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Objective To examine associations between changes in Rheumatoid Arthritis (RA) symptoms and depressive symptoms, adjusted for other time-varying characteristics, and to test if these associations differed by education, race/ethnicity, or gender. Methods Data from the 1988-98 United States National Rheumatoid Arthritis Study were analyzed (n = 854). Time-varying covariates included year of the study, pain, functional ability, household work disability, parental status, marital status, employment status, and social support. The time-invariant covariates included years since diagnosis, education, race/ethnicity, and gender. Multivariate multilevel-model analyses were used to estimate associations within people over time. Results People with RA experience considerable change in depressive symptoms, pain, functional disability and household work disability over the study period. Depressive symptoms were driven more by differences between people compared to changes within people over time. Findings show patients experienced increases in depressive symptoms over the study period. The rate of change in depressive symptoms did not differ by education, race/ethnicity, nor gender. Times of worse pain, functional disability, and household disability were associated with worse depressive symptoms. The association of functional disability and depressive symptoms was stronger for men than women. Conclusion Increases in pain and disability were associated with worse depressive symptoms, adjusted for co-variates. It is important to monitor and treat both mental and physical health symptoms. Future research efforts should focus on collecting data reflecting the educational, gender, and racial-ethnic diversity of people with RA.

Little is known about the long-term functional outcomes of restorative proctocolectomy.The aim of this study was to examine ileoanal pouch outcomes 20 and 30 years postoperatively.This is a retrospective case series.This study was conducted at a tertiary care referral center.Patients who underwent restorative proctocolectomy between 1980 and 1994 were identified. Those with ≥20 years of in-person follow-up were included.Pouch function, pouchitis, anal stricture, and pouch failure rates were analyzed.A total of 203 patients had ≥20 years of follow-up. Of those, 71 had ≥30 years of follow-up. Initial diagnoses included ulcerative colitis (83%), indeterminate colitis (9%), familial adenomatous polyposis (4%), and Crohn's disease (3%). Twenty-one percent of those with ulcerative or indeterminate colitis later transitioned to Crohn's disease. Mean daily stool frequency was 7 (IQR 6-8), 38% experienced seepage, 31% had anal stenosis, 47% experienced pouchitis, and 18% had pouch failure. Over time, stool frequency increased in 41% of patients, stayed the same in 43%, and decreased in 16%. Patients older than 50 years at the time of construction had more daily bowel movements (median 8 vs 6; p = 0.02) and more seepage (77% vs 35%; p = 0.005) than those younger than 50 years. Patients with Crohn's disease had higher stool frequency (median 8 vs 6; p0.001) and higher rates of anal stenosis (44% vs 26%; p = 0.02), pouchitis (70% vs 40%; p0.001), and pouch failure (38% vs 12%; p0.001) compared to non-Crohn's patients. Patients with ≥30 years of follow-up had similar function as those with 20-30 years of follow-up.This was a retrospective, single-institution study. Only 35% of pouches created during the study period had20 years of follow-up.Most patients maintain reasonably good function and retain their pouches after 20 years. Over time, stool frequency and seepage increase. Older age and Crohn's disease are associated with worse outcomes. See Video Abstract at http://links.lww.com/DCR/B801.ANTECEDENTES:se sabe poco sobre los resultados funcionales a largo plazo de la proctocolectomía restauradora.OBJETIVO:El objetivo de este estudio fue examinar los resultados del reservorio ileoanal 20 y 30 años después de la operación.DISEÑO:Serie de casos retrospectiva.ENTORNO CLÍNICO:Centro de referencia de atención terciariaPACIENTES:Se identificaron pacientes que se sometieron a proctocolectomía restauradora entre 1980 y 1994. Se incluyeron aquellos con ≥20 años de seguimiento en persona.PRINCIPALES MEDIDAS DE VALORACIÓN:Se analizaron la función, inflamación, tasas de falla del reservorio y estenosis anal.RESULTADOS:Un total de 203 pacientes tuvieron ≥20 años de seguimiento. De ellos, 71 tenían ≥30 años de seguimiento. Los diagnósticos iniciales incluyeron colitis ulcerosa (83%), colitis indeterminada (9%), poliposis adenomatosa familiar (4%) y enfermedad de Crohn (3%). El 21% de las personas con colitis ulcerosa o indeterminada pasaron posteriormente a la enfermedad de Crohn. La frecuencia promedio de las deposiciones diarias fue de 7 (rango intercuartil 6-8), el 38% experimentó filtración, el 31% tuvo estenosis anal, el 47% experimentó pouchitis y el 18% tuvo falla del reservorio. Con el tiempo, la frecuencia de las deposiciones aumentó en el 41% de los pacientes, se mantuvo igual en el 43% y disminuyó en el 16%. Los pacientes mayores de 50 años en el momento de la construcción tenían más evacuaciones intestinales diarias (media 8 vs 6, p = 0,02) y más filtraciones (77% vs 35%, p = 0,005) que los menores de 50 años. Los pacientes con enfermedad de Crohn tenían mayor frecuencia de deposiciones (media 8 vs 6, p0,001) y tasas más altas de estenosis anal (44% vs 26%, p = 0,02), inflamacion (70% vs 40%, p0,001) y falla del reservorio (38% frente a 12%, p0,001) en comparación con pacientes que tenian enfermedad de Crohn. Los pacientes con ≥30 años de seguimiento tuvieron una función similar a aquellos con 20-30 años de seguimiento.LIMITACIONES:Este fue un estudio retrospectivo de una sola institución. Solo el 35% de los reservorios creados durante el período de estudio tuvieron más de 20 años de seguimiento.CONCLUSIONES:La mayoría de los pacientes mantienen una función razonablemente buena y conservan el reservorio después de 20 años. Con el tiempo, la frecuencia de las deposiciones y la filtración aumentan. La vejez y la enfermedad de Crohn se asocian con peores resultados. Consulte Video Resumen en http://links.lww.com/DCR/B801. (Traducción - Dr. Ingrid Melo).

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.

Precise foot placement is dependent on changes in spatial and temporal coordination between two legs in response to a perturbation during walking. Here, we used a ‘virtual’ split-belt adaptation task to examine the effects of reinforcement (reward and punishment) feedback about foot placement on the changes in error, step length and step time asymmetry. Twenty-seven healthy adults (20 ± 2.5 years) walked on a treadmill with continuous feedback of the foot position and stepping targets projected on a screen, defined by a visuomotor gain for each leg. The paradigm consisted of a baseline period (same gain on both legs), visuomotor adaptation period (split: one high = ‘fast’, one low = ‘slow’ gain) and post-adaptation period (same gain). Participants were divided into 3 groups: control group received no score, reward group received increasing score for each target hit, and punishment group received decreasing score for each target missed. Re-adaptation was assessed 24 ± 2 h later. During early adaptation, the slow foot undershot and fast foot overshot the stepping target. Foot placement errors were gradually reduced by late adaptation, accompanied by increasing step length asymmetry (fast slow step time). Only the punishment group showed greater error reduction and step length re-adaptation on the next day. The results show that (1) explicit feedback of foot placement alone drives adaptation of both step length and step time asymmetry during virtual split-belt walking, and (2) specifically, step length re-adaptation driven by visuomotor errors may be enhanced by punishment feedback.

Background Scrotal abscesses are common skin abscesses seen in the general population; however, intraperitoneal abscesses tracking into the scrotum are rare. Intraperitoneal and retroperitoneal abscesses contiguous with the scrotum have been reported in the literature in specific populations. Wound cultures can aid in differentiating the source of the infections. Recurrent abscesses have been observed in high-risk populations, such as those with malignancy or who are immunocompromised. Case presentation We present a 71-year-old male with pericolonic abscess following perforated diverticulitis. The abscess was drained with interventional radiology and was complicated by an extraperitoneal abscess that tracked to the scrotum. Incision and drainage of the extraperitoneal abscess and the scrotal abscess were required with intravenous antibiotic therapy. The abscess tracking into the scrotum is reported without evidence of patent processus vaginalis. Conclusion We conclude that an intraperitoneal abscess can track to the scrotum through extraperitoneal fascial planes in the absence of a patent processus vaginalis. We show that extraperitoneal abscess spread to the scrotum is possible, with wound cultures helping to differentiate the source of the infection. High-risk patients with recurrent abscesses can also be susceptible to contiguous spread.

The purpose of this article was to report a case of unilateral late-onset nontuberculous mycobacterial keratitis after small incision lenticule extraction (SMILE).This was a case report.A 27-year-old woman presented with Mycobacterium chelonae keratitis 3 weeks after uncomplicated SMILE with a solitary interface infiltrate. The keratitis worsened after an initial response to topical fortified and interface antibiotic irrigation. Despite repeated interface irrigation and topical and oral antibiotics, progressive, diffuse stromal infiltrates followed by melting of the cap ensued over the next 6 weeks. Cap amputation and intrastromal antibiotic injection followed by prolonged topical and oral antibiotics usage for the following 5 weeks led to infiltrate resolution and re-epithelization of the residual stromal bed. All medications were tapered off over 6 months after initial presentation without recurrence, but anterior stromal scarring and corneal neovascularization persisted.Cap amputation and intrastromal antibiotic injection for intractable post-SMILE keratitis can prevent the need for therapeutic keratoplasty.

BACKGROUND Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts. METHODS OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort. RESULTS The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase. CONCLUSIONS This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.

This study assessed the feasibility and benefits of high-intensity interval training (HIIT) plus lifestyle education among inactive adults with celiac disease. Forty-one participants were randomized to receive the intervention (HIIT plus lifestyle education; HIIT+) for 12 weeks or waitlist control (WLC). Testing was completed at baseline, immediately post-intervention, and 3 months post-intervention. Generalized estimating equations were used to assess changes in the outcome variables over time between the groups. Mean percent of age-predicted maximum heart rate was 97.9% and average rating of perceived exertion was 6.33 (out of 10) during HIIT intervals. Following the intervention, the HIIT+ showed enrichment in relative abundance of Parabacteroides and Defluviitaleaceae_UCG_011 while WLC showed enrichment in relative abundance of Roseburia intestinalis, Klebsiella, and Adlercreutzia. A unique set of taxa were differentially abundant between the groups at 3 months post-intervention. HIIT+ participants experienced a reduction in resting heart rate (−6.6 bpm) immediately post-intervention compared with WLC. Further research is needed to establish an optimal HIIT protocol that may improve maximal oxygen uptake and metabolic syndrome biomarkers. Findings from this pilot study provide preliminary evidence that an HIIT intervention is feasible for inactive adults with celiac disease and leads to favourable changes in resting heart rate alongside potentially beneficial shifts in gut microbiota. Trial registration number: ClinicalTrials.gov number NCT03520244. Novelty: HIIT leads to potentially beneficial changes in the gut microbiota of adults with celiac disease. An HIIT exercise intervention is feasible and well tolerated for patients with celiac disease.

Background: Pediatric salivary gland-type neoplasms (SGTNs) pose a significant diagnostic problem due to histo-morphological heterogeneity. Previous reports have shown that Mucin 4 (MUC4) expression is associated with adult mucoepidermoid carcinoma (MEC). We hypothesize that MUC4 is also a sensitive marker for distinguishing MEC from other SGTNs in the pediatric population. Objective: To evaluate MUC4 expression in pediatric SGTNs. Methods: A retrospective review of 74 SGTNs diagnosed between 1993–2015 at Children’s Hospital Los Angeles, Boston Children’s Hospital, and Rhode Island Hospital was performed. H&E sections of 31 MECs were compared to 3 adenoid cystic carcinomas (AdCCs), 6 acinic cell carcinomas (AcCCs), 30 pleomorphic adenomas (PAs), 3 mammary analogue secretory carcinomas (MASCs), and one sialoblastoma (SB). Samples underwent immunohistochemical staining for MUC4, with expression score criteria: 0% positivity = 0, 1-10% = +, 11-50% = ++, 51-90% = +++, >90% = ++++. Results: All MECs were MUC4-positive, with 25 (80.65%) having an expression score ≥ +++. AdCCs and PAs demonstrated no to minimal MUC4-positivity. Subsets of AcCCs and MASCs were unexpectedly MUC4-positive. As a novel marker for pediatric MEC, MUC4’s sensitivity = 100%, specificity = 79.41%, positive predictive value = 75.86%, and negative predictive value = 100%. Conclusion: MUC4 is a sensitive marker for pediatric MEC

Major surgery involving resection and free flap reconstruction is a mainstay of head and neck cancer (HNC) treatment, but postoperative morbidity and complications are common. One of the foundations for better surgical outcomes is early mobilization, which is included in enhanced recovery guidelines for all surgical specialties. However, a major unsolved challenge with early mobilization after surgery is quantifying how much a patient moves. To date, mobilization after major HNC surgery has been reported as the time to mobilization, i.e. the interval between the date of surgery and the date of the initial meaningful mobilization. Other data on postoperative mobilization in these patients are limited. Although clinicians can document mobilization via multidisciplinary progress notes, an estimate of mobilization for each postoperative day would be subjective and based on observations from several clinicians and/or the recall of the patient. Advancing research on postoperative mobilization requires the ability to objectively measure patient activity, particularly ambulatory activity, without placing a further burden on the inpatient team. Wearable activity trackers may provide a solution. Data from other surgical specialties indicate that such objective monitoring of patient ambulation in real-time to support interventions to increase mobilization may provide opportunities to improve clinical care. Objective measurement of step counts after HNC surgery would lead to an understanding of the dose-response relationship (the required quantity and frequency of mobilization that is safe and beneficial). In conclusion, the integration of wearable activity trackers in the care plan for patients undergoing HNC surgery will facilitate the measurement and improvement of postoperative mobilization to reduce complications, improve surgical outcomes and enhance patient recovery.

Physical activity (PA) is important for well-being and coping among cancer survivors. Social support (SS) encourages adoption and maintenance of PA behavior, and PA contexts can provide opportunities for obtaining support for coping with cancer. The qualitative literature examining cancer survivors’ experience with SS in and for PA could inform understanding of behaviors experienced as supportive. The purpose of this meta-study was to synthesize the research on adult cancer survivors’ experiences with SS related to PA. Following meta-study guidelines, we searched nine databases and retrieved 39 articles describing intervention and observation studies, and extracted, analyzed, and synthesized information addressing SS and PA in cancer survivors. Results emphasized ways that PA contexts facilitate relationships, which are a foundation for obtaining supportive behaviors that enable PA (e.g., providing encouragement and accountability) and assist with coping with cancer (e.g., understanding and talking about cancer). Some themes identified were unique to studies with female breast cancer, advanced cancer, interventions or programs, and that used interviews versus focus groups. Understanding supportive behaviors could improve PA and coping with cancer in interventions. Future research should focus on identifying supportive behaviors, incorporating theory and methods to address the development of supportive relationships, and recruiting more diverse samples of participants in terms of gender, race/ethnicity, and cancer type. PA can provide opportunities for positive social connections ranging from loose to close social ties, and this research identifies several behaviors in the PA context that may be supportive of PA behavior (e.g., providing actionable information), and coping with cancer (e.g., opportunities but low obligation to talk about cancer).

Currently approved immune checkpoint inhibitor therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, most patients across cancer types still fail to respond. Consequently, there is interest in discovering and blocking alternative pathways that mediate immune suppression. One such mechanism is an upregulation of sialoglycans in malignancy, which has been recently shown to inhibit immune cell activation through multiple mechanisms and therefore represents a targetable glycoimmune checkpoint. Since these glycans are not canonically druggable, we designed an αHER2 antibody–sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells. In syngeneic breast cancer models, desialylation enhanced immune cell infiltration and activation and prolonged the survival of mice, an effect that was dependent on expression of the Siglec-E checkpoint receptor found on tumor-infiltrating myeloid cells. Thus, antibody–sialidase conjugates represent a promising modality for glycoimmune checkpoint therapy. An αHER2 antibody–neuraminidase conjugate, which selectively targets the removal of sialic acids from glycans on breast cancer cells, bypasses a glycoimmune checkpoint and enhances tumor cell killing by the host immune system.

Objectives Crystal-storing histiocytosis (CSH) is rare in plasma cell dyscrasias, with only 3 cases reported in the setting of amyloid. No cases of crystal-negative histiocytosis coincident with multiple myeloma and amyloidosis have been reported previously. Methods A 58-year-old woman presented with pain due to destructive bone lesions and was found to have plasma cell myeloma (PCM) and marrow amyloid deposition associated with crystal-negative histiocytosis. Differential diagnoses included Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai Dorfman disease. BRAF mutations were negative, and there was no evidence of paraprotein crystals, arguing against typical CSH. Results The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, and she subsequently underwent autologous stem cell transplant and ixazomib maintenance. She achieved complete remission with improvement of her symptoms and preserved remission after following up at 60 months. Conclusions We describe a case of crystal-negative histiocytosis associated with PCM. CSH is a rare disorder associated with paraprotein-producing conditions in which immunoglobulins aggregate as intracellular crystals in the lysosomes of organ-specific phagocytic macrophages. Light chain tropism in PCM can also lead to the development of amyloid deposition in organs and, in rare cases, is associated with light chain aggregation as intracellular crystals in macrophages.

Purpose The main characteristics of mechanically ventilated ARDS patients affected with COVID-19, and the adherence to lung-protective ventilation strategies are not well known. We describe characteristics and outcomes of confirmed ARDS in COVID-19 patients managed with invasive mechanical ventilation (MV). Methods This is a multicenter, prospective, observational study in consecutive, mechanically ventilated patients with ARDS (as defined by the Berlin criteria) affected with with COVID-19 (confirmed SARS-CoV-2 infection in nasal or pharyngeal swab specimens), admitted to a network of 36 Spanish and Andorran intensive care units (ICUs) between March 12 and June 1, 2020. We examined the clinical features, ventilatory management, and clinical outcomes of COVID-19 ARDS patients, and compared some results with other relevant studies in non-COVID-19 ARDS patients. Results A total of 742 patients were analysed with complete 28-day outcome data: 128 (17.1%) with mild, 331 (44.6%) with moderate, and 283 (38.1%) with severe ARDS. At baseline, defined as the first day on invasive MV, median (IQR) values were: tidal volume 6.9 (6.3–7.8) ml/kg predicted body weight, positive end-expiratory pressure 12 (11–14) cmH2O. Values of respiratory system compliance 35 (27–45) ml/cmH2O, plateau pressure 25 (22–29) cmH2O, and driving pressure 12 (10–16) cmH2O were similar cto values from non-COVID-19 ARDS observed in other studies. Recruitment maneuvers, prone position and neuromuscular blocking agents were used in 79%, 76% and 72% of patients, respectively. The risk of 28-day mortality was lower in mild ARDS [hazard ratio (RR) 0.56 (95% CI 0.33–0.93), p = 0.026] and moderate ARDS [hazard ratio (RR) 0.69 (95% CI 0.47–0.97), p = 0.035] when compared to severe ARDS. The 28-day mortality was similar to other observational studies in non-COVID-19 ARDS patients. Conclusions In this large series, COVID-19 ARDS patients have features similar to other causes of ARDS, compliance with lung-protective ventilation was high, and the risk of 28-day mortality increased with the degree of ARDS severity. Electronic supplementary material The online version of this article (10.1007/s00134-020-06192-2) contains supplementary material, which is available to authorized users.

Neighborhood conditions are associated with health outcomes, but whether individual health behaviors are independent of or associated with the settings are not clear. We analyzed the California Health Interview Survey (CHIS) (N = 11,152) data to determine if the perceptions and behaviors of similar individuals with an income low enough to be eligible for SNAP-Ed services differed based on whether they lived in high- or low-income neighborhoods. We found that SNAP-Ed eligible individuals living in low-income neighborhoods walked for transportation more frequently (3.04 times versus 2.38 times, p = 0.001), drank sugary beverages more frequently in the past month (2.93 times versus 1.69 times, p = 0.000), and had a higher risk of obesity than similar low-income individuals living in high-income neighborhoods (0.34 versus 0.26, p = 0.012). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11524-020-00433-x) contains supplementary material, which is available to authorized users.

The first child carried by a surrogate after in vitro fertilization in the United States was born in 1985. Since then, the number of such births has steadily grown. According to the Centers for Disease Control and Prevention, the number of gestational carrier cycles increased from 727 in 1999 to 3,432 in 2013, encompassing more than 18,000 children born over this period. Surrogacy offers an alternative to adoption. However, it also disrupts traditional notions of parentage and gestation and complicates the role of obstetrician-gynecologists (ob-gyns) in helping their patients navigate difficult ethical issues. Surrogacy legislation falls under the jurisdiction of each individual state, which results in a variety of approaches. In this article, we review the legal aspects of surrogacy important for specialist ob-gyns, including select landmark court cases, states' approaches to surrogacy legislation, and unique components of informed consent. We also provide clinical recommendations specific to the United States for working with gestational surrogates and intended parents, spanning preconception, prenatal care, and delivery.

TP53 alteration in chronic lymphocytic leukemia indicates a high-risk disease that is usually refractory to chemotherapy. It may be caused by deletion of 17p involving the loss of TP53 gene, which occurs in low percentage of patients at diagnosis but can be acquired as the disease progresses. Since patients may harbor TP53 mutation without chromosome 17p deletion, consensus recommendations call for both cytogenetic and PCR mutation analysis of TP53 in chronic lymphocytic leukemia. We conducted a single-institution retrospective study to investigate the clinicopathologic features of chronic lymphocytic leukemia with TP53 alterations as well as the utility of different diagnostic modalities to identify p53 alterations. Forty percent of chronic lymphocytic leukemia patients with TP53 alterations demonstrated atypical lymphocytes with cleaved/irregularly shaped nuclei and/or large atypical lymphoid cells with abundant cytoplasm in the peripheral blood. Progression was also observed in lymph node and bone marrow samples (21% with Richter transformation; 33% with findings suggestive of “accelerated phase” of chronic lymphocytic leukemia including prominent proliferation centers and/or increased numbers of prolymphocytes). However, the presence of the morphologic features suggestive of “accelerated phase” had no effect on overall survival within the chronic lymphocytic leukemia group with TP53 abnormalities (p > 0.05). As previously reported by others, a subset of patients with TP53 alterations were only identified by either PCR mutation analysis (12%) or cytogenetic studies (14%). p53 immunostain positivity was only identified in approximately half of the patients with TP53 alterations identified by either method, and it failed to identify any additional patients with p53 abnormalities. In summary, chronic lymphocytic leukemia patients with TP53 alterations frequently show atypical morphologic features. Use of multiple modalities to identify p53 abnormalities is recommended to ensure optimal sensitivity and specificity.

OBJECTIVES: Blacks and Hispanics face a higher incidence rate of end-stage renal disease (ESRD) and tend to experience poorer access to quality health care compared with Whites. Income, education, and insurance coverage differentials are typically identified as risk factors, but neighborhood-level analyses may provide additional insights. We examine whether neighborhood racial composition contributes to racial/ethnic inequities in access to high-quality dialysis care in Chicago. METHODS: Data are drawn from the United States Renal Data System merged to the ESRD Quality Incentive Program file and the American Community Survey (2005–2009) for facility and neighborhood characteristics (N = 2797). Outcomes included (1) spatial access (travel time to dialysis facilities) and (2) realized access (actual use of quality care). Neighborhood racial/ethnic composition was categorized into four types: predominantly White, Black, and Hispanic neighborhoods, and racially integrated neighborhoods. RESULTS: Blacks lived closer to a dialysis facility but traveled the same distance to their own dialysis compared with Whites. Hispanics had longer travel time to any dialysis than Whites, and the difference between Hispanics and Whites became no longer significant after adjusting for neighborhood racial/ethnic composition. Blacks and Hispanics had better access to a high-quality facility if they lived in integrated neighborhoods (OR = 1.85 and 3.77, respectively, p < 0.01) or in neighborhoods with higher concentrations of their own race/ethnicity (OR = 1.68 for Blacks in Black neighborhoods and 1.92 for Hispanics in Hispanic neighborhoods, p < 0.05) compared with Whites in predominantly White neighborhoods. CONCLUSION: Expanding opportunities for Blacks and Hispanics to gain access to racially integrated and minority neighborhoods may help alleviate racial/ethnic inequities in access to quality care among kidney disease patients.

Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.

Providers specializing in reproductive medicine are treating increasing numbers of women pursuing parenthood in their 40s, 50s, and beyond. The rise in later-life parenting can be linked to factors ranging from the advent of assisted reproductive technologies and donor oocytes to the highly publicized pregnancies of older celebrities. We explore the medical and psychosocial implications of this trend for both older parents and their children. We also discuss ethical arguments regarding older parents' access to fertility care, existing professional guidelines, and both public and provider opinions about setting age limits for fertility treatment. Finally, we share preliminary considerations of whether age policies should be established, applied to men as well as women, and standardized or considered on a case-by-case basis.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell–like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.

Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic., Here, the authors present cryoEMPEM, a method for high-resolution structural analysis of vaccine-elicited polyclonal antibody responses. They apply cryoEMPEM in combination with standard serology experiments to characterize the polyclonal antibody (pAb) responses elicited in rhesus macaques by HIV Env trimer immunogens and were able to determine up to 8 different polyclonal antibody structures in complex with their respective antigen from a single cryoEM dataset.

PurposeThe primary objective was to investigate the feasibility of a synchronous, online delivered, group-based, supervised, exercise oncology maintenance program supported with health coaching.MethodsAll participants had previously completed a 12-week group-based exercise study. In the current study, participants were randomized to a 12-week exercise oncology maintenance class with or without health coaching. The primary outcome was feasibility, assessed as intervention attendance, safety and fidelity, study recruitment, attrition and outcome assessment completion. Additionally, semi-structured interviews at the end of the intervention provided participants’ perspectives on intervention feasibility.ResultsForty participants (n8WK=25; n12WK=15) enrolled in the study. Feasibility was confirmed for recruitment rate (42.6%), attrition rate (2.5%), safety (no adverse events), health coaching attendance (97%), health coaching fidelity (96.7%), class attendance (91.2%), class fidelity (92.6%), and assessment completion (questionnaire=98.8%; physical functioning=97.5%). Based on the qualitative feedback, feasibility was facilitated by the convenience, while the diminished ability to connect with other participants online was a drawback compared to in-person delivery.ConclusionThe synchronous online delivery of an exercise oncology maintenance class, the additional health coaching support, and the tools used to measure the intervention effectiveness were feasible for individuals living with and beyond cancer.

The split-belt treadmill (SBT) has been used to examine the adaptation of spatial and temporal gait parameters. Historically, SBT studies have focused on anterior-posterior (AP) spatiotemporal gait parameters because SBT is primarily a perturbation in the anterior-posterior direction, but it is important to understand whether and how ML control adapts in this scenario. The medial-lateral (ML) control of balance must be actively controlled and adapted in different walking environments. Furthermore, we seek to determine whether ML balance adaptation differs in older age. We analyzed SBT-induced changes in gait parameters including variables which inform us about ML balance control in younger and older adults. Our primary finding is that younger adults showed sustained asymmetric changes in these ML balance parameters during the split condition of the SBT. Specifically, younger adults sustained a greater displacement between their fast stance foot and their upper body, relative to the slow stance foot, in the ML direction. This finding suggests that younger adults may be exploiting passive dynamics in the ML direction during the SBT, which may be more metabolically efficient. Additionally, the ML parameters did not show any aftereffects despite large adjustments during the split condition, which may indicate higher level neural control than AP parameters.

BackgroundPatients with primary brain tumours lack access to exercise oncology and wellness resources. The purpose of the Alberta Cancer Exercise – Neuro-Oncology (ACE-Neuro) study is to assess the feasibility of a tailored neuro-oncology exercise program for patients across Alberta, Canada. The primary outcome is to assess the feasibility of ACE-Neuro. The secondary outcome is to examine preliminary effectiveness of ACE-Neuro on patient-reported outcomes and functional fitness.MethodsNeuro-oncology patients with a malignant or benign primary brain tumour that are pre, on, or completed treatment, are >18 years, and able to consent in English are eligible to participate in the study. Following referral from the clinical team to cancer rehabilitation and the study team, participants are triaged to determine their appropriateness for ACE-Neuro or other cancer rehabilitation or physiatry resources. In ACE-Neuro, participants complete a tailored 12-week exercise program with pre-post assessments of patient-reported outcomes, functional fitness, and physical activity. ACE-Neuro includes individual and group-based exercise sessions, as well as health coaching.ConclusionWe are supporting ACE-Neuro implementation into clinical cancer care, with assessment of needs enabling a tailored exercise prescription.

Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I–expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9–mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring.

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.

The inferior colliculus (IC), the midbrain hub of the central auditory system, receives extensive cholinergic input from the pontomesencephalic tegmentum. Activation of nicotinic acetylcholine receptors (nAChRs) in the IC can alter acoustic processing and enhance auditory task performance. However, how nAChRs affect the excitability of specific classes of IC neurons remains unknown. Recently, we identified vasoactive intestinal peptide (VIP) neurons as a distinct class of glutamatergic principal neurons in the IC. Here, in experiments using male and female mice, we show that cholinergic terminals are routinely located adjacent to the somas and dendrites of VIP neurons. Using whole-cell electrophysiology in brain slices, we found that acetylcholine drives surprisingly strong and long-lasting excitation and inward currents in VIP neurons. This excitation was unaffected by the muscarinic receptor antagonist atropine. Application of nAChR antagonists revealed that acetylcholine excites VIP neurons mainly via activation of α3β4∗ nAChRs, a nAChR subtype that is rare in the brain. Furthermore, we show that acetylcholine excites VIP neurons directly and does not require intermediate activation of presynaptic inputs that might express nAChRs. Lastly, we found that low frequency trains of acetylcholine puffs elicited temporal summation in VIP neurons, suggesting that in vivo-like patterns of cholinergic input can reshape activity for prolonged periods. These results reveal the first cellular mechanisms of nAChR regulation in the IC, identify a functional role for α3β4∗ nAChRs in the auditory system, and suggest that cholinergic input can potently influence auditory processing by increasing excitability in VIP neurons and their postsynaptic targets.

BackgroundNPM1 mutation status can influence prognosis and management in AML. Accordingly, clinical testing (i.e., RT-PCR, NGS and IHC) for mutant NPM1 is increasing in order to detect residual disease in AML, alongside flow cytometry (FC). However, the relationship of the results from RT-PCR to traditional NGS, IHC and FC is not widely known among many practitioners. Herein, we aim to: i) describe the performance of RT-PCR compared to traditional NGS and IHC for the detection of mutant NPM1 in clinical practice, and also compare it to FC, and ii) provide our observations regarding the advantages and disadvantages of each approach in order to inform future clinical testing algorithms.MethodsPeripheral blood and bone marrow samples collected for clinical testing at variable time points during patient management were tested by quantitative, real-time, RT-PCR and results were compared to findings from a Myeloid NGS panel, mutant NPM1 IHC and FC.ResultsRT-PCR showed superior sensitivity compared to NGS, IHC and FC with the main challenge of NGS, IHC and FC being the ability to identify a low disease burden (NPM1-mutated residual disease not already detected by RT-PCR, NGS or IHC.ConclusionOverall, our findings demonstrate that RT-PCR shows superior sensitivity compared to a traditional Myeloid NGS, suggesting the need for “deep-sequencing” NGS panels for NGS-based monitoring of residual disease in NPM1-mutant AML. IHC provides complementary cytomorphologic information to RT-PCR. Lastly, FC may not be necessary in the setting of post-therapy follow up for NPM1-mutated AML. Together, these findings can help inform future clinical testing algorithms.

We present the case of a 29-year-old male who presented to the office with three years of persistent lower urinary tract symptoms and hematuria. On workup, the patient was determined to have an atypical condition contributing to his symptoms. There are numerous causes of lower urinary tract symptoms that can occur in young men. These symptoms, including frequency, urgency, dysuria, and hematuria, are typically caused by common benign conditions such as urethritis, urolithiasis, and urinary tract infections. Prostatic pathology does not typically manifest in this population. Likewise, a more serious condition such as a mass or carcinoma may contribute to persistent lower urinary tract symptoms and hematuria less often in young men. In our patient, a benign mass later identified as cystitis cystica et glandularis was discovered to be contributing to his reported discomfort.

Up to 40% of advance lung, melanoma and breast cancer patients suffer from brain metastases (BM) with increasing incidence. Here, we assessed whether circulating tumor cells (CTCs) in peripheral blood can serve as a disease surrogate, focusing on CD44 and CD74 expression as prognostic markers for BM. We show that a size-based microfluidic approach in combination with a semi-automated cell recognition system are well suited for CTC detection in BM patients and allow further characterization of tumor cells potentially derived from BM. CTCs were found in 50% (7/14) of breast cancer, 50% (9/18) of non-small cell lung cancer (NSCLC) and 36% (4/11) of melanoma patients. The next-generation sequencing (NGS) analysis of nine single CTCs from one breast cancer patient revealed three different CNV profile groups as well as a resistance causing ERS1 mutation. CD44 and CD74 were expressed on most CTCs and their expression was strongly correlated, whereas matched breast cancer BM tissues were much less frequently expressing CD44 and CD74 (negative in 46% and 54%, respectively). Thus, plasticity of CD44 and CD74 expression during trafficking of CTCs in the circulation might be the result of adaptation strategies.

Methylcellulose (MC) is widely used as a rheology modifier because, upon heating in aqueous solutions, MC reversibly self-assembles into ∼7–10 nm radius fibrils that percolate into a network, resulting in physical gelation. Here, we have chemically cross-linked both MC solutions at room temperature and MC physical fibril gels at 80 °C and compared the swelling and shear modulus properties of both materials. To achieve this, hydroxyl moieties on MC (Mw ≈ 150 kDa) were substituted with allyl groups, with a degree of substitution of about one pendant carbon–carbon double bond per nine anhydroglucose repeat units. The allyl groups undergo cross-linking in the presence of a photoinitiator and UV light. Chemically cross-linking MC fibril gels (“xfib-MC”) at 80 °C results in opaque solid materials and locks in the fibril structure, which persists even on cooling back to room temperature. From small-angle X-ray scattering analysis, the fibril radius is larger at room temperature ∼20 nm and decreases to ∼10 nm at ...

Hematologic malignancies with Fibroblast Growth Factor Receptor-1 gene (FGFR) gene rearrangement are a rare group of myeloid/lymphoid neoplasms with eosinophilia and a variety of translocations at ...