A rare presentation of Rosai-Dorfman-Destombes disease with central nervous system involvement and cutaneous wounds.

OBJECTIVE: The aim of this case report is to investigate an uncommon presentation of Rosai-Dorfman-Destombes (RDD) disease, and discuss possible differential diagnoses and treatment options for this pathology. RDD is a rare disorder of histiocytes that typically presents in patients as painless cervical lymphadenopathy. However, this case involves a patient with the central nervous system (CNS) type of RDD who later developed cutaneous lesions. METHOD: Several differential diagnoses were examined, including hidradenitis suppurativa, pilonidal cyst and pressure ulcers. It is important to be able to exclude these diagnoses based on the presentation, patient demographic and wound location. RESULTS: Biopsies verified the presence of RDD in the patient's suprasellar hypothalamic mass and skin lesions, confirming the patient had both CNS-RDD and cutaneous-RDD in the absence of lymphadenopathy. CONCLUSION: Recognising the unique manifestations of rare diseases such as RDD prevents delay of proper intervention and treatment.

Dystrophic Calcinosis Cutis Leading to a Nonhealing Wound in a Patient with Chronic Venous Insufficiency.

The presence of bony-appearing fragments and calcifications appearing superficially in a chronic, nonhealing wound raises suspicion for osteomyelitis. When radiological imaging and tissue biopsy of the lesion return negative for osteomyelitis, however, the differentials must be widened to successfully manage and heal a chronic wound. In this report, we discuss a case of an 80-year-old morbidly obese woman with a history of chronic venous insufficiency, hereditary hemochromatosis, and squamous cell carcinoma who presented to the wound clinic with a 5-month history of a nonhealing wound with bony-appearing fragments and calcifications on her left anterior leg status postbiopsy during routine skin examination. Upon clinical correlation with laboratories and imaging, it was determined that the cause of her nonhealing wound was due to dystrophic calcinosis cutis.

Malignant wound aetiology, diagnosis and management: a case series and literature review.

OBJECTIVE: Malignant wounds develop when neoplastic cells invade the skin either locally or by lymphatic and haematogenous spread. They can present as hard-to-heal wounds and underlying causes include: primary skin cancer; metastasis of extracutaneous primary malignancy; malignant transformation of a hard-to-heal wound; iatrogenic injury; and cutaneous forms of cancers of non-skin origin. High clinical suspicion for a malignant wound should be confirmed with skin biopsy. The aim of this case series is to highlight a combination of both clinically clear cutaneous malignancies and not-so-obvious wounds caused by malignancy. METHOD: This case series examines patients with malignant wounds of varying aetiology and appearance. For each case, we explain the pathophysiology, atypical features, diagnostic approach and treatment. We also discuss types of wound biopsy and general wound management principles. RESULTS: Among the 11 cases analysed using descriptive statistics, median wound duration before presentation at our clinic was one year, while median age at presentation was 65 years. Our case series included the following diagnoses: cutaneous metastasis of invasive ductal carcinoma of the breast (n=2); cutaneous metastasis of colorectal adenocarcinoma (n=1); Marjolin's ulcer (n=1), basal cell carcinoma (BCC) (n=2), primary cutaneous squamous cell carcinoma (SCC) (n=1), metastatic malignant melanoma (n=1), cutaneous T-cell lymphoma (n=1), cutaneous angiosarcoma (n=1), Kaposi sarcoma (n=1) and recurrent tonsillar SCC with osteoradionecrosis (n=1); one case had both BCC and SCC. CONCLUSION: Punch and excisional biopsies were the most frequently used diagnostic techniques. Local wound therapy addressed bleeding, malodour, exudate, pain and infection. However, wound healing is usually achieved once the underlying malignancy is treated. In advanced or metastatic disease, palliative wound care aims to prevent exacerbation of existing wounds and focuses on patient comfort.

Using cognitive interviews to improve a measure of organizational readiness for implementation.

BACKGROUND: Organizational readiness is a key factor for successful implementation of evidence-based interventions (EBIs), but a valid and reliable measure to assess readiness across contexts and settings is needed. The R = MC2 heuristic posits that organizational readiness stems from an organization's motivation, capacity to implement a specific innovation, and its general capacity. This paper describes a process used to examine the face and content validity of items in a readiness survey developed to assess organizational readiness (based on R = MC2) among federally qualified health centers (FQHC) implementing colorectal cancer screening (CRCS) EBIs. METHODS: We conducted 20 cognitive interviews with FQHC staff (clinical and non-clinical) in South Carolina and Texas. Participants were provided a subset of items from the readiness survey to review. A semi-structured interview guide was developed to elicit feedback from participants using "think aloud" and probing techniques. Participants were recruited using a purposive sampling approach and interviews were conducted virtually using Zoom and WebEx. Participants were asked 1) about the relevancy of items, 2) how they interpreted the meaning of items or specific terms, 3) to identify items that were difficult to understand, and 4) how items could be improved. Interviews were transcribed verbatim and coded in ATLAS.ti. Findings were used to revise the readiness survey. RESULTS: Key recommendations included reducing the survey length and removing redundant or difficult to understand items. Additionally, participants recommended using consistent terms throughout (e.g., other units/teams vs. departments) the survey and changing pronouns (e.g., people, we) to be more specific (e.g., leadership, staff). Moreover, participants recommended specifying ambiguous terms (e.g., define what "better" means). CONCLUSION: Use of cognitive interviews allowed for an engaged process to refine an existing measure of readiness. The improved and finalized readiness survey can be used to support and improve implementation of CRCS EBIs in the clinic setting and thus reduce the cancer burden and cancer-related health disparities.

Implementation During a Pandemic: Findings, Successes, and Lessons Learned from Community Grantees.

Funding communities through mini-grant programs builds community capacity by fostering leadership among community members, developing expertise in implementing evidence-based practices, and increasing trust in partnerships. The South Carolina Cancer Prevention and Control Research Network (SC-CPCRN) implemented the Community Health Intervention Program (CHIP) mini-grants initiative to address cancer-related health disparities among high-risk populations in rural areas of the state. One community-based organization and one faith-based organization were funded during the most recent call for proposals. The organizations implemented National Cancer Institute evidence-based strategies and programs focused on health and cancer screenings and physical activity and promotion of walking trails. Despite the potential for the COVID-19 pandemic to serve as a major barrier to implementation, grantees successfully recruited and engaged community members in evidence-based activities. These initiatives added material benefits to their local communities, including promotion of walking outdoors where it is less likely to contract the virus when socially distanced and provision of COVID-19 testing and vaccines along with other health and cancer screenings. Future mini-grants programs will benefit from learning from current grantees' flexibility in program implementation during a pandemic as well as their intentional approach to modifying program aspects as needed.

Development of a comprehensive measure of organizational readiness (motivation × capacity) for implementation: a study protocol.

BACKGROUND: Organizational readiness is important for the implementation of evidence-based interventions. Currently, there is a critical need for a comprehensive, valid, reliable, and pragmatic measure of organizational readiness that can be used throughout the implementation process. This study aims to develop a readiness measure that can be used to support implementation in two critical public health settings: federally qualified health centers (FQHCs) and schools. The measure is informed by the Interactive Systems Framework for Dissemination and Implementation and R = MC2 heuristic (readiness = motivation × innovation-specific capacity × general capacity). The study aims are to adapt and further develop the readiness measure in FQHCs implementing evidence-based interventions for colorectal cancer screening, to test the validity and reliability of the developed readiness measure in FQHCs, and to adapt and assess the usability and validity of the readiness measure in schools implementing a nutrition-based program. METHODS: For aim 1, we will conduct a series of qualitative interviews to adapt the readiness measure for use in FQHCs. We will then distribute the readiness measure to a developmental sample of 100 health center sites (up to 10 staff members per site). We will use a multilevel factor analysis approach to refine the readiness measure. For aim 2, we will distribute the measure to a different sample of 100 health center sites. We will use multilevel confirmatory factor analysis models to examine the structural validity. We will also conduct tests for scale reliability, test-retest reliability, and inter-rater reliability. For aim 3, we will use a qualitative approach to adapt the measure for use in schools and conduct reliability and validity tests similar to what is described in aim 2. DISCUSSION: This study will rigorously develop a readiness measure that will be applicable across two settings: FQHCs and schools. Information gained from the readiness measure can inform planning and implementation efforts by identifying priority areas. These priority areas can inform the selection and tailoring of support strategies that can be used throughout the implementation process to further improve implementation efforts and, in turn, program effectiveness.

The Use of Ripple Effect Mapping to Understand Successes of the SC Pregnancy Assistance Fund: A Participatory Evaluation Approach.

OBJECTIVES: The South Carolina Pregnancy Assistance Fund (SCPAF) funded four counties to increase the amount, quality, and awareness of services for young parents; increase educational attainment among expectant and parenting youth; reduce the number of repeat teen pregnancies among youth; and improve parenting skills. The purpose of this paper is twofold: (1) to describe our application of the Ripple Effect Mapping (REM) technique as an innovative evaluation strategy to gather perspectives from SCPAF stakeholders and (2) to share key findings generated by participants in REM sessions on the perceived success of local SCPAF community collaboratives. METHODS: REM, an innovative evaluation strategy, was used to gather perspectives from SCPAF stakeholders. Five REM sessions were conducted with 52 participants. REM sessions included partner interviews and collective development of visual maps to illustrate stakeholder perspectives of program successes. Visual maps, as well as transcripts of discussions, were analyzed using an inductive approach. RESULTS: Stakeholders reported that the connections to resources, supports, and services provided through SCPAF had the potential to alter the life trajectories of expectant and parenting teens (EPT). Stakeholders also described that SCPAF fostered growth in collaboration among partners and reduced duplication of services in funded communities CONCLUSIONS FOR PRACTICE: This paper describes how an innovative evaluation strategy was used to provide a space for stakeholders to dialogue, synthesize their experiences, and construct a collective narrative of key program successes. This paper also illustrates how such approaches can be applied to complex community initiatives.

TRAF2 Ser-11 Phosphorylation Promotes Cytosolic Translocation of the CD40 Complex To Regulate Downstream Signaling Pathways.

CD40 plays an important role in immune responses by activating the c-Jun N-terminal protein kinase (JNK) and NF-κB pathways; however, the precise mechanisms governing the spatiotemporal activation of these two signaling pathways are not fully understood. Here, using four different TRAF2-deficient cell lines (A20.2J, CH12.LX, HAP1, and mouse embryonic fibroblasts [MEFs]) reconstituted with wild-type or phosphorylation mutant forms of TRAF2, along with immunoprecipitation, immunoblotting, gene expression, and immunofluorescence analyses, we report that CD40 ligation elicits TANK-binding kinase 1 (TBK1)-mediated phosphorylation of TRAF2 at Ser-11. This phosphorylation interfered with the interaction between TRAF2's RING domain and membrane phospholipids and enabled translocation of the TRAF2 complex from CD40 to the cytoplasm. We also observed that this cytoplasmic translocation is required for full activation of the JNK pathway and the secondary phase of the NF-κB pathway. Moreover, we found that in the absence of Ser-11 phosphorylation, the TRAF2 RING domain interacts with phospholipids, leading to the translocation of the TRAF2 complex to lipid rafts, resulting in its degradation and activation of the noncanonical NF-κB pathway. Thus, our results provide new insights into the CD40 signaling mechanisms whereby Ser-11 phosphorylation controls RING domain-dependent subcellular localization of TRAF2 to modulate the spatiotemporal activation of the JNK and NF-κB pathways.

TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice.

The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated owing to the accumulation of conflicting data. Here, we report that 7-day-old TRAF2-knockout (KO) and TRAF2 TRAF5 double KO (TRAF2/5-DKO) mice exhibit enhanced canonical IκB kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNFα-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing to elevated basal and TNFα-induced delayed IKK activation, TNFα stimulation leads to significantly increased induction of a subset of NF-κB-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5-DKO mice succumb to a sublethal dose of TNFα owing to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of IAP1 and IAP2 (also known as BIRC2 and BIRC3, respectively) also results in elevated basal IKK activation that is independent of autocrine TNFα production and that impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.

RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival.

Although TRAIL is considered a potential anticancer agent, it enhances tumor progression by activating NF-κB in apoptosis-resistant cells. Cellular FLICE-like inhibitory protein (cFLIP) overexpression and caspase-8 activation have been implicated in TRAIL-induced NF-κB activation; however, the underlying mechanisms are unknown. Here, we report that caspase-8-dependent cleavage of RIP1 in the kinase domain (KD) and intermediate domain (ID) determines the activation state of the NF-κB pathway in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment. In apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID immediately after the recruitment of RIP1 to the receptor complex, impairing IκB kinase (IKK) recruitment and NF-κB activation. In apoptosis-resistant cells, cFLIP restricts caspase-8 activity, resulting in limited RIP1 cleavage and generation of a KD-cleaved fragment capable of activating NF-κB but not apoptosis. Notably, depletion of the cytoplasmic pool of TRAF2 and cIAP1 in lymphomas by CD40 ligation inhibits basal RIP1 ubiquitination but does not prompt cell death, due to CD40L-induced cFLIP expression and limited RIP1 cleavage. Inhibition of RIP1 cleavage at the KD suppresses NF-κB activation and cell survival even in cFLIP-overexpressing lymphomas. Importantly, RIP1 is constitutively cleaved in human and mouse lymphomas, suggesting that cFLIP-mediated and caspase-8-dependent limited cleavage of RIP1 is a new layer of mechanism that promotes NF-κB activation and lymphoma survival.

TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways.

The death receptor (DR) ligand TRAIL is being evaluated in clinical trials as an anti-cancer agent; however, many studies have found that TRAIL also enhances tumor progression by activating the NF-κB pathway in apoptosis-resistant cells. Although RIP1, cFLIP and caspase-8 have been implicated in TRAIL-induced JNK and NF-κB activation, underlying mechanisms are unclear. By examining the kinetics of pathway activation in TRAIL-sensitive lymphoma cells wild-type or deficient for RIP1, TRAF2, cIAP1/2 or HOIP, we report here that TRAIL induces two phases of JNK and NF-κB activation. The early phase is activated by TRAF2- and cIAP1-mediated ubiquitination of RIP1, whereas the delayed phase is induced by caspase-dependent activation of MEKK1 independent of RIP1 and TRAF2 expression. cFLIP overexpression promotes the early phase but completely suppresses the delayed phase of pathway activation in lymphoma cells, whereas Bcl-2 overexpression promotes both the early and delayed phases of the pathways. In addition, stable overexpression of cFLIP in RIP1- or TRAF2-deficient cells confers resistance to apoptosis, but fails to mediate NF-κB activation. HOIP is not essential for, but contributes to, TRAIL-induced NF-κB activation in cFLIP-overexpressing cells. These findings not only elucidate details of the mechanisms underlying TRAIL-induced JNK and NF-κB activation, but also clarify conflicting reports in the field.

Physical activity and health-related quality of life: US adults with and without limitations.

PURPOSE: The purpose of this study was to examine the dose-response relationship between physical activity (PA) and health-related quality of life (HRQOL) among adults with and without limitations. METHODS: We dichotomized HRQOL as ≥14 unhealthy (physical or mental) days (past 30 days), or <14 unhealthy days. By using a moderate-intensity minute equivalent, PA categories were as follows: inactive, 10-60, 61-149, 150-300, and >300 min/week. Persons with limitations reported having problems that limited their activities or required use of special equipment. Age-adjusted prevalence estimates and logistic regression analyses were performed with 2009 Behavioral Risk Factor Surveillance System data (n = 357,665), controlling for demographics, BMI, smoking, and heavy alcohol use. RESULTS: For adults without limitations, the odds of ≥14 unhealthy days were lower among adults obtaining any PA (10-60 min/week, AOR = 0.79, 95 % CI 0.70, 0.88), compared with those inactive. A quadratic trend (P < 0.001) indicated enhanced HRQOL with each PA level, but improvements were less marked between lower and upper sufficient PA categories (150-300 and >300 min/week). Because of a significant age interaction, persons with limitations were stratified by age (18-34, 35-64, and 65+ years). Findings for persons aged 35 years or older with limitations were similar to those without limitations. Lower odds of poor HRQOL for persons aged 18-34 years with limitations were associated with recommended levels of PA (150-300 min/week; AOR = 0.61, 95 % CI 0.43, 0.88 and >300 min/week; AOR = 0.58, 95 % CI 0.43, 0.80). CONCLUSIONS: PA is positively associated with HRQOL among persons with and without limitations.

TNFR1 signaling kinetics: spatiotemporal control of three phases of IKK activation by posttranslational modification.

TNFα is a pleotropic cytokine that plays a central role in the inflammatory response by activating the NF-κB signaling pathway, and is targeted in a range of chronic inflammatory diseases, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. Although K63-linked ubiquitination of RIP1 by TRAF2/5 and cIAP1/2 was thought to serve as a scaffold to activate the NF-κB pathway, the recent accumulation of conflicting results has challenged the necessity of these proteins in NF-κB activation. In addition, several serine/threonine kinases have been implicated in TNFα-induced IKK activation; however, the targeted disruption of these kinases had no effect on transient IKK activation. The recent discovery of RIP1-dependent and -independent activation of the early and delayed phases of IKK and TRAF2 phosphorylation-dependent activation of the prolonged phase of IKK offers a reconciliatory model for the interpretation of contradictory results in the field. Notably, the TNFα-induced inflammatory response is not exclusively controlled by the NF-κB pathway but is subject to regulatory crosstalk between NF-κB and other context-dependent pathways. Thus further elucidation of these spatiotemporally-coordinated signaling mechanisms has the potential to provide novel molecular targets and therapeutic strategies for NF-κB intervention.

Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed IκB kinase activation.

Tumor necrosis factor alpha (TNF-α)-induced NF-κB activation has been believed to depend on TRAF2- and cIAP1-mediated RIP1 ubiquitination. However, recent findings have challenged the notion that these proteins play essential roles in NF-κB activation. Here, by assessing the kinetics and amplitude of IκB kinase (IKK) activation, we report that TNF-α-induced immediate and robust activation of IKK requires K63-linked and linearly linked ubiquitination of RIP1 and that in the absence of RIP1 expression, TRAF2 and cIAP1 cooperatively induce delayed IKK activation by recruiting LUBAC to TNFR1. Knockdown of HOIP (a component of LUBAC) in RIP1-deficient cells completely impairs the recruitment and activation of IKK but does not affect K63-linked ubiquitination of TRAF2 and recruitment of TAK1 to TNFR1, suggesting that the K63-linked ubiquitin chain is not capable of recruiting IKK in vivo. We also demonstrate that TRAF2 and cIAP1 together, but not either one alone, directly catalyze linearly linked ubiquitination of RIP1. Importantly, in embryonic hepatocytes, TNF-α activates NF-κB through a RIP1-independent pathway. Thus, our findings clarify molecular details of this important signaling mechanism by providing evidence for the existence of two phases of IKK activation: the immediate phase, induced by TRAF2/cIAP1-mediated ubiquitination of RIP1, and the delayed phase, activated by TRAF2/cIAP1-dependent recruitment of LUBAC.

Conceptualizing, implementing, and monitoring a structural health promotion intervention in an organizational setting.

This article presents a framework for developing and carrying out an implementation monitoring plan of a complex structural intervention in an organizational setting and describes seven steps for analyzing and reporting results for fidelity and completeness of implementation. This process is illustrated using the Environmental Interventions in Children's Homes (ENRICH) Wellness Project. ENRICH aimed to promote physical activity and healthful nutrition behaviors among children residing in children's group homes by working collaboratively with organizational staff. A comprehensive implementation monitoring plan was developed based on the particulars of the setting, context, and the program framework and used multiple data sources, criteria for evidence of implementation, and data triangulation to examine evidence for organizational implementation. Eleven of 17 organizations (65%) met the criteria for nutrition implementation whereas 9 of 17 (53%) met the criteria for physical activity implementation. Implementation data can be used descriptively, as described here, and may also be used in future outcome analyses to better understand project outcomes. The framework and evaluation approach are applicable to complex interventions in other organizational settings.