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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.

Context Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. Objective We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts. Methods We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene. Results We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment. Conclusion A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.

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.

Objective To identify strategies and barriers to career progression in early-career colorectal surgeons. Design Qualitative research study performed via semi-structured interviews with early-career, board-certified colon, and rectal surgeons. Responses were analyzed, coded, and categorized to understand strategies towards career progression, perceived barriers to career progression, beliefs about case mix, and referral patterns. Setting Interviews conducted in person and via telephone across the United States and Canada. Participants Early-career board-certified colorectal surgeons Results Twenty-two board-certified colorectal surgeons currently employed in 14 states and 1 foreign country were interviewed. Fourty-five percent were female. Their current practice environment was described as academic (77%), private practice (18%), or military (5%). Seventy-seven percent of surgeons were satisfied with their career progression. Seventy-two percent were satisfied with the case volume. Seventy-two percent were satisfied with their case mix. When asked about strategies for career progression, surgeons made 77 comments focused on three main themes: optimization of their job search, optimization of relationships while on the job, and efforts to augment individual achievement. When asked about barriers to career advancement, surgeons most frequently commented on a lack of time and a lack of mentors. When asked about case mix, 63% of surgeons felt that they had no control over it. They were evenly divided between believing that a broad case mix or a niche specialized case mix was more instrumental for career progression. Conclusions Early-career colorectal surgeons were mostly satisfied with their career progression, volume, and case mix. In discussing their careers, many have developed a number of strategies focused on growth as an individual as well as relationship building. They also identified a number of barriers including lack of time and lack of mentorship. Early-career surgeons may be able to utilize these strategies and anticipate barriers prior to starting their first job, leading to greater likelihood of career satisfaction.

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.

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.

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.

Children with fetal alcohol spectrum disorders (FASD) are known to experience cognitive and neurobehavioral difficulties, including in areas of executive function and social skills development. Interventions for these challenges have focused on a number of areas, including parent-based training. Despite the general consensus that specific parenting styles consistent with an "authoritative" - warm but firm - parenting approach may influence behavioral self-regulation, it is not known what specific parental interaction styles are associated with child engagement and emerging executive function in this population. The current study used an observation-based behavioral coding scheme during parent-child play interactions and associated parent report-based executive function measures in children with FASD. Here, we demonstrate that parental interaction styles with increased responsive/child-oriented behavior and parental affect are associated with higher levels of child play engagement, while parental interaction that has increased achievement-orientation is associated with higher levels of emerging executive function in children with FASD. These findings help inform future studies on behavioral targets in parent-based training programs and highlight the importance of considering certain parental interaction styles during parent-child play.

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.

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.

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.

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.

Acute undifferentiated leukemia is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited and it is uncertain if acute undifferentiated leukemia is biologically distinct from acute myeloid leukemia with minimal differentiation, which also shows limited myeloid marker expression and has been reported to have a poor prognosis. We identified 92 cases initially diagnosed as acute undifferentiated leukemia or acute myeloid leukemia with minimal differentiation from pathology databases of nine academic institutions with available diagnostic flow cytometric data, cytogenetic findings, mutational and clinical data. Outcome analysis was performed using Kaplan Meier test for the 53 patients who received induction chemotherapy. Based on cytogenetic abnormalities (N = 30) or history of myelodysplastic syndrome (N = 2), 32 cases were re-classified as acute myeloid leukemia with myelodysplasia related changes. The remaining 24 acute undifferentiated leukemia patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the remaining 30 acute myeloid leukemia with minimal differentiation patients. Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 (5/15 vs 0/19, p = 0.016) and more frequent expression of TdT on blasts (p = 0.003) while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression (p = 0.042). Outcome data showed no difference in overall survival, relapse free survival, or rates of complete remission between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation groups (p > 0.05). Acute myeloid leukemia with myelodysplasia-related changes patients showed shorter survival when censoring for bone marrow transplant as compared to acute undifferentiated leukemia (p = 0.03) and acute myeloid leukemia with minimal differentiation (p = 0.002). In this largest series to date, the acute undifferentiated leukemia group shows distinct characteristics from acute myeloid leukemia with minimal differentiation, including more frequent PHF6 mutations and expression of TdT.

Objective Social support is conceptualized and operationalized in many ways, making it challenging to understand what types of support best predict physical activity (PA) in cancer survivors. This review examined associations between social support and PA among cancer survivors. Methods Following PRISMA guidelines, we searched eight databases for studies that reported an association between social support and PA among adult cancer survivors. We conducted an appraisal and a narrative synthesis of the findings from quantitative studies. Results Fifty studies representing 28 366 participants were included. Studies collectively included concepts addressing the presence of relationships, others' PA behavior, perceptions of being supported, and function/quality. Findings were mixed in suggesting a positive or null association with PA. Conclusions While results are not definitive, this review takes a step toward mapping the social support literature in PA for cancer survivors. Limitations include the homogeneity of the participants in extant studies, and the secondary focus on testing the effects of social support on outcomes. Future research systematically testing the effects of social support is important for facilitating PA in this population.

We investigated age-related differences in corticospinal control of muscle activity during normal and visually guided (VG) walking. Young (n = 15, 22.1 ± 1.7 years) and older (n = 15, 68.3 ± 2.7 years) participants performed normal walking and VG walking requiring precise foot placement based on visual cues. Coherence analysis was used to quantify coupling between electroencephalography and electromyography from the anterior tibial muscle (corticomuscular) and between the 2 ends of the anterior tibial muscle (intramuscular) at 15–50 Hz during the swing phase of walking as markers of corticospinal activity. Our results indicated that corticomuscular and intramuscular coherence was lower in older compared to young participants during both tasks. In addition, coherence was generally greater during VG than during normal walking across age groups, although during late swing, older participants drove several of the observed task-related coherence increases. Performance on the VG task was lower in older compared to young participants and was correlated with task-related corticomuscular coherence modulations within the older group. These results suggest age-related differences in the corticospinal control of walking, with possible implications for precision control of foot placement based on visual information.

OBJECTIVE Colorectal surgery (CRS) training has seen many changes over the years. This study sought to identify aspects of CRS residency curriculum that were most valued by recent graduates and what changes could be made to improve training. DESIGN Semistructured interviews were performed with board-certified colorectal surgeons 2 to 7years removed from their CRS residency. Interview responses were qualitatively analyzed and converted to coded, categorizable data. Subjects were recruited via a snowball sampling method. SETTING Interviews were conducted in person and via telephone with surgeons in a variety of practices across the United States and Canada. Analysis was performed by a team at Lahey Clinic, Burlington, MA, an academic, tertiary care center. PARTICIPANTS Board certified colorectal surgeons 2 to 7years removed from CRS residency. RESULTS Twenty surgeons from 11 different CRS residencies were interviewed. At the time of the interview, surgeons were employed in 13 states and 1 foreign country. When asked what aspects of their CRS residency were of value, surgeons produced 74 comments emphasizing: volume of cases (65% of subjects), variety of cases (55%), development of technical skills (40%), management of specific diseases (35%), faculty (30%), mentorship (30%), and practice management (15%). With regard to technical skills, surgeons cited pelvic surgery (40%) and minimally invasive techniques (45%) as the exposures that helped them become successful. When discussing what could be added to training, subjects made 54 comments identifying: more robotic exposure (35%), more anorectal disease (30%), more pelvic floor exposure (25%), and practice management/billing (35%) as items to incorporate. Sixty five percent of subjects believed that “nothing” should be eliminated from their training. CONCLUSIONS Young colon and rectal surgeons valued their training highly and strongly declined to eliminate any substantial part of the existing curriculum. They also expressed a strong desire to add more elements to the CRS residency including further robotic training, more anorectal, more pelvic floor, and further training in practice management.

Horseshoe fistula is a challenging benign anorectal condition to treat. The aim of this study was to assess the utilization and success of different definitive fistula repair techniques in the treatment of horseshoe fistula.This was a retrospective case series which included all patients who were treated for horseshoe fistula from 2006 to 2019 at a single, tertiary care center and whom had at least one follow-up visit. Patients were excluded if 18 years of age or carried a diagnosis of Crohn's disease. Patients were assessed for fistula recurrence and incontinence.Sixty-eight patients were identified. On average, they were 47 years old, 63% male, and 18% current smokers. Seventy-nine percent required seton during their treatment course. Of the 8 first attempts at fistula repair, the types of repair included flap (15%), LIFT (35%), fistulotomy (31%), plug (12%), and fistulotomy and immediate reconstruction (1%). Recurrence for these procedures was as follows: flap 30%, LIFT 21%, fistulotomy 14%, plug 88%, and fistulotomy and immediate reconstruction 0%. Twelve patients who recurred underwent 17 additional procedures to attempt to cure their fistula. Overall, of those who underwent any attempt at definitive repair, 82% of patients were cured of their fistula, 12% had a chronic seton, and 6% had a chronic fistula. Thirteen percent of those who were cured had incontinence. The mean follow-up time was 1.1 years. Patients required a median of 3 procedures (range 1-11).Horseshoe fistula remains a complex anorectal condition. Successful repair can be performed in 80% of patients. However, repair can often require multiple surgical procedures.

OBJECTIVE/BACKGROUND: Illness severity and resultant dysfunction are often linearly related and tightly coupled (concordant). Some percentage of individuals, however, exhibit discordant associations (high illness severity and low dysfunction [HL] or low illness severity and high dysfunction [LH]). In the present study, a sample of subjects with insomnia complaints were evaluated to determine what percentage of subjects exhibited discordant associations. PARTICIPANTS: Archival data were drawn from a community-based sample (n = 4,680; 61.8% female; Ages 18–105). METHODS: Median splits were calculated for illness severity and daytime dysfunction and each individual was typed as High (H) or Low (L) for the concordant (HH and LL) and discordant domains (HL and LH). RESULTS: Given this typology, 61% were classified as concordant and 39% were classified as discordant. Of these, 38% were sub-typed as HH, 23% as LL, 26% as LH, and 13% as HL. CONCLUSIONS: We propose that some of the discordance may be ascribable to a mismatch between sleep need and sleep ability. Those “who need a lot, may suffer a lot, in the face of only a little (LH)”, whereas those “who need a little, may suffer only a little, in the face of a lot (HL)”.

Background Advanced lung cancer patients face significant physical and psychological burden leading to reduced physical function and quality of life. Separately, physical activity, nutrition, and palliative symptom management interventions have been shown to improve functioning in this population, however no study has combined all three in a multimodal intervention. Therefore, we assessed the feasibility of a multimodal physical activity, nutrition, and palliative symptom management intervention in advanced lung cancer. Methods Participants received an individually tailored 12-week intervention featuring in-person group-based exercise classes, at-home physical activity prescription, behaviour change education, and nutrition and palliative care consultations. Patients reported symptom burden, energy, and fatigue before and after each class. At baseline and post-intervention, symptom burden, quality of life, fatigue, physical activity, dietary intake, and physical function were assessed. Post-intervention interviews examined participant perspectives. Results The multimodal program was feasible, with 44% (10/23) recruitment, 75% (75/100) class attendance, 89% (8/9) nutrition and palliative consult attendance, and 85% (17/20) assessment completion. Of ten participants, 70% (7/10) completed the post-intervention follow-up. Participants perceived the intervention as feasible and valuable. Physical activity, symptom burden, and quality of life were maintained, while tiredness decreased significantly. Exercise classes prompted acute clinically meaningful reductions in fatigue, tiredness, depression, pain, and increases in energy and well-being. Conclusion A multimodal physical activity, nutrition, and palliative symptom management intervention is feasible and shows potential benefits on quality of life that warrant further investigation in a larger cohort trial. Trial registration NCT04575831, Registered 05 October 2020 – Retrospectively registered.

Background Emergency colon cancer surgery is associated with increased mortality and complication risk, which can be due to differences in the organization of hospital care. This study aimed. Objective To explore which structural factors in the preoperative, perioperative and postoperative periods influence outcomes after emergency colon cancer surgery. Methods An observational study was performed in 30 Dutch hospitals. Medical records from 1738 patients operated in the period 2012 till 2015 were reviewed on the type of referral, intensive care unit (ICU) level, surgeon specialization and experience, duration of surgery and operating room time, blood loss, stay on specialized postoperative ward, complication occurrence, reintervention and day of surgery and linked to case-mix data available in the Dutch Colorectal Audit. Multivariate logistic regression analysis was used to estimate the influence of these factors on 30-day mortality, severe complication and failure to rescue (FTR), after adjustment for case-mix. Results Patients operated by a non-Gastro intestinal/oncology specialized surgeon have significantly increased mortality (Odds Ratio (OR) 2.28 [95% confidence interval (95% CI) 1.23–4.23]) and severe complication risk (OR 1.61 [95% CI 1.08–2.39]). Also, duration of stay in the operating room was significantly associated with increased risk on severe complication (OR 1.03 [95% CI 1.01–1.06]). Patients admitted to a non-specialized ward have significantly increased mortality (OR 2.25 [95% CI 1.46–3.47]) and FTR risk (OR 2.39 [95% CI 1.52–3.75]). A low ICU level (basic ICU) was associated with a lower severe complication risk (OR 0.72 [95% CI 0.52–1.00]). Surgery on Tuesday was associated with a higher mortality risk (OR 2.82 [95% CI 1.24–6.40]) and a severe complication risk (OR 1.77, [95% CI 1.19–2.65]). Conclusion This study identified a non-specialized surgeon and ward, operating room, time and day of surgery to be risk factors for worse outcomes in emergency colon cancer surgery.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

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).

OBJECTIVE To evaluate whether a focused education program and implementation of a treatment bundle increases the rate of early evidence-based interventions in patients with acute infections. DESIGN Single-center, prospective, before-and-after feasibility trial. SETTING Emergency department of a sub-Saharan African district hospital. PATIENTS Patients > 28 days of life admitted to the study hospital for an acute infection. INTERVENTIONS The trial had three phases (each of four months). Interventions took place during the second (educational program followed by implementation of the treatment bundle) and third (provision of resources to implement treatment bundle) phases. MEASUREMENTS AND MAIN RESULTS Demographic, clinical, and laboratory data were collected at study enrollment; 24, 48, and 72 hours after hospital admission; and at discharge. A total of 1,594 patients were enrolled (pre-intervention, n = 661; intervention I, n = 531; intervention II, n = 402). The rate of early evidence-based interventions per patient during Intervention Phase I was greater than during the pre-intervention phase (74 ± 17 vs. 79 ± 15%, p < 0.001). No difference was detected when data were compared between Intervention Phases I and II (79 ± 15 vs. 80 ± 15%, p = 0.58). No differences in the incidence of blood transfusion (pre-intervention, 6%; intervention I, 7%; intervention II, 7%) or severe adverse events in the first 24 hours (allergic reactions: pre-intervention, 0.2%; intervention I, 0%; intervention II, 0%; respiratory failure: pre-intervention, 2%; intervention I, 2%; intervention II, 2%; acute renal failure: pre-intervention, 2%; intervention I, 2%; intervention II, 1%) were observed. CONCLUSIONS Our results indicate that a focused education program and implementation of an infection treatment bundle in clinical practice increased the rate of early evidence-based interventions in patients with acute infections (mostly malaria) admitted to a sub-Saharan African district hospital. Provision of material resources did not further increase this rate. While no safety issues were detected, this could be related to the very low disease severity of the enrolled patient population (www.clinicaltrials.gov: NCT02697513).

Myeloproliferative neoplasms arise from hematopoietic stem cells with somatically altered tyrosine kinase signaling. Classification of myeloproliferative neoplasms is based on hematologic, histopathologic and molecular characteristics including the presence of the BCR-ABL1 and JAK2 V617F. Although thought to be mutually exclusive, a number of cases with co-occurring BCR-ABL1 and JAK2 V617F have been identified. To characterize the clinicopathologic features of myeloproliferative neoplasms with concomitant BCR-ABL1 and JAK2 V617F, and define the frequency of co-occurrence, we conducted a retrospective multi-institutional study. Cases were identified using a search of electronic databases over a decade at six major institutions. Of 1570 patients who were tested for both BCR-ABL1 and JAK2 V617F, six were positive for both. An additional five patients were identified via clinical records providing a total of 11 cases for detailed evaluation. For each case, clinical variables, hematologic and genetic data, and bone marrow histomorphologic features were analyzed. The sequence of identification of the genetic abnormalities varied: five patients were initially diagnosed with a JAK2 V617F+ myeloproliferative neoplasm, one patient initially had BCR-ABL1+ chronic myeloid leukemia, while both alterations were identified simultaneously in five patients. Classification of the BCR-ABL1-negative myeloproliferative neoplasms varied, and in some cases, features only became apparent following tyrosine kinase inhibitor therapy. Seven of the 11 patients showed myelofibrosis, in some cases before identification of the second genetic alteration. Our data, reflecting the largest reported study comprehensively detailing clinicopathologic features and response to therapy, show that the co-occurrence of BCR-ABL1 and JAK2 V617F is rare, with an estimated frequency of 0.4%, and most often reflects two distinct ('composite') myeloproliferative neoplasms. Although uncommon, it is important to be aware of this potentially confounding genetic combination, lest these features be misinterpreted to reflect resistance to therapy or disease progression, considerations that could lead to inappropriate management.

Anastomotic leakage remains a major complication after surgery for colorectal carcinoma, but its origin is still unknown. Our hypothesis was that early anastomotic leakage is mostly related to technical failure of the anastomosis, and that late anastomotic leakage is mostly related to healing deficiencies.The aim of this study was to assess differences in risk factors for early and late anastomotic leakage.This was a retrospective cohort study.The Dutch ColoRectal Audit is a nationwide project that collects information on all Dutch patients undergoing surgery for colorectal cancer.All patients undergoing surgical resection for colorectal cancer in the Netherlands between 2011 and 2015 were included.Late anastomotic leakage was defined as anastomotic leakage leading to reintervention later than 6 days postoperatively.In total, 36,929 patients were included; early anastomotic leakage occurred in 863 (2.3%) patients, and late anastomotic leakage occurred in 674 (1.8%) patients. From a multivariable multinomial logistic regression model, independent predictors of early anastomotic leakage relative to no anastomotic leakage and late anastomotic leakage relative to no anastomotic leakage included male sex (OR, 1.8; p0.001 and OR, 1.2; p = 0.013) and rectal cancer (OR, 2.1; p0.001 and OR, 1.6; p = 0.046). Additional independent predictors of early anastomotic leakage relative to no anastomotic leakage included BMI (OR, 1.1; p = 0.001), laparoscopy (OR, 1.2; p = 0.019), emergency surgery (OR, 1.8; p0.001), and no diverting ileostomy (OR, 0.3; p0.001). Independent predictors of late anastomotic leakage relative to no anastomotic leakage were Charlson Comorbidity Index of ≥II (OR, 1.3; p = 0.003), ASA score III to V (OR, 1.2; p = 0.030), preoperative tumor complications (OR, 1.1; p = 0.048), extensive additional resection because of tumor growth (OR, 1.7; p = 0.003), and preoperative radiation (OR, 2.0; p = 0.010).This was an observational cohort study.Most risk factors for early anastomotic leakage were surgery-related factors, representing surgical difficulty, which might lead to technical failure of the anastomosis. Most risk factors for late anastomotic leakage were patient-related factors, representing the frailty of patients and tissues, which might imply healing deficiencies. See Video Abstract at http://links.lww.com/DCR/A730.

Although outcomes improved during the past decade for patients receiving maintenance dialysis, gains were few in certain key areas, as highlighted in the 2016 Peer Kidney Care Initiative Report. Overall incidence rates of dialysis therapy initiation in adults remained relatively stable (∼42 per 100,000 US population, 2009-2013), but rates varied more than 2-fold, from 26 to 54, across US geographic regions. Hospitalization rates in incident patients decreased from 261 hospitalizations per 100 patient-years in 2003 to 207 in 2012, but observation stay rates increased from 40 to 67, attenuating the decline in hospitalizations by half. Decreases in prevalent patient hospitalizations for heart failure, from 15.6 per 100 patient-years in 2004 to 9.5 in 2013, were partially offset by increases in hospitalizations for volume overload, from 3.0 in 2004 to 6.1 in 2013. Prevalent patient rates of hospitalizations for arrhythmias (∼4.6 per 100 patient-years) did not improve during the past decade, whereas sudden cardiac death as a proportion of total cardiovascular deaths increased from 53% to 73%. Hospitalization rates for pneumonia/influenza, at about 8.3 per 100 patient-years in prevalent patients, did not decrease during this period, while hospitalization rates for bacteremia/sepsis increased from 8.6 to 12.0. If decreases in mortality rates are to be sustained, novel approaches to these challenges will be required.

Cancer treatment with doxorubicin (DOX) can induce cumulative dose-dependent cardiotoxicity. Currently, there are no specific biomarkers that can identify patients at risk during the initial doses of chemotherapy. The aim of this study was to examine plasma cytokines/chemokines and potential cardiovascular biomarkers for the prediction of DOX-induced cardiotoxicity. Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-based chemotherapy of 27 breast cancer patients, including five patients who presented with >10% decline of left ventricular ejection fraction (LVEF), five patients with LVEF decline of 5–10%, and 17 patients who maintained normal LVEF at the end of chemotherapy (240 mg/m2 cumulative dose of DOX from four cycles of treatment). Multiplex immunoassays were used to screen plasma samples for 40 distinct chemokines, nine matrix metalloproteinases, 33 potential markers of cardiovascular diseases, and the fourth-generation cardiac troponin T assay. The results showed that the patients with abnormal decline of LVEF (>10%) had lower levels of CXCL6 and sICAM-1 and higher levels of CCL23 and CCL27 at T0; higher levels of CCL23 and lower levels of CXCL5, CCL26, CXCL6, GM-CSF, CXCL1, IFN-γ, IL-2, IL-8, CXCL11, CXCL9, CCL17, and CCL25 at T1; and higher levels of MIF and CCL23 at T2 than the patients who maintained normal LVEF. Patients with LVEF decline of 5–10% had lower plasma levels of CXCL1, CCL3, GDF-15, and haptoglobin at T0; lower levels of IL-16, FABP3, and myoglobin at T1; and lower levels of myoglobin and CCL23 at T2 as compared to the patients who maintained normal LVEF. This pilot study identified potential biomarkers that may help predict which patients are vulnerable to DOX-induced cardiotoxicity although further validation is needed in a larger cohort of patients. Impact statement Drug-induced cardiotoxicity is one of the major concerns in drug development and clinical practice. It is critical to detect potential cardiotoxicity early before onset of symptomatic cardiac dysfunction or heart failure. Currently there are no qualified clinical biomarkers for the prediction of cardiotoxicity caused by cancer treatment such as doxorubicin (DOX). By using multiplex immunoassays, we identified proteins with significantly changed plasma levels in a group of breast cancer patients who were treated with DOX-based chemotherapy and produced cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment or at early doses of treatment, thus they could be potential predictive biomarkers of cardiotoxicity although further validation is required to warrant their clinical values.

Visual cues can be used to train walking patterns. Here, we studied the performance and learning capacities of healthy subjects executing a high-precision visuomotor walking task, in an augmented reality training set-up. A beamer was used to project visual stepping targets on the walking surface of an instrumented treadmill. Two speeds were used to manipulate task difficulty. All participants (n = 20) had to change their step length to hit visual stepping targets with a specific part of their foot, while walking on a treadmill over seven consecutive training blocks, each block composed of 100 stepping targets. Distance between stepping targets was varied between short, medium and long steps. Training blocks could either be composed of random stepping targets (no fixed sequence was present in the distance between the stepping targets) or sequenced stepping targets (repeating fixed sequence was present). Random training blocks were used to measure non-specific learning and sequenced training blocks were used to measure sequence-specific learning. Primary outcome measures were performance (% of correct hits), and learning effects (increase in performance over the training blocks: both sequence-specific and non-specific). Secondary outcome measures were the performance and stepping-error in relation to the step length (distance between stepping target). Subjects were able to score 76% and 54% at first try for lower speed (2.3 km/h) and higher speed (3.3 km/h) trials, respectively. Performance scores did not increase over the course of the trials, nor did the subjects show the ability to learn a sequenced walking task. Subjects were better able to hit targets while increasing their step length, compared to shortening it. In conclusion, augmented reality training by use of the current set-up was intuitive for the user. Suboptimal feedback presentation might have limited the learning effects of the subjects.

Psoriasis is a common chronic inflammatory skin disease linked to increased cardiovascular risk. Functional impairment of high-density lipoprotein (HDL) may contribute to excessive cardiovascular mortality in psoriasis patients. Anti-cytokine therapies with biologics have been efficiently used for the management of psoriasis, however little data is available on the effects of biologic anti-psoriatic therapies on the composition and functionality of HDL. Blood samples were taken from 17 healthy volunteers and from 27 real-world psoriasis patients at baseline (no therapy with biologics) and after short-term (3 to 6 months) and intermediate-term (1 to 2 years) therapy. The biologics used included anti-interleukin (IL)-12/23p40 (ustekinumab), anti-IL17A (secukinumab) or anti-tumor necrosis factor-α (etanercept or adalimumab) antibodies. We observed that in psoriasis patients at baseline, metrics of HDL function including cholesterol efflux capacity of apolipoprotein B-depleted serum (p = 0.021), paraoxonase (p < 0.001) and lecithin-cholesterol acyltransferase (p < 0.001) activities were impaired, when compared to controls. Unexpectedly, we observed that short- and especially intermediate-term therapy with biologics markedly reduced HDL cholesterol efflux capacity (p < 0.001) and rendered HDL pro-inflammatory (p < 0.001), but increased paraoxonase (p = 0.009) and lecithin-cholesterol acyltransferase (p = 0.019) activities. All biologics caused similar changes in HDL composition, subclass distribution and cholesterol efflux capacity. Our results provide evidence that anti-psoriatic therapy with biologic agents is associated with changes in HDL functionality, particle composition and subclass distribution.

Objective: Immune thrombocytopenia (ITP) is characterized by low platelet counts and a tendency toward increased bleeding and bruising. We aimed to describe bleeding frequency and use of rescue ITP therapy to treat or prevent bleeding in elderly ITP patients in a real-world setting. Methods: Using Medicare 20% sample data, 2007–2012, we identified elderly (ages ≥67 years) Medicare fee-for-service enrollees diagnosed with primary ITP between 1 January 2009 and 30 September 2012. Bleeding-related episodes (BREs) were defined as ≥1 bleeding event or use of ITP therapies commonly considered for rescue or emergency therapy. BRE rates were examined for the cohort overall, by time since ITP onset, and by splenectomy status. Patients were followed from ITP onset until the earliest of death, disenrollment from fee-for-service coverage, or 31 December 2012. Results: We identified 3007 elderly patients diagnosed with primary ITP (mean [SD] age: 79.6 [7.5] years; 55% female); 2178 (72%) experienced at least one BRE (8867 BREs); 92 (3%) underwent splenectomy. Nearly half of BREs were defined by rescue therapy use alone. The overall rate was 1.72 BREs per patient-year (95% CI; 1.68–1.75); rates were higher during the first 3 months after ITP onset and after splenectomy. Conclusion: Elderly ITP patients experienced about two BREs per patient-year after ITP onset. Most patients experienced at least one BRE. These real-world results demonstrate the importance of examining both bleeding and use of rescue or emergency ITP therapy in the assessment of disease burden in elderly patients with ITP.

Growth factors and antimicrobials can reduce complications of chemotherapy-induced myelosuppression. Their prophylactic use in elderly patients is important given the associated comorbidity in this age group. There is a developing trend by payers to include supportive care agents in chemotherapy care bundles, which could affect clinical practice. We examined whether the febrile neutropenia (FN) risk categories can be used to describe utilization in the Centers for Medicare & Medicaid fee-for-service system in older adults. We conducted a retrospective cohort study using the Medicare 20% sample data to describe growth factor and antimicrobial use patterns in patients receiving chemotherapy for breast cancer, lung cancer, and non-Hodgkin lymphoma (NHL). The highest percentage of patients receiving granulocyte colony-stimulating factor (GCSF) within the first 5 days of a chemotherapy cycle were on high-FN-risk regimens, particularly for cycle 1 (73.7%, breast cancer; 61.5%, NHL) and cycle 2 (75.9%, breast cancer; 77.5%, NHL). Chemotherapy regimens for lung cancer are less myelotoxic, and growth factor use was more likely with latter cycles. Antibiotic use was lower at 15% within a cycle and appeared to be in response to complications. Practitioners use GCSF and antibiotics for elderly patients treated with potentially toxic chemotherapy, while comorbidity burden plays a role for patients treated with less myelotoxic regimens. The complexity of these choices in clinical practice should be considered in the proposed reimbursement changes being piloted by Medicare and private insurance companies seeking treatment cost reductions, as altered use could affect safety and efficacy.

Open communication between healthcare professionals about care concerns, also known as 'speaking up', is essential to patient safety.Compare interns' and residents' experiences, attitudes and factors associated with speaking up about traditional versus professionalism-related safety threats.Anonymous, cross-sectional survey.Six US academic medical centres, 2013-2014.1800 medical and surgical interns and residents (47% responded).Attitudes about, barriers and facilitators for, and self-reported experience with speaking up. Likelihood of speaking up and the potential for patient harm in two vignettes. Safety Attitude Questionnaire (SAQ) teamwork and safety scales; and Speaking Up Climate for Patient Safety (SUC-Safe) and Speaking Up Climate for Professionalism (SUC-Prof) scales.Respondents more commonly observed unprofessional behaviour (75%, 628/837) than traditional safety threats (49%, 410/837); p0.001, but reported speaking up about unprofessional behaviour less commonly (46%, 287/628 vs 71%, 291/410; p0.001). Respondents more commonly reported fear of conflict as a barrier to speaking up about unprofessional behaviour compared with traditional safety threats (58%, 482/837 vs 42%, 348/837; p0.001). Respondents were also less likely to speak up to an attending physician in the professionalism vignette than the traditional safety vignette, even when they perceived high potential patient harm (20%, 49/251 vs 71%, 179/251; p0.001). Positive perceptions of SAQ teamwork climate and SUC-Safe were independently associated with speaking up in the traditional safety vignette (OR 1.90, 99% CI 1.36 to 2.66 and 1.46, 1.02 to 2.09, respectively), while only a positive perception of SUC-Prof was associated with speaking up in the professionalism vignette (1.76, 1.23 to 2.50).Interns and residents commonly observed unprofessional behaviour yet were less likely to speak up about it compared with traditional safety threats even when they perceived high potential patient harm. Measuring SUC-Safe, and particularly SUC-Prof, may fill an existing gap in safety culture assessment.

Patients with congenital thrombocytopenia have an increased risk of developing myeloid neoplasms. In these cases, the morphologic distinction between disease at baseline and at progression is challenging. This report analyzes clinicopathologic features of congenital thrombocytopenia with long-term follow-up at one referral center. Records from the last 20 years were searched for cases of congenital thrombocytopenia with bone marrow biopsies and peripheral blood smears. The clinical, morphologic, immunophenotypic, and molecular features were analyzed. Six adult and two pediatric patients were identified (six male, two female). Age range at first biopsy was 1-47 (median, 31) years. Underlying diseases included thrombocytopenia-absent radius syndrome, congenital thrombocytopenia with radial-ulnar synostosis, MYH9-related disorder, shortened telomere syndrome, congenital thrombocytopenia with ANKRD26 mutation, and familial platelet disorder with predisposition to acute myeloid leukemia. Four patients had myelodysplastic/myeloproliferative neoplasm-like marrow changes such as hypercellularity, increased myeloid to erythroid ratio, numerous micromegakaryocytes (highlighted by CD42b), and marrow fibrosis. Two patients had marrow hypoplasia and two had unremarkable marrow morphology. Three patients-all in the myelodysplastic/myeloproliferative neoplasm-like group-developed disease progression characterized by erythroid and myeloid dysplasia, elevated bone marrow blasts, and new cytogenetic abnormalities. Unlike non-familial myeloid neoplasms, congenital thrombocytopenia patients in the myelodysplastic/myeloproliferative neoplasm-like group had a long and indolent clinical course (average age at disease progression, 47 years). In summary, three distinct morphologic types of congenital thrombocytopenia were identified: a hyperplastic myelodysplastic/myeloproliferative neoplasm-like group, a hypoplastic bone marrow failure-like group, and a group with relatively normal marrow morphology. Emergence of cytogenetic abnormalities and dysplasia in non-megakaryocyte lineages correlated with disease progression.

In adults on chronic hemodialysis, achieving a hemoglobin concentration of 12g/dl and above with erythropoiesis stimulating agents leads to increased cardiovascular events and mortality, but this may not be true in children. Therefore, we conducted a retrospective cohort study of pediatric patients (under 18) from the Centers for Medicare and Medicaid Services End Stage Renal Disease (ESRD) Clinical Performance Measures (CPM) project (2000 to 2008) merged with the United States Renal Data System. Hemoglobin was determined from the Clinical Performance Measures data, and beginning annually on January 1st of the next year, patients were followed for up to 1 year. We determined the outcomes (mortality, hospitalization, and cardiovascular events) during follow-up by hemoglobin group at baseline. Models were adjusted for demographic and clinical characteristics of 1569 children studied. The hemoglobin 12 g/dl and above group was older, had fewer years of ESRD, and was more often transplanted. Inpatient and outpatient visits for congestive heart failure, cardiomyopathy, and valvular heart disease were most common in the hemoglobin under 10g/dl group and the frequency of these diagnoses decreased with increasing hemoglobin. The hazard ratio of all-cause mortality (0.33, 95% confidence interval 0.14-0.81) and the adjusted relative rate of all-cause hospitalizations (0.81, 0.74-0.89) were significantly lower in the hemoglobin 12 g/dl and above group. Cardiovascular hospitalizations were significantly higher in the hemoglobin under 10g/dl group (1.31, 1.05-1.64). Thus, in children on hemodialysis, hemoglobin 12g/dl and above is not associated with increased cardiovascular visits, mortality, or all-cause and cardiovascular-related hospitalizations.

Background: Previous studies showing higher mortality after elective surgery performed on a Friday were based on administrative data, known for insufficient case-mix adjustment. The goal of this study was to investigate the risk of adverse events for patients with colon and rectal cancer by day of elective surgery using clinical data from the Dutch ColoRectal Audit. Patients and Methods: Prospectively collected data from the 2012–2015 Dutch ColoRectal Audit (n=36,616) were used to examine differences in mortality, severe complications, and failure to rescue by day of elective surgery (Monday through Friday). Monday was used as a reference, analyses were stratified for colon and rectal cancer, and case-mix adjustments were made for previously identified variables. Results: For both colon and rectal cancer, crude mortality, severe complications, and failure-to-rescue rates varied by day of elective surgery. After case-mix adjustment, lower severe complication risk was found for rectal cancer surgery performed on a Friday (odds ratio, 0.84; 95% CI, 0.72–0.97) versus Monday. No significant differences were found for colon cancer surgery performed on different weekdays. Conclusions: No weekday effect was found for elective colon and rectal cancer surgery in the Netherlands. Lower severe complication risk for elective rectal cancer surgery performed on a Friday may be caused by patient selection.

When walking on a split-belt treadmill where one belt moves faster than the other, the nervous system consistently attempts to maintain symmetry between legs, quantified as deviation from double support time or step length symmetry. It is known that the cerebellum plays a critical role in locomotor adaptation. Less is known about the role of corticospinal drive in maintaining this type of proprioceptive-driven locomotor adaptation. The objective of this study was to examine the functional role of oscillatory drive in relation to changes in spatiotemporal gait parameters during split-belt walking adaptation. Eighteen healthy participants adapted and deadapted on a split-belt treadmill; 13 out of 18 participants repeated the paradigm two more times to examine the effects of reexposure. Coherence analysis was used to quantify the coupling between electromyography (EMG) from the proximal (TAprox) and distal tibialis anterior (TAdist) muscle during the swing phase of walking. EMG-EMG coherence was examined within the alpha (8–15 Hz), beta (15–30 Hz), and gamma (30–45 Hz) frequencies. Our results showed that 1) beta- and gamma-band coherence (markers of corticospinal drive) increased during early split-belt walking compared with baseline walking in the slow leg, 2) beta-band coherence decreased from early to late split-belt adaptation in the fast leg, 3) alpha-, beta-, and gamma-band coherence decreased from first to third split-belt exposure in the fast leg, and 4) there was a relationship between higher beta coherence in the slow leg TA and smaller double support asymmetry. Our results suggest that corticospinal drive may play a functional role in the temporal control of split-belt walking adaptation. NEW & NOTEWORTHY This is the first study to examine the functional role of intramuscular coherence in relation to changes in spatiotemporal gait parameters during split-belt walking adaptation. We found that the corticospinal drive measured by intramuscular coherence in tibialis anterior changes with adaptation and that the corticospinal drive is related to temporal but not spatial parameters. This study may give insight as to the specific role of the motor cortex during gait.

ObjectivesRare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date.MethodsWe present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL.ResultsBoth HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy.ConclusionsTo our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.

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.

NPM1-mutated myeloid neoplasms (NPM1(+) MNs) with

Summary Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study ( ClinicalTrials.gov identifier: NCT02673515 ), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.