Citations

Abstract This study evaluated the effect of the Certified Child Life Specialist (CCLS) on pediatric pain and pain management during routine immunization administration in the pediatric primary care clinic. Children 4–12 years of age ( n = 125) presenting for a well child physical examination at a rural primary care clinic were selected to receive standard nursing care or standard nursing care plus CCLS support during routine immunization administration. Patient reported pain was measured using the Faces Pain Scale‐Revised (FPS‐R), and patient behavioral responses were measured during immunization administration using the Children's Emotional Manifestation Scale (CEMS). The performance of psychosocial interventions and administration of topical pain‐relieving interventions were measured between both groups. CCLS support was associated with fewer negative emotional behaviors during immunization administration among 7‐ to 12‐year‐old children and a significantly higher provision of psychosocial interventions and topical pain‐relieving interventions among all ages. This study demonstrates that the presence of a CCLS can increase the provision of psychosocial and pain‐relieving interventions and reduce distress during immunization administration in a busy pediatric primary care clinic.

Background Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. Methods A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN . Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. Results Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. Conclusions These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Update This article was updated on May 12, 2023, because of a previous error. In the Note on page 612, Byson P. Lesniak, MD, had not been listed as a member of the STaR Trial for Multiple Ligament Knee Injuries Network. The Note now reads “The STaR Trial for Multiple Ligament Knee Injuries Network includes Robert Arciero, MD; Brandee S. Black, MD; Catherine M. Coady, MD, FRSCS; Jonathan M. Cooper, DO; Katherine J. Coyner, MD; Cory M. Edgar, MD, PhD; Al M.J. Getgood, MD, FRCS(Tr&Orth); Joe M. Hart, PhD, ATC; Jonathan D. Hodax, MD, MS; Jonathan D. Hughes, MD; Cale A. Jacobs, PhD, ATC; Darren L. Johnson, MD; Ryan M. Khan, MSc, CCRP; Byson P. Lesniak, MD; Jeffrey A. Macalena, MD; Robert G. Marx, MD; Mark D. Miller, MD; Bradley Nelson, MD; Alicia Oostdyk, PhD; Charity G. Patterson, PhD, MSPH; Adam J. Popchak, PT, PhD; Anil S. Ranawat, MD; Michael J. Stuart, MD; Caroline E. Taber, AB; Ryan J. Warth, MD; Daniel B. Whelan, MD, MSc, FRCSC; and Isabel Wolfe, BS.” An erratum has been published: J Bone Joint Surg Am. 2023 Jun 21;105(12):e33. Background: Multiple ligament knee injuries (MLKIs) represent a spectrum of injury patterns that are often associated with concomitant musculoskeletal and neurovascular injuries, complex treatment, and postoperative complications. However, there has not been high-level evidence describing the presentation and treatment of MLKIs. The purpose of this multicenter retrospective study was to describe characteristics of MLKIs, their management, and related complications using a pathoanatomic MLKI classification system based on the Schenck Knee Dislocation classification system. Methods: This review identified and analyzed MLKIs that occurred between 2011 and 2015. Cases with an MLKI were included in this study if there was a complete tear of ≥2 ligaments and at least 1 ligament was repaired or reconstructed. Cases in which a ligament was deemed clinically incompetent due to a partial ligament tear and required surgical repair or reconstruction were considered equivalent to grade-III tears for inclusion and classification. Demographic information, the mechanism of injury, times from injury to presentation to an orthopaedic surgeon and to surgery, the ligament injury pattern, associated injuries, surgical procedures, and complications were captured. Data were analyzed descriptively. Results: A total of 773 individuals from 14 centers who underwent surgery for an MLKI were reviewed. The mean age of the individuals was 30.5 ± 12.7 years, and 74.2% were male. The most common mechanism involved sports (43.2%). The median time from injury to presentation to the orthopaedic surgeon was 11 days (interquartile range [IQR], 3 to 48 days), and the time to initial ligament surgery was 64 days (IQR, 23 to 190 days). While the most common injury patterns were an anterior cruciate ligament tear combined with either a medial-sided (MLK 1-AM, 20.7%) or lateral-sided (MLK 1-AL, 23.2%) injury, one-third (34.7%) were bicruciate injuries. Associated injuries most often involved menisci (55.6%), nerves (18.5%) and tendons (15.6%). The method of surgical intervention (repair versus reconstruction), external fixator use, and staging of procedures varied by MLKI classification. Loss of motion (11.4%) was the most common postoperative complication. Conclusions: A better understanding of the clinical characteristics and management of the various MLKI patterns can be used to support clinical decision-making and individualized treatment of these complex injuries, and may ultimately lead to enhanced outcomes and reduced associated risks. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000–2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75–79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.

76 Background: The prevalence of Lynch syndrome in Iceland is the highest described so far or 1:226 with three founder mutations, one in MSH6 and two in PMS2, and was first reported in 2017. Lynch syndrome predisposes carriers to colorectal cancer and metachronous primaries. Most data on metachronous colorectal cancer reflects on MLH1 and MSH2 carriers and is not well described in MSH6 and PMS2 carriers. The purpose of this study was to examine the cumulative incidence of metachronous colorectal cancer in Icelandic Lynch syndrome carriers diagnosed with colorectal cancer from 1955-2017. Methods: This retrospective study included all individuals with pathogenic variants in mismatch repair genes identified in a nationwide genotype database and a colorectal cancer diagnosis in the Icelandic Cancer Registry from 1955-2017. DeCODE genetics has collected extensive genotypic information on the Icelandic population sequencing the whole genomes of 49,708 Icelanders and imputing genotypes into 116,573 Icelanders whose DNA had been genotyped with SNP chips. Cancer information was obtained from patient charts and cause of death obtained from the Cause of Death Register. All polyp pathology was accessed in the pathology registry and reassessed by two pathologists. Results: A total of 65 individuals developed colorectal cancer during the study period with 34 (52.3%) PMS2 carriers and 25 (38.5%) MSH6 carriers. The cumulative incidence of metachronous colorectal cancer was low or one case (1.5%) in an MSH2 carrier with a median follow-up time of 58 months (Q1 8.0, Q3 167.0, range 0-365 months) in the cohort. Only two (3.1%) individuals, one with MSH2 and one with MSH6 pathogenic variants, underwent a total colectomy. Median age at first colorectal cancer diagnosis was 63 years (Q1 54.0, Q3 72.5, range 28-94). Thirty-one (47.7%) individuals had polyps resected during the study period with adenomas (67.1%) being the most common. Significantly more MSH6 carriers had a history of advanced adenomas as compared to PMS2 carriers (36.0 % vs 11.8%, p = 0.026). Five-year colorectal cancer survival was 81.4% for PMS2 carriers and 71.5% for MSH6 carriers. Conclusions: The incidence of metachronous colorectal cancer was zero in Lynch syndrome carriers with MSH6 or PMS2 pathogenic variants from 1955-2017 despite these individuals not undergoing rigorous Lynch syndrome screening. This would support performing segmental colectomies and following European screening guidelines for MSH6 and PMS2 carriers in Iceland.

AbstractBackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.ResultsWe collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.ConclusionsWithin the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Ligation of the Fc γ R on NK cells by Ab-coated target cells initiates a mode of killing referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). There is clear evidence that the release from NK cells of granules containing pore-forming proteins and serine proteases can result in the rapid (within minutes) cell death of Ab-coated targets. However, little information is available as to whether NK cells can initiate subsequent killing through granule-independent mechanisms and as to the mechanisms that down-regulate NK cell-mediated responses. We demonstrate in this study that FcR stimulation of activated human NK cells not only induces granule exocytosis, but also subsequently results in the transcriptional up-regulation of Fas ligand. These FcR-stimulated NK cells can then kill targets that bear Fas (CD95/APO-1), as this cytotoxicity can be inhibited by blocking Abs to the Fas receptor. In addition, as resting NK cells become activated, their Fas receptors become competent to deliver autocrine suicide signals. We demonstrate in this work that the interaction of Fas ligand on the FcR-stimulated NK cells with their Fas receptors can result in apoptosis of the NK cells. These results suggest that the FcR-induced expression of Fas ligand on activated NK cells can critically influence the capacity of these cells to mediate paracrine and autocrine cell death.

Abstract Activation-induced cell death of peripheral T cells results from the interaction between Fas and Fas ligand. Resting peripheral T cells are resistant to Fas-induced apoptosis and become susceptible only after their activation. We have investigated the molecular mechanism mediating the sensitization of resting peripheral T cells to Fas-mediated apoptosis following TCR stimulation. TCR activation decreases the steady state protein levels of FLIP (FLICE-like inhibitory protein), an inhibitor of the Fas signaling pathway. Reconstitution of intracellular FLIP levels by the addition of a soluble HIV transactivator protein-FLIP chimera completely restores resistance to Fas-mediated apoptosis in TCR primary T cells. Inhibition of IL-2 production by cyclosporin A, or inhibition of IL-2 signaling by rapamycin or anti-IL-2 neutralizing Abs prevents the decrease in FLIP levels and confers resistance to Fas-mediated apoptosis following T cell activation. Using cell cycle-blocking agents, we demonstrate that activated T cells arrested in G1 phase contain high levels of FLIP protein, whereas activated T cells arrested in S phase have decreased FLIP protein levels. These findings link regulation of FLIP protein levels with cell cycle progression and provide an explanation for the increase in TCR-induced apoptosis observed during the S phase of the cell cycle.

Abstract Activation-induced cell death (AICD) is initiated by the TCR-dependent up-regulation of Fas ligand (FasL) mRNA. The subsequently generated soluble or cell-associated FasL gene products bind Fas, leading to apoptosis of the T cells. Although TCR stimulation is essential to initiate AICD, little is known about which TCR-initiated second messengers are required for FasL expression. We provide evidence in this work that T cells lacking the tyrosine kinase ZAP-70 are unable to up-regulate FasL and undergo AICD. Transfection of wild-type ZAP-70 into the ZAP-70-deficient T cells restores their sensitivity to TCR-induced apoptosis, whereas transfection of catalytically inactive ZAP-70 does not. These results provide clear evidence that ZAP-70 tyrosine kinase is essential in up-regulating FasL for TCR-induced apoptosis.

Abstract Mycoplasma arthritidis produces a soluble protein which is active for murine and human lymphocytes when presented by Ia-bearing accessory cells. By using fibroblasts transfected in vitro with various class II Ag, we demonstrated that presentation of the M. arthritidis mitogen (MAM) to T cells was mediated by E alpha-containing molecules. We also showed that splenocytes from transgenic mice expressing E alpha heterozygously (B10.TRG E alpha+) or homozygously (B10.E alpha TG +/+) underwent a similar proliferation in response to MAM as compared with the failure of control B10.TRG E alpha- splenocytes to respond to MAM. Although splenocytes from inbred C3H and CBA mice exhibited much higher proliferative responses to MAM than did those from B10.TRG.E alpha+ or B10.E alpha TG +/+ mice, flow cytometry showed similar levels of E alpha expression. Furthermore, gamma-irradiated splenocytes from B10.TRG E alpha + mice presented MAM to T hybridoma cells with a similar efficacy as did splenocytes from C3H mice. The lesser response to MAM of lymphocytes from the E alpha transgenic mice as compared with those from C3H and B10.K mice was likewise not due to differential expression of their V beta TCR. We conclude that presentation of MAM to T cells is accomplished by E alpha-containing molecules. The studies also suggest that the conserved, nonpolymorphic regions of class II molecules may play an important role in host immune response to microbial products.