Treatment of early oligoarticular psoriatic arthritis with apremilast: primary outcomes at week 16 from the FOREMOST randomised controlled trial.

OBJECTIVES: Oligoarticular psoriatic arthritis (PsA) is frequent but rarely studied. The objective was to assess the efficacy of apremilast in early oligoarticular PsA. METHODS: FOREMOST (NCT03747939) was a phase 4 multicentre, randomised, double-blind, placebo-controlled trial. Patients had early (symptom duration ≤5 years) oligoarticular PsA (>1 but ≤4 swollen and >1 but ≤4 tender joints; 2-8 total active joints). Patients were randomised 2:1 to apremilast 30 mg two times per day or placebo for 24 weeks, with an early escape at week 16. The primary endpoint was the proportion of patients at week 16 who achieved minimal disease activity (MDA)-Joints (modification of MDA mandating ≤1 swollen joint and ≤1 tender joint) based on sentinel joints (those affected at baseline) with a combination of non-responder imputation and multiple imputations. Exploratory analysis assessed all joints. RESULTS: Of 308 patients randomised (apremilast: n=203; placebo: n=105), mean (SD) PsA duration was 9.9 (10.2) months, mean (SD) age was 50.9 (12.5) years and 39.9% of patients were using a conventional synthetic disease-modifying antirheumatic drug. MDA-Joints (sentinel joints (primary endpoint) and all joints) were achieved by significantly more patients with apremilast (33.9% and 21.3%) vs placebo (16.0% and 7.9%) at week 16 (p=0.0008 and nominal p=0.0028, respectively). Greater improvements in patient-reported outcomes, clinical disease activity and skin involvement were also seen with apremilast versus placebo. CONCLUSIONS: FOREMOST is the first randomised controlled trial designed for early oligoarticular PsA and showed apremilast improves clinical and patient-reported outcomes. This trial may inform the optimal management of PsA in these patients. TRIAL REGISTRATION NUMBER: NCT03747939.

Effective Risk Assessment for Distal Radius Fractures: A Rigorous Multivariable Regression Analysis, Using a Novel 8-Item Modified Frailty Index.

Introduction Distal radius fractures (DRFs) are among the most common orthopaedic injuries. The prevalence of DRFs is increasing across all age groups but remains the second most common fracture in the elderly. The modified frailty index (MFI) often predicts morbidity and mortality in orthopaedic injuries. This study aims to determine the predictive value of MFI on complication rates following DRF and the patient length of stay and discharge outcomes. Methods We utilized our MFI to perform a retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database. Results In a total of 22,313 patients, the average age was 46 ± 16. An increase in MFI led to an increase in the odds ratio of readmission and reoperation ( p < 0.001). MFI predicted complications, doubling the rate as the score increased from 1 to 2 ( p < 0.001). An MFI of 2 also led to a delayed hospital stay of 5 days ( p < 0.001), as well as an increase in the odds of patients not being sent home at discharge ( p < 0.001). Finally, life-threatening complications were also predicted with an increased MFI, the odds of a life-threatening complication increasing 488.20 times at an MFI of 3 ( p < 0.001). Discussion and Conclusion While surgical decision-making for frail patients with DRFs remains contentious, this novel 8-item MFI score was significantly associated with the probability of hospital readmission/reoperation, postoperative complications, and delayed hospital length of stay. Three new parameters were incorporated into our 8-item score compared with the conventional 5; hypoalbuminemia status (< 3.5 mg/dL), previous diagnosis of osteoporosis, and severe obesity (body mass index > 35) enhancing its sensitivity. Future studies are warranted for its prospective utility in ruling out postsurgical comorbidity.

Rates and Characteristics of Patients Leaving against Medical Advice after Spine Surgery.

Introduction: Leaving against medical advice (AMA) has been associated with higher rates of readmission and worse postoperative outcomes in various surgical fields. Patients who have undergone spine surgery often require careful postoperative follow-up to ensure an uncomplicated recovery. In this study, we aim to investigate the demographic and hospital variables that may have contributed to patients leaving the hospital AMA following spine surgery. Methods: We performed a retrospective analysis of patients receiving spine surgery; we used the data from the Healthcare Cost and Utilization Project (HCUP) database for the years 2011-2020. Demographics, household income status, insurance status, time from admission to operation, length of stay, length of recovery, and discharge disposition were collected and analyzed. Multivariate linear regression was used to determine the odds ratios of each factor and their association to patient decision of leaving AMA. Results: As per our findings, patients aged 30-49 had 1.666 times greater odds of leaving AMA following spine surgery (P<0.001), patients aged 50-64 had 1.222 times greater odds of leaving AMA (P=0.001), and patients older than 65 had 0.490 times lesser odds of leaving AMA (P<0.001). Additionally, black patients were 1.612 times more likely to leave AMA (P<0.001), whereas white patients were 0.675 times less likely to do so (<0.001). Women were 0.555 times less likely to leave AMA than the rest of the population (P<0.001). Moreover, patients with private insurance were 0.268 times less likely to leave AMA (P<0.001), while patients on Medicare and Medicaid were 1.692 times (P<0.001) and 3.958 times more likely to leave AMA (P<0.001) following spine surgery, respectively. Finally, patients in the lowest quartile of income were 1.691 times more likely to leave AMA (P<0.001), while patients in the higher quartile of income were 0.521 times less likely to do so (P<0.001). Conclusions: It is critical that spine surgeons are aware of the factors that predispose patients to leave AMA in order to mitigate postoperative complications.

Characterizing a panel of amino acid auxotrophs under auxotrophic starvation conditions.

Auxotrophic strains starving for their cognate nutrient, termed auxotrophic starvation, are characterized by a shorter lifespan, higher glucose wasting phenotype, and inability to accomplish cell cycle arrest when compared to a "natural starvation," where a cell is starving for natural environmental growth-limiting nutrients such as phosphate. Since evidence of this physiological response is limited to only a subset of auxotrophs, we evaluated a panel of auxotrophic mutants to determine whether these responses are characteristic of a broader range of amino acid auxotrophs. Based on the starvation survival kinetics, the panel of strains was grouped into three categories-short-lived strains, strains with survival similar to a prototrophic wild type strain, and long-lived strains. Among the short-lived strains, we observed that the tyrosine, asparagine, threonine, and aspartic acid auxotrophs rapidly decline in viability, with all strains unable to arrest cell cycle progression. The three basic amino acid auxotrophs had a survival similar to a prototrophic strain starving in minimal media. The leucine, tryptophan, methionine, and cysteine auxotrophs displayed the longest lifespan. We also demonstrate how the phenomenon of glucose wasting is limited to only a subset of the tested auxotrophs, namely the asparagine, leucine, and lysine auxotrophs. Furthermore, we observed pleiotropic phenotypes associated with a subgroup of auxotrophs, highlighting the importance of considering unintended phenotypic effects when using auxotrophic strains especially in chronological aging experiments.

Disorders of hyperpigmentation. Part I. Pathogenesis and clinical features of common pigmentary disorders.

Disorders of hyperpigmentation are common and, depending on the extent and location of involvement, can affect the quality of life and pose a significant psychologic burden for patients. Given the similarities in presentation of the various causes of hyperpigmentation, it is often difficult to elucidate the etiology of these conditions, which is important to guide management. Furthermore, certain disorders, such as lichen planus pigmentosus and ashy dermatosis, have similar clinical and/or histologic presentations, and their classification as distinct entities has been debated upon, leading to additional confusion. In this review, the authors selected commonly encountered disorders of hyperpigmentation of the skin, subdivided into epidermal, dermal, or mixed epidermal-dermal disorders based on the location of pigment deposition, along with disorders of hyperpigmentation of the mucosa and nails. Melanocytic nevi, genetic disorders, and systemic causes of hyperpigmentation were largely excluded and considered to be outside the scope of this review. We discussed the pathogenesis of hyperpigmentation as well as the clinical and histologic features of these conditions, along with challenges encountered in their diagnosis and classification. The second article in this 2-part continuing medical education series focuses on the medical and procedural treatments of hyperpigmentation.

Disorders of hyperpigmentation. Part II. Review of management and treatment options for hyperpigmentation.

Key challenges in the management of pigmentary disorders such as melasma and postinflammatory hyperpigmentation are their resistance to treatment, tendency to recur after treatment, and the risk of exacerbating hyperpigmentation with many treatment modalities. The second article in this 2-part continuing medical education series on pigmentary disorders focuses on the evidence behind medical and procedural treatments of dyschromias, including photoprotection, topical lightening agents, oral agents, chemical peels, and laser therapy.

Preparing for colorectal surgery: a qualitative study of experiences and preferences of patients in Western Canada.

OBJECTIVES: The burden and costs of abdominal surgery for chronic conditions are on the rise, but could be reduced through self-management support. However, structured support to prepare for colorectal surgery is not routinely offered to patients in Canada. This study aimed to describe experiences and explore preferences for multimodal prehabilitation among colorectal surgery patients. METHODS: A qualitative descriptive study using three focus groups (FG) was held with 19 patients who had a surgical date for abdominal surgery (April 2017-April 2018) and lived close (≤ 50 km radius) to a tertiary hospital in Western Canada (including a Surgical Lead for the British Columbia Enhanced Recovery After Surgery (ERAS) Collaborative). FGs were audio-taped and verbatim transcribed with coding and pile-and-sort methods performed by two independent reviewers, confirmed by a third reviewer, in NVivo v9 software; followed by thematic analysis and narrative synthesis. RESULTS: Four themes emerged: support, informed decision-making, personalization of care, and mental/emotional health, which patients felt was particularly important but rarely addressed. Patient preferences for prehabilitation programming emphasised regular support from a single professional source, simple health messages, convenient access, and flexibility. CONCLUSIONS: There is an unmet need for structured preoperative support to better prepare patients for colorectal surgery. Future multimodal prehabilitation should be flexible and presented with non-medical information so patients can make informed decisions about their preoperative care and surgical outcomes. Healthcare providers have an important role in encouraging healthy lifestyle changes before colorectal surgery, though clearer communication and accurate advice on self-care, particularly mental health, are needed for improving patient outcomes.

Active Tuberculosis After Solid Organ Transplantation in Individuals With Negative Pretransplant QuantiFERON-TB Gold Testing: A Case Series.

Active tuberculosis (TB) in solid organ transplant (SOT) recipients most commonly occurs due to reactivation of latent infection and is associated with poor clinical outcomes, including allograft loss and death. National transplant societies, including the American Society of Transplantation, recommend screening for latent TB prior to transplant, with treatment in the peritransplant setting to reduce the subsequent risk of TB reactivation. Though screening is traditionally conducted using laboratory-based assays, such as the QuantiFERON-TB Gold, false negatives may occur in SOT candidates due to anergy from end-stage organ dysfunction, highlighting the need for a multimodal diagnostic approach. In this case series, we describe the clinical characteristics and outcomes of 3 SOT recipients at the University of Pennsylvania with negative pretransplant QuantiFERON-TB Gold testing who subsequently developed active TB in the posttransplant setting, contributing to a growing body of knowledge regarding this challenging population. Each patient experienced a complicated clinical course that arose in part from the lack of diagnosis of TB prior to transplant. Because all had epidemiologic risk factors for TB, the findings of our study highlight the need for more individualized approaches to pretransplant TB screening.

Folliculotropic mycosis fungoides in a pediatric patient mimicking black dot tinea capitis.

Immunosuppression following organ transplantation is a known risk factor for the development of lymphoproliferative disorders. Mycosis fungoides, a rare entity in pediatric patients, has seldom been reported as a post-transplant lymphoproliferative disorder. We report a case of folliculotropic mycosis fungoides in a pediatric patient following liver transplantation that was initially diagnosed as tinea capitis.

The Effectiveness of an International Cleft Mission Model in Asia: An Update.

BACKGROUND: Cleft lip/palate is a congenital craniofacial anomaly affecting patients physically and psychosocially and has contributed to the global burden of surgical disease, especially in underprivileged areas. For 20 years, Noordhoff Craniofacial Foundation (NCF) and the Chang Gung Craniofacial Center (CGCFC) have carried out missions to these areas. Rather than implementing short-term missions that lack proper follow-up care, the team has provided an effective, long-term, and multidisciplinary approach for the treatment of patients with cleft lip/palate. In this study, we evaluate the sustainability and effectiveness of the cleft mission model implemented by NCF and CGCFC. METHODS: Data from the years 1998-2017 were retrieved from the NCF database. All local centers were evaluated by a 3-stage categorization, levels 1 to 3, based on 4 criteria: (1) capacity to carry out independent missions, (2) diversity of cleft-care professionals, (3) diversity of surgical service offered, and (4) collaboration with local hospitals. Support and training of personnel were provided based on deficiency in these criteria. Noordhoff Craniofacial Foundation made close collaborations and partnerships with several organizations that shared its mission for comprehensive cleft care in developing countries. RESULTS: In all, 19 partner cleft teams in 9 different countries were established. In coordination with these teams, NCF and CGCFC have treated 1846 patients across 78 mission trips. To date, 158 personnel from 19 different countries have been successfully trained to provide cleft care in local centers. Most partner cleft teams centers have progressively reached category level 3, including those in the Philippines, Cambodia, and Mongolia. CONCLUSIONS: In order to establish and maintain sustainable cleft care in developing regions, commitment and compassion toward those who lack essential resources are necessary. Noordhoff Craniofacial Foundation and CGCFC have achieved a successful and practicable model through seeding medical personnel in order to provide effective and sustainable cleft care to the regions in need.

miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the BCL2L11 and BAX Proapoptotic Genes.

The development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on the promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of the activated FGFR1 kinase on gene transcription, which includes miRNA dysregulation. In a screen for miRNAs that are directly regulated by FGFR1, and which stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhances cell survival and inhibition of its function leads to reduced cell viability. miR-339-5p overexpression protects cells from the consequences of FGFR1 inactivation, promoting cell-cycle progression and reduced apoptosis. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-339-5p expression in stably transduced cell lines demonstrated that BCR-FGFR1 can directly regulate miR-339-5p expression. This correlation between miR-339-5p and FGFR1 expression is also seen in primary human B-cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the BCL2L11 and BAX genes, which can promote apoptosis. In vivo, SCLL cells forced to overexpress miR-339-5p show a more rapid onset of disease and poorer survival compared with parental cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL shows a significant higher expression of miR339-5p compared with the two cohorts of CLL patient samples, suggesting direct roles in disease progression and supporting the evidence generated in mouse models of SCLL.Significance: Proapoptiotic genes that are direct targets of miR-339-5p significantly influence promotion and aggressive development of leukemia/lymphomas associated with FGFR1 overexpression. Cancer Res; 78(13); 3522-31. ©2018 AACR.

Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice.

Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral SMase-2 (nSMase2), an enzyme generating ceramide from SM, as a potential repressor for hepatocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed a marked increase of SM in the tumor. Unexpectedly, tumor tissues presented with more than a 7-fold increase of C16-ceramide, concurrent with upregulation of ceramide synthase 5. The fro/fro liver tumor, but not adjacent tissue, exhibited substantial accumulation of lipid droplets, suggesting that nSMase2 deficiency is associated with tumor growth and increased neutral lipid generation in the tumor. Tumor tissue expressed significantly increased levels of CD133 and EpCAM mRNA, two markers of liver cancer stem-like cells (CSCs) and higher levels of phosphorylated signal transducer and activator of transcription 3, an essential regulator of stemness. CD133(+) cells showed strong labeling for SM and ceramide. In conclusion, these results suggest that SMase-2 deficiency plays a role in the survival or proliferation of CSCs, leading to spontaneous tumors, which is associated with tumor-specific effects on lipid homeostasis.

A Retrospective Review of New-onset Dermatitis in Patients Aged 60 Years or Older.

Background: New-onset dermatitis in the elderly can be attributed to a variety of disease processes. We defined new-onset dermatitis in which the etiology is attributed solely to age-related processes as "dermatitis of immune senescence"-a diagnosis of exclusion based on clinical presentation and further diagnostic testing. Objective: Retrospective cohort of elderly patients with new-onset dermatitis to examine the differences in demographics, work-up, and treatments between patients with dermatitis of immune senescence and those patients ultimately given more specific diagnoses. Methods: Four hundred and thirty-three patients aged 60 years and older with new-onset dermatitis from 2011 to 2016 at Ohio State University were identified by chart review and categorized as "dermatitis of immune senescence" or "alternate diagnosis" based on patch testing, biopsy, and physician documentation. Results: In this subset of patients, 10.2 percent (44/433) underwent patch testing and 16.2 percent (70/433) underwent biopsy. Furthermore, 86.4 percent of patients who underwent patch testing (38/44) and 57.1 percent who underwent biopsy (40/70) were given a more specific diagnosis following their test. Use of intramuscular steroids (p<.001), oral steroids (p=.004), and antihistamines (p=.002) were significantly higher in the alternate diagnosis group. Conclusion: The low rate of patch testing and biopsy and the high rate of diagnosis change post-procedure demonstrate an underutilization of diagnostic testing in this population.

Development of a Three-Dimensional Adipose Tissue Model for Studying Embryonic Exposures to Obesogenic Chemicals.

Obesity is a rising issue especially in the United States that can lead to heart problems, type II diabetes, and respiratory problems. Since the 1970s, obesity rates in the United States have more than doubled in adults and children. Recent evidence suggests that exposure to certain chemicals, termed "obesogens," in utero may alter metabolic processes, predisposing individuals to weight gain. There is a need to develop a three-dimensional human tissue system that is able to model the effects of obesogens in vitro in order to better understand the impact of obesogens on early development. Human embryonic-derived stem cells in three-dimensional collagen embedded silk scaffolds were exposed to three different obesogens: Bisphenol A (BPA), Bisphenol S (BPS), and Tributyltin (TBT). The exposed tissues accumulated triglycerides and increased expression of adipogenic genes (Perilipin (PLIN1), peroxisome proliferator-activated receptor gamma (PPARy), fatty acid binding protein 4 (FABP4)) compared to equivalent control cultures with no obesogen exposure. These cultures were also compared to human adult stem cell cultures, which did not respond the same upon addition of obesogens. These results demonstrate the successful development of a representative tissue model of in utero obesogen exposures. This tissue system could be used to determine mechanisms of action of current obesogens and to screen other potential obesogens.

Factors associated with childhood cancer survivors' knowledge about their diagnosis, treatment, and risk for late effects.

BACKGROUND: While most children with cancer survive their initial disease, cancer therapy places them at risk for late effects (LE). Knowledge of their diagnosis, treatment, and LE risk may motivate survivors to attend long-term follow-up care. The aims of this study were to examine knowledge of cancer history and future risks, and to identify factors associated with such knowledge, in a cohort of childhood cancer survivors. METHODS: Survivors (i.e., patients finished cancer treatment, regardless of time since completion) aged 15 to 26 years from three Canadian cancer centers were invited to complete a questionnaire that assessed knowledge of cancer history and potential LE of treatments, including five specific LE known to have considerable long-term health impact. Clinical data were extracted from hospital records and used to validate participants' answers. RESULTS: Of 250 participants, 16 (6%) were unable to name their cancer, 79 (32%) had partial or no knowledge of their therapy, and 83 (33%) were unaware of at least some of their risks for LE. Decreasing age (OR for increase in age = 1.2 (1.1-1.4)), having had a renal tumor compared to leukemia (OR = 0.3 (0.1-0.9)), and lacking knowledge about treatment (OR = 0.4 (0.2-0.9)) were associated with lack of knowledge of LE. Of the five, the most and least familiar LE was LE associated with impaired pulmonary function and risk of second malignancy, respectively. CONCLUSION: This study highlights knowledge deficits in survivors, specifically regarding their risk for LE. IMPLICATIONS FOR CANCER SURVIVORS: Findings can be utilized to target survivors at risk for knowledge deficits.

Exploring Cancer Worry in Adolescent and Young Adult Survivors of Childhood Cancers.

PURPOSE: Adolescent and young adult (AYA) survivors of cancers in childhood experience cancer worry, defined as concerns about cancer-related issues such as relapse and late effects of treatment. Cancer worry is an important determinant of successful transition to long-term follow-up care. The primary aim of this study was to identify patient-, cancer-, and treatment-related factors associated with cancer worry in AYA survivors. A secondary aim was to explore and understand inappropriate cancer worry (e.g., worry of developing a late effect when not at risk) in this population. METHODS: Two hundred and fifty AYA survivors, aged 15­26 years, completed a 6-item Cancer Worry Scale. Selection of factors potentially associated with cancer worry was guided by literature and expert opinion for inclusion in univariable and multivariable regression analyses. RESULTS: Female survivors reported significantly more cancer worry than males did (b=-9.4; 95% CI -14.4 to -4.5; p < 0.001). Survivors treated with the most intensive therapies reported more cancer worry compared with those who received the least intensive therapies (b=-18.5; 95% CI -31.2 to -5.9; p = 0.004). Thirty-one percent of participants had inappropriate worry regarding infertility and/or secondary malignancy. CONCLUSIONS: In AYA survivors, female sex and higher treatment intensity were associated with increased cancer worry. Inappropriate worry was prevalent among survivors and may contribute to unnecessary distress. These findings can help identify survivors who are more likely to worry and support the development of appropriate services to reduce the effect of cancer worry on survivor well-being.