulation with HDE. ß2-Agonist treatment significantly increased PKA activation and significantly decreased HDE-stimulated IL-6 and IL-8 production in a concentration- and time-dependent manner. Salbutamol treatment significantly reduced HDE-induced intracellular adhesion molecule-1 expression and neutrophil adhesion to epithelial cells. Using an established intranasal inhalation exposure model, we found that salbutamol pretreatment reduced airway neutrophil influx and IL-6, TNF-α, CXCL1, and CXCL2 release in bronchoalveolar lavage fluid following a one-time exposure to HDE. Likewise, when mice were pretreated daily with salbutamol prior to HDE exposure for 3 wk, HDE-induced neutrophil influx and inflammatory mediator production were also reduced. The severity of HDE-induced lung pathology in mice repetitively exposed to HDE for 3 wk was also decreased with daily salbutamol pretreatment. Together, these results support the need for future clinical investigations to evaluate the utility of ß2-agonist therapies in the treatment of airway inflammation associated with CAFO dust exposure.

Caregiving and social support for gay and bisexual men with prostate cancer.

OBJECTIVE: Prostate cancer, the second most common cancer among men, typically onsets in middle or older age. Gay/bisexual men have different social networks and unique social support needs, particularly as it pertains to health care access and prostate side effects. Few studies have investigated the availability and provision of social support for gay and bisexual men with prostate cancer (GBMPCa). METHODS: This study used qualitative data from in-depth, semistructured, one-on-one telephone interviews with 30 GBMPCa recruited from a national cancer support group network, Malecare. Inductive and deductive codes were used to identify themes about social support provided to GBMPCa during diagnosis and treatment. RESULTS: GBMPCa reported help from friends, family (parents and siblings), ex-partners, and paid caregivers. Men in relationships reported varying levels of reliance on their partners for support, in part due to relationship dynamics and living arrangements. Single men showed a theme of independence ("I turned down all help," "My friends don't want to be bothered"). After diagnosis, many men reported seeking informational and emotional support from prostate cancer support groups; most expressed wanting more support groups specifically for GBMPCa. During or after treatment, men reported receiving a range of instrumental support, largely a function of relationship status and treatment type. CONCLUSIONS: GBMPCa received variable, but generally low, social support during diagnosis and treatment and from a diverse social network, including a prominence of friends and family. Clinicians should be aware of GBMPCa's distinct patterns of social support needs and providers.

The Effects of Radical Prostatectomy on Gay and Bisexual Men's Mental Health, Sexual Identity and Relationships: Qualitative Results from the Restore Study.

The effect of prostate cancer treatment in gay and bisexual men is an under-researched area. In 2015, we conducted in-depth telephone interviews with 19 gay and bisexual men who had undergone radical prostatectomies. Across the respondents' five emotional themes emerged: (1) shock at the diagnosis, (2) a reactive, self-reported "depression", (3) sex-specific situational anxiety, (4) a sense of grief, and, (5) an enduring loss of sexual confidence. Identity challenges included loss of a sense of maleness and manhood, changes in strength of sexual orientation, role-in-sex identity, and immersion into sexual sub-cultures. Relationship challenges identified included disclosing the sexual effects of treatment to partners, loss of partners, and re-negotiation of sexual exclusivity. Most to all of these effects stem from sexual changes. To mitigate these negative effects of radical prostatectomy, and to address health disparities n outcomes observed in gay and bisexual men, all these challenges need to be considered in any tailored rehabilitation program for gay and bisexual men.

The effects of radical prostatectomy on gay and bisexual men's sexual functioning and behavior: qualitative results from the restore study.

To advance research on the sexual effects of prostate cancer in sexual minorities, we conducted telephone interviews with 19 gay and bisexual men (GBM) who had undergone radical prostatectomies. Challenges to sexual functioning included anatomical penile changes, loss of ejaculate, climacturia, and erectile dysfunction. All sexual behavior with other men, not just insertive anal sex, was affected, across all stages of the sexual response cycle. Rather than narrowly focusing on erectile functioning, rehabilitation for GBM needs to be comprehensive in addressing anatomical changes, sexual behavior comprehensively, and functioning across the sexual response cycle. Seven recommendations for practitioner education are identified.

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation.

Workers exposed to aerosolized dust present in concentrated animal feeding operations (CAFOs) are susceptible to inflammatory lung diseases, such as chronic obstructive pulmonary disease. Extracts of dust collected from hog CAFOs [hog dust extract (HDE)] are potent stimulators of lung inflammatory responses in several model systems. The observation that HDE contains active proteases prompted the present study, which evaluated the role of CAFO dust proteases in lung inflammatory processes and tested whether protease-activated receptors (PARs) are involved in the signaling pathway for these events. We hypothesized that the damaging proinflammatory effect of HDE is due, in part, to the proteolytic activation of PARs, and inhibiting the proteases in HDE or disrupting PAR activation would attenuate HDE-mediated inflammatory indexes in bronchial epithelial cells (BECs), in mouse lung slices in vitro, and in a murine in vivo exposure model. Human BECs and mouse lung slice cultures stimulated with 5% HDE released significantly more of each of the cytokines measured (IL-6, IL-8, TNF-α, keratinocyte-derived chemokine/CXC chemokine ligand 1, and macrophage inflammatory protein-2/CXC chemokine ligand 2) than controls, and these effects were markedly diminished by protease inhibition. Inhibition of PARs also blunted the HDE-induced cytokine release from BECs. In addition, protease depletion inhibited HDE-induced BEC intracellular PKCα and PKCε activation. C57BL/6J mice administered 12.5% HDE intranasally, either once or daily for 3 wk, exhibited increased total cellular and neutrophil influx, bronchial alveolar fluid inflammatory cytokines, lung histopathology, and inflammatory scores compared with mice receiving protease-depleted HDE. These data suggest that proteases in dust from CAFOs are important mediators of lung inflammation, and these proteases and their receptors may provide novel targets for therapeutic intervention in CAFO dust-induced airways disease.

Enormous, rapidly growing breast mass.

BACKGROUND: Signs and symptoms of a rapidly enlarging breast mass are not only important for all clinicians to recognize and assess, but also are not uncommon occurrences. We describe a similar but unique case that developed into an enormous, 36 cm exophytic mass. CASE PRESENTATION: A 51-year-old woman with history of psychiatric conditions presented for signs and symptoms of sepsis. It was determined that the source was an enormous 36 cm mass originating from the breast/chest wall. After stabilizing the patient with antibiotics, she underwent successful resection. Surgical margins were positive, and histopathology demonstrated bland spindle cells with stromal overgrowth. Together with clinical and histopathological information, the patient was diagnosed with a phyllodes tumor. CONCLUSION: Differential diagnosis of rapidly growing breast masses is discussed, which are not uncommon occurrences in clinical medicine. One etiology, phyllodes tumors, can grow into large, exophytic masses as described. Oncologic treatment is discussed, usually consisting of surgery with postoperative radiotherapy for high-risk features.

Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure.

Agricultural workers have high rates of airway and skeletal health disease. Studies recently demonstrated that inhaled agricultural organic dust extract (ODE)-induced airway injury is associated with bone deterioration in an animal model. However, the effect of age in governing these responses to organic dusts is unclear, but might be important in future approaches. Young (7-9 wk) and older (12-14,o) male C57BL/6 mice received intranasal (i.n.) inhalation exposure to ODE from swine confinement facilities once or daily for 3 wk. Acute ODE-induced neutrophil influx and cytokine and chemokine (tumor necrosis factor [TNF]-α, interleukin [IL]-6, keratinocyte chemoattractant [CXCL1], macrophage inflammatory protein-2 [CXCL2]) airway production were reduced in older compared to young mice. Repetitive ODE treatment, however, increased lymphocyte recruitment and alveolar compartment histopathologic inflammatory changes in older mice. Whole lung cell infiltrate analysis revealed that young, but not older, mice repetitively treated with ODE demonstrated an elevated CD4:CD8 lymphocyte response. Acute inhalant ODE exposure resulted in a 4-fold and 1.5-fold rise in blood neutrophils in young and older mice, respectively. Serum IL-6 and CXCL1 levels were elevated in young and older mice i.n. exposed once to ODE, with increased CXCL1 levels in younger compared to older mice. Although older mice displayed reduced bone measurements compared to younger mice, younger rodents demonstrated ODE-induced decrease in bone mineral density, bone volume, and bone microarchitecture quality as determined by computed tomography (CT) analysis. Collectively, age impacts the airway injury and systemic inflammatory and bone loss response to inhalant ODE, suggesting an altered and enhanced immunologic response in younger as compared to older counterparts.

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) eliminates many epigenetic modifications that characterize differentiated cells. In this study, we tested whether functional differences between chronic obstructive pulmonary disease (COPD) and non-COPD fibroblasts could be reduced utilizing this approach. Primary fibroblasts from non-COPD and COPD patients were reprogrammed to iPSCs. Reprogrammed iPSCs were positive for oct3/4, nanog, and sox2, formed embryoid bodies in vitro, and induced teratomas in nonobese diabetic/severe combined immunodeficient mice. Reprogrammed iPSCs were then differentiated into fibroblasts (non-COPD-i and COPD-i) and were assessed either functionally by chemotaxis and gel contraction or for gene expression by microarrays and compared with their corresponding primary fibroblasts. Primary COPD fibroblasts contracted three-dimensional collagen gels and migrated toward fibronectin less robustly than non-COPD fibroblasts. In contrast, redifferentiated fibroblasts from iPSCs derived from the non-COPD and COPD fibroblasts were similar in response in both functional assays. Microarray analysis identified 1,881 genes that were differentially expressed between primary COPD and non-COPD fibroblasts, with 605 genes differing by more than twofold. After redifferentiation, 112 genes were differentially expressed between COPD-i and non-COPD-i with only three genes by more than twofold. Similar findings were observed with microRNA (miRNA) expression: 56 miRNAs were differentially expressed between non-COPD and COPD primary cells; after redifferentiation, only 3 miRNAs were differentially expressed between non-COPD-i and COPD-i fibroblasts. Interestingly, of the 605 genes that were differentially expressed between COPD and non-COPD fibroblasts, 293 genes were changed toward control after redifferentiation. In conclusion, functional and epigenetic alterations of COPD fibroblasts can be reprogrammed through formation of iPSCs.

Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells.

BACKGROUND: The serine-threonine kinase AKT1 plays essential roles during normal mammary gland development as well as the initiation and progression of breast cancer. AKT1 is generally considered a ubiquitously expressed gene, and its persistent activation is transcriptionally controlled by regulatory elements characteristic of housekeeping gene promoters. We recently identified a novel Akt1 transcript in mice (Akt1m), which is induced by growth factors and their signal transducers of transcription from a previously unknown promoter. The purpose of this study was to examine whether normal and neoplastic human breast epithelial cells express an orthologous AKT1m transcript and whether its expression is deregulated in cancer cells. METHODS: Initial sequence analyses were performed using the UCSC Genome Browser and GenBank to assess the potential occurrence of an AKT1m transcript variant in human cells and to identify conserved promoter sequences that are orthologous to the murine Akt1m. Quantitative RT-PCR was used to determine the transcriptional activation of AKT1m in mouse mammary tumors as well as 41 normal and neoplastic human breast epithelial cell lines and selected primary breast cancers. RESULTS: We identified four new AKT1 transcript variants in human breast cancer cells that are orthologous to the murine Akt1m and that encode the full-length kinase. These transcripts originate from an alternative promoter that is conserved between humans and mice. Akt1m is upregulated in the majority of luminal-type and basal-type mammary cancers in four different genetically engineered mouse models. Similarly, a subset of human breast cancer cell lines and primary breast cancers exhibited a higher expression of orthologous AKT1m transcripts. CONCLUSIONS: The existence of an alternative promoter that drives the expression of the unique AKT1m transcript may provide a mechanism by which the levels of AKT1 can be temporally and spatially regulated at particular physiological states, such as cancer, where a heightened activity of this kinase is required.

Sociodemographic and Clinical Predictors of Prolonged Length of Corneal Ulcer Hospitalizations.

Importance: The length of stay (LOS) of hospitalizations may be a useful indicator of the burden of disease of corneal ulcers. Identifying variables associated with longer LOS may help to enhance delivery of care for high-risk patients. Objective: To investigate the sociodemographic, social, and clinical factors associated with LOS in hospitalizations for corneal ulcers in the US. Design, Setting, and Participants: This was a retrospective cross-sectional study of adult patients (aged >18 years) admitted with a primary diagnosis of corneal ulcer between quarter 4 of 2015 through 2020 and conducted using data from the National Inpatient Sample (NIS). Patients were stratified into 2 even cohorts based on LOS: LOS of 4 days or less and LOS greater than 4 days. Individual-level sociodemographic, social risk factors, and medical comorbidities associated with longer LOS were examined by multivariable regression. Data were analyzed from October 2015 to December 2020. Exposure: Potential sociodemographics or medical comorbidities at hospital admission. Main Outcome and Measure: The primary outcome of interest was factors associated with extended length of stay. The hypothesis being tested was formulated during data collection. Results: A total of 1187 patients (mean [SD] age, 53.5 [20.9] years; 602 female [50.7%]) were included for analysis. The cohort with LOS greater than 4 days had higher total charges than the cohort with LOS of 4 days or less (mean [SD] charges, $79 504 [$86 719] vs $26 474 [$20 743]; P < .001). Sociodemographic variables associated with LOS greater than 4 days were Black race (adjusted odds ratio [aOR], 1.41; 95% CI, 1.03-1.92; P = .03), Medicare insurance (aOR, 1.42; 95% CI, 1.09-1.85; P = .009), and housing insecurity (aOR, 1.99; 95% CI, 1.29-3.06; P = .002). Medical comorbidities associated with LOS greater than 4 days were alcohol use (aOR, 1.50; 95% CI, 1.00-2.26; P = .05), dementia (aOR, 2.35; 95% CI, 1.36-4.07; P = .002), complicated diabetes (aOR, 1.75; 95% CI, 1.21-2.53; P = .003), uncomplicated diabetes (aOR, 1.57; 95% CI, 1.02-2.42; P = .04), drug misuse (aOR, 1.66; 95% CI, 1.08-2.57; P = .02), and legal blindness (aOR, 3.42; 95% CI, 1.19-9.82; P = .02). Based on NIS national estimates, corneal ulcers were estimated to have a direct annual health care expenditure of $35 819 590 in the US. Conclusion and Relevance: Corneal ulcer hospitalizations represent a significant burden of disease for patients and health care systems. This study highlights sociodemographic and clinical factors that may help clinicians identify high-risk patients vulnerable to complications and morbidity due to corneal ulcers.

Outcomes of Thumb Metacarpophalangeal Joint Arthrodesis Using the XMCP Intramedullary Interlocking Device.

Purpose: The intramedullary interlocking device for metacarpophalangeal (MCP) joint arthrodesis (XMCP, Extremity Medical, Parsippany, NJ) has been shown to promote union at a precise angle, provide strong fixation without the need for prolonged immobilization, and lower the incidence of hardware irritation and revision surgery. In this study, we evaluated the clinical outcomes of patients undergoing MCP joint arthrodesis with the XMCP system using a retrospective chart review, patient reported outcomes, and radiographic analysis. Methods: A retrospective chart review and phone survey was conducted on 57 patients (58 cases) from a single institution between 2017 and 2022. The primary outcome was patient satisfaction, including pre- and postoperative Numeric Rating Scale (NRS) pain scores, Disabilities of Arm Shoulder and Hand (QuickDASH) outcomes, perceived grip strength, and willingness to undergo the procedure again. Secondary outcomes included the need for revision procedures, successful fusion of arthrodesis, and postoperative complications. Results: Of the 57 patients who underwent MCP joint arthrodesis of the thumb using the XMCP fusion device, a total of 43 (75%) completed the phone survey. The average age of patients was 67 years with an average clinical follow-up of 9 months (range 1-65 months). Patients who participated in the phone survey questionnaire had an average QuickDASH score of 24.7 ± 20.5. Average perceived NRS scores were 6.2 ± 3.5 and 1.2 ± 2.1 before and after surgery, respectively. Average perceived grip strength of patients was 3 ± 1.3 out of 5. When evaluating for concurrent procedures, there was no statistically significant difference in pre- or postoperative NRS scores. In total, 38 (88%) patients were satisfied with the procedure, and 39 (91%) patients would undergo the procedure again. Conclusion: Metacarpophalangeal joint arthrodesis of the thumb with the intramedullary fusion device is reproducible, allows for immediate use without immobilization, has a low number of complications, and provides improved function and pain relief. Level of Evidence: Therapeutic III.