Benign goiters requiring thyroidectomy as the signal for PTEN hamartoma tumor syndrome diagnosis.

PTEN hamartoma tumor syndrome (PHTS) is a rare genetic cancer and tumor predisposition syndrome. Due to the wide spectrum of clinical manifestations and variable age at onset, the pathways leading to a PHTS diagnosis are difficult and highly variable. Many patients were found to have PHTS after a cancer diagnosis, missing the opportunity of prevention or enhanced cancer screening. This retrospective study evaluated a PHTS cohort followed in a high-risk surveillance clinic in a comprehensive cancer institution. A significant portion of the patients (60.9%, 14/23) had at least one cancer diagnosis (average age 34.6 years at diagnosis). A significant portion (78.3%, 18/23) were affected with clinically significant goiters (age 27.9 years), and many (60.9%, 14/23) had partial or total thyroidectomy (age 27.1 years). The average age at goiter diagnosis or thyroidectomy is younger than a cancer diagnosis. In 12 individuals who were affected with clinically significant goiter and cancer, all cancers were diagnosed after the thyroid disease (6.3 years). As clinically significant thyroid nodules in childhood or early young adulthood are common in PHTS, but uncommon for general population, these early onset thyroid nodules may alert the clinician to initiate PHTS-targeted evaluation and genetic testing.

Interpretation of ambiguous TP53 test results: Mosaicism, clonal hematopoiesis, and variants of uncertain significance.

The increased use of next-generation sequencing has led to the detection of pathogenic TP53 variants in the germline setting in patients without a personal or family history consistent with Li-Fraumeni syndrome (LFS). These variants can represent low-penetrance LFS, mosaic LFS, or clonal hematopoiesis of indeterminate potential. Additionally, TP53 variants of uncertain significance can be detected in patients with a history suspicious for LFS. The interpretation of the significance of these variants can be challenging but is crucial for an accurate diagnosis and appropriate medical management. This retrospective case review provides illustrative examples of the interpretation of challenging TP53 results through multidisciplinary expertise and use of a flowchart. The authors describe eight patients with TP53 variants associated with ambiguous diagnoses and, for each case, describe how the results were interpreted and the medical care that was implemented. This report presents illustrative cases to help guide clinicians to reach definitive diagnoses for patients when confronted with TP53 variants that are inconsistent with the clinical picture and to add to the body of literature regarding interpretation and medical management of TP53 variants discovered on germline testing.

GeneHome - a Novel Model to Deliver Care to Individuals with Genetic Predisposition to Cancer.

Genetic testing for hereditary cancer predisposition is more widely available, resulting in more patients being identified as carriers of pathogenic variants (PV) of cancer susceptibility genes. PV carriers may be at high risk for multiple cancers of different organ systems. Traditional high-risk cancer screening is often organ specific and conducted separately by specialists. However, with many genes associated with 3 or more types of cancer risks, coordination of such cancer screening can be overwhelming for patients and providers. At Moffitt Cancer Center (MCC), GeneHome clinic functions as a "home" to conduct and coordinate prevention, screening, counseling, and education for individuals carrying germline genetic PVs across the entire spectrum of cancer genes. The screening includes, but is not limited to, history review, physical examination, image studies, blood tests, urine tests, and endoscopy. GeneHome is a novel model for genetic high-risk cancer surveillance and has grown in 4 years since establishment. We sought to study various characteristics of the patient population it serves, common themes in referral patterns and evolution of the clinic since its inception. A total of 821 patients were seen over 42 months, encompassing PV carriers of 46 genes. Patients were 84.9% female and 13.3% male. Most PVs were of BRCA1 and BRCA2. Most patients had private insurance, and most were from Florida. Annual increase in patient visits was over 74.7% over the last year. Overall, GeneHome has been well accepted by providers and patients and is a valuable service for patients with a genetic predisposition to cancer.

Lessons Learned in Implementing Patient-Reported Outcome Measures (PROMs) in the Australian Breast Device Registry (ABDR).

BACKGROUND: The Australian Breast Device Registry (ABDR) is a clinical quality registry which utilizes both surgical data and patient-reported outcome measures (PROMs) to understand device performance. The ABDR is the first national breast device registry utilizing the BREAST-Q Implant Surveillance module to conduct PROMs via text messaging as the primary method of contact for most patients. ABDR PROMs are structured upon a successful acceptability and feasibility study and a pilot study. OBJECTIVES: This aim of this paper was to examine the challenges we faced and consider how lessons learned in implementing PROMs might inform future registry studies and interventions. METHODS: We tracked the number of completed follow-ups and documented feedback between October 2017 and December 2018 from various stakeholders, including sites, surgeons, and patients. RESULTS: In total, 10,617 patients were contacted: 59% of breast augmentation and 77% breast reconstruction patients responded to our PROMs survey. We encountered challenges and developed solutions to overcome several key issues, including database setup; follow-up contact methods; ethics; education of surgeons and patients; associated costs; and ongoing evaluation and modification. The strategies we devised to address these challenges included drawing on experiences from previous studies, greater communication with sites and surgeons, and having the flexibility to improve and modify our PROMs. CONCLUSIONS: The ABDR PROMs experience and lessons learned can inform a growing number of registries seeking to conduct PROMs. We describe our approach, obstacles encountered, and strategies to increase patient participation. As more breast device registries worldwide adopt PROMs, data harmonization is crucial to better understand patient outcomes and device performance.

Identification of Predictive Factors for Patient-Reported Outcomes in the Prospective Australian Breast Device Registry.

BACKGROUND: Patient-reported outcome measures (PROMs) are an important tool for evaluating outcomes following breast device procedures and are used by breast device registries. PROMs can assist with device monitoring through benchmarked outcomes but need to account for demographic and clinical factors that may affect PROM responses. OBJECTIVES: This study aimed to develop appropriate risk-adjustment models for the benchmarking of PROM data to accurately track device outcomes and identify outliers in an equitable manner. METHODS: Data for this study were obtained from the Australian Breast Device Registry, which consists of a large prospective cohort of patients with primary breast implants. The 5-question BREAST-Q implant surveillance module was used to assess PROMs at 1 year following implant insertion. Logistic regression models were used to evaluate associations between demographic and clinical characteristics and PROMs separately by implant indication. Final multivariate risk-adjustment models were built sequentially, assessing the independent significant association of these variables. RESULTS: In total, 2221 reconstructive and 12,045 aesthetic primary breast implants with complete 1-year follow-up PROMs were included in the study. Indication for operation (post-cancer, risk reduction, or developmental deformity) was included in the final model for all reconstructive implant PROMs. Site type (private or public hospital) was included in the final breast reconstruction model for look, rippling, and tightness. Age at operation was included in the reconstruction models for rippling and tightness and in the aesthetic models for look, rippling, pain, and tightness. CONCLUSIONS: These multivariate models will be useful for equitable benchmarking of breast devices by PROMs to help track device performance.

Fiber type composition of contiguous palmaris longus and abductor pollicis brevis muscles: Morphological evidence of a functional synergy.

The palmaris longus (PL) tendon is used in surgical opponensplasty to restore functional hand movements in thenar paralysis. Although successful PL autologous tendon transfer has been attributed to an established synergistic relationship between the PL and abductor pollicis brevis (APB) muscles in vivo, this functional relationship may be dependent on the quality of their spatial relationship and properties of their constituent muscle fibers. The purpose was to compare the proportion of type I and type II muscle fibers in the APB based on its contiguous morphological relationship with the PL tendon for indirect insight into their functional synergy, contractile capacity, and digastric arrangement. Twenty-four contiguous PL and APB specimens were harvested from the upper limbs (12 right and 12 left) of twelve formalin-embalmed cadavers (mean age: 74 ± 10 years). The fiber type composition of these muscles was determined by labeling serial cross sections with myosin heavy chain (MyHC) type I and type II monoclonal antibodies. The PL consisted of a relatively heterogeneous fiber type composition irrespective of the presence of a discrete (type I: 41 ± 11%; type II: 55 ± 12%; hybrid: 4 ± 3%) or rudimentary (type I: 49 ± 10%; type II: 45 ± 9%; hybrid: 6 ± 4%) tendinous connection with the APB. The APB fascicles arranged contiguously with the PL through a discrete tendon had significantly greater proportions of type II fibers (41 ± 19%) compared to those with rudimentary PL connections (type II: 15 ± 8%). Therefore, the APB fascicles arranged in a digastric relationship with the PL may have the capacity to produce more powerful contractions than those with rudimentary PL tendons based on the known contractile properties of type II muscle fibers. Knowledge of the spatial relationship between the PL and thenar musculature prior to PL autologous tendon transfer may be a useful indicator of the quality of established synergy in vivo.

Polycarboxylated Dextran as a Multivalent Linker: Synthesis and Target Recognition of the Antibody-Nanoparticle Bioconjugates in PBS and Serum.

Nanoparticles (NPs) functionalized with antibodies on their surface are used in a wide range of research applications. However, the bioconjugation chemistry between the antibodies and the surface of nanoparticles can be very challenging, often accompanied by several undesired effects such as nanoparticle aggregation, antibody denaturation, or poor target recognition of the surface-bound antibodies. Here, we report on a synthesis of fluorescent silica nanoparticle-antibody (NP-Ab) conjugates, in which polycarboxylated dextran is used as the multivalent linker. First, we present a synthetic methodology to prepare polycarboxylated dextrans with molecular weights of 6, 40, and 70 kDa. Second, we used water-soluble, polycarboxylated dextrans as a multivalent spacers/linkers to immobilize antibodies onto fluorescent silica nanoparticles. The prepared NP-Ab conjugates were tested in a direct binding assay format in both phosphate-buffered saline buffer and whole serum to investigate the role of the spacer/linker in the capacity of the NP-Ab to specifically recognize their target in "clean" and also in complex media. We have compared the dextran conjugates with two standards: (a) NP-Ab with antibodies attached on the surface of nanoparticles through the classical physical adsorption method and (b) NP-Ab where an established poly(amidoamine) (PAMAM) dendrimer was used as the linker. Our results showed that the polycarboxylated 6 kDa dextran facilitates antibody immobilization efficiency of nearly 92%. This was directly translated into the improved molecular recognition of the NP-Ab, which was measured by a direct binding assay. The signal-to-noise ratio in buffered solution for the 6 kDa dextran NP-Ab conjugates was 81, nearly 3 times higher than that of PAMAM G4.5 conjugates and 9 times higher than the physically adsorbed NP-Ab sample. In whole serum, the effect of 6 kDa dextran was more hindered due to the formation of protein corona but the signal-to-noise ratio was at least double that of the physically adsorbed NP-Ab conjugates.

Patient-Reported Outcome Measures for Breast Implant Surgery: A Pilot Study.

BACKGROUND: The Breast-Q Implant Surveillance module (BREAST-Q IS) is a patient-reported outcome measure (PROM) that asks 5 questions on satisfaction (shape, feel, and rippling) and symptoms (pain and tightness) derived from the BREAST-Q. OBJECTIVES: We aimed to pilot BREAST-Q IS on patients within the Australian Breast Device Registry (ABDR), an opt-out clinical quality device registry, and explored Short Message Service (SMS) communication as a follow-up method. METHODS: Patients with a breast device surgery in the previous 10 to 15 months, age ≥18 years, with a mobile phone number, were invited to complete the 5-question PROM via SMS initially, followed by 3 phone call attempts if no response, an e-mail, and then a letter by post as a final engagement strategy. RESULTS: The study included 197 participants [breast augmentation (BA) = 118; breast reconstruction (BR) = 79]. Mean ± SD age was 40 ± 12 years (BA) and 44 ± 11 years (BR). Mean ± SD time since surgery was 414 ± 36 days (BA) and 413 ± 51 days (BR). The total response rate, including opt-outs, was 76%. Responses indicated that >90% of BA and >79% of BR were very or somewhat satisfied with shape, feel, and wrinkling; >70% of BA and >46% of BR reported no pain or tightness. Completion of survey via SMS was 51% (BA) and 55% (BR). Further responses were received by phone (25%, 26%), post (21%, 16%), and e-mail (3%, 3%). CONCLUSIONS: This pilot demonstrated high levels of satisfaction and low levels of pain and tightness in patients with breast augmentation and breast reconstruction 1 year postoperatively. It also showed the effectiveness of our engagement strategy, which achieved a 76% response rate. Over 50% of respondents used SMS to reply to a 5-question PROM assessing long-term surgical outcomes. This engagement strategy will be used as BREAST-Q IS is rolled out nationally.

Revisiting the functional anatomy of the palmaris longus as a thenar synergist.

Surgical studies describe the palmaris longus (PL) as a synergist in thumb abduction, which may facilitate its use in restoring thumb function using opponensplasty. However, beyond morphological descriptions and isometric thenar abduction strength measures, the evidence supporting the PL as a thenar synergist in-vivo is limited. The purpose here was to determine whether the PL provides synergistic contributions to thenar musculature by: (1) recording PL muscle activity using indwelling electromyography (EMG) during thumb movements; and (2) quantifying changes in PL muscle architecture using ultrasonography. In 10 healthy males, PL muscle activity was recorded during maximal thenar muscle contractions (abduction, flexion, opposition, adduction, and extension) with the wrist secured in a neutral position. The PL EMG was normalized to its maximal EMG recorded during isometric wrist flexion. Dynamic changes in PL muscle thickness (MT ) were determined during abduction and adduction using ultrasound imaging. The results indicate that the PL is activated during thenar movements with greatest relative PL EMG recorded during thenar abduction (46%), flexion (35%) and opposition (37%). Compared to rest, PL MT significantly increased (21%) during maximal thenar abduction. With direct measures in vivo, this study supports morphological and surgical observations indicating the PL acts as an extrinsic hand muscle in enhancing thenar muscle actions. Knowledge of the synergistic relationship between the PL and thenar musculature may allow for further development of surgical opponensplasty approaches using the abductor pollicis brevis and PL as a functional digastric unit. Clin. Anat. 31:760-770, 2018. © 2017 Wiley Periodicals, Inc.

The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy.

There is an urgent need to develop new combination therapies beyond existing surgery, radio- and chemo-therapy, perhaps initially combining chemotherapy with the targeting specificities of immunotherapy. For this, strategies to limit inflammation and immunosuppression and evasion in the tumour microenvironment are also needed. To devise effective new immunotherapies we must first understand tumour immunology, including the roles of T cells, macrophages, myeloid suppressor cells and of exosomes and microvesicles (EMVs) in promoting angiogenesis, tumour growth, drug resistance and metastasis. One promising cancer immunotherapy discussed uses cationic liposomes carrying tumour RNA (RNA-lipoplexes) to provoke a strong anti-viral-like (cytotoxic CD8+ ) anti-tumour immune response. Mesenchymal stem cell-derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumours, have also been used. As tumour EMVs clearly exacerbate the tumour microenvironment, another therapy option could involve EMV removal. Affinity-based methods to deplete EMVs, including an immunodepletion, antibody-based affinity substrate, are therefore considered. Finally EMV and exosome-mimetic nanovesicles (NVs) delivery of siRNA or chemotherapeutic drugs that target tumours using peptide ligands for cognate receptors on the tumour cells are discussed. We also touch upon the reversal of drug efflux in EMVs from cancer cells which can sensitize cells to chemotherapy. The use of immunotherapy in combination with the advent of EMVs provides potent therapies to various cancers.

Structural and functional anatomy of the palmaris brevis: grasping for answers.

The palmaris brevis (PB) is a small cutaneous hand muscle that has been described as the most mysterious muscle from a functional and developmental perspective [Kaplan () Kaplan's Functional and Surgical Anatomy of the Hand]. Functionally, the PB is considered to deepen the hollow of the palm and to protect the neurovasculature of the ulnar canal. Although the function of the PB has been inferred from cadaveric observations, the electromyographic (EMG) activity of this muscle has not been explored systematically during specific movements of the hand. The purpose of this study was to record PB intramuscular EMG activity during dynamic grasping tasks, and to quantify the change in PB muscle length (ML ) and thickness (MT ) incurred during maximal contraction using ultrasound imaging. Intramuscular EMG was recorded from the PB in the dominant hands of 12 healthy participants (11 males, one female; age: 27 ± 4 years) during maximal abduction, flexion and opposition of the 5th digit, and two grasping tasks. Abduction of the 5th digit yielded the greatest EMG activity in most individuals (seven out of 11), and produced significantly less PB EMG activity when compared with grasping a cylindrical-shaped object (P = 0.003) but not a spherical-shaped object (P = 0.130). During maximal abduction of the 5th digit, PB ML decreased in both the left (28 ± 11%; P = 0.002) and right (32 ± 5%; P = 0.002) hands. Similarly, a concomitant increase in PB MT was observed in the left (68 ± 30%; P = 0.002) and right (85 ± 44%; P = 0.002) hands during the same contraction. These EMG results indicate that the PB is voluntarily activated during prehensile and non-prehensile movements of the hand with significant changes in muscle architecture. The study supports the preservation of the PB in surgical procedures based on its proposed protective role as a muscular barrier to the neurovasculature within the ulnar canal.

Fiber type composition of the palmaris brevis muscle: implications for palmar function.

The palmaris brevis (PB) is a small muscle of variant morphology located on the ulnar aspect of the palm, superficial to the hypothenar eminence. Functionally, the PB has been proposed to protect the neurovasculature of the ulnar canal from compressive forces during repetitive or intermittent trauma associated with grasping. Although PB function has been inferred from cadaveric observations, it is unknown whether it has the contractile capacity and fatigue-resistance necessary to withstand these functional demands. Insight into the functional specialization of the PB can be provided through investigating the proportions of type I and type II muscle fibers by staining for myosin heavy chain (MHC) isoforms using immunohistochemical methods. Therefore, the purpose of this study was to quantify the proportion of type I and type II muscle fibers to provide insight into the role of the PB in palmar function based on its gross histological structure. Sixteen PB specimens were harvested from the hands (eight right, eight left) of eight formalin-embalmed cadavers (mean age: 75 ± 14 years; three males, five females). PB muscle composition was determined by labeling serial cross-sections with MHC type I and type II monoclonal antibodies. The results indicate that the PB is primarily composed of type I muscle fibers (72.2 ± 13.7%), with no significant differences between left and right hands. Given the predominance of type I muscle fibers, our findings indicate the PB may be fatigue-resistant and thus, capable of contracting for prolonged durations. This supports cadaveric observations indicating that the PB functions to protect the ulnar neurovasculature of the palm by providing a muscular barrier in addition to serving as a functional anchor to the hypothenar fat pad when objects are firmly compressed into the palm.

Human COL5A1 polymorphisms and quadriceps muscle-tendon mechanical stiffness in vivo.

NEW FINDINGS: What is the central question of the study? Do COL5A1 gene variants, previously reported to have diminished transcript stability, manifest in physiological phenotypes of quadriceps muscle-tendon contractile properties and mechanical stiffness in humans? What is the main finding and its importance? COL5A1 gene variants influence mechanical stiffness, not seeming to affect low-level contractile properties in humans. Functional differences in COL5A1 manifest during moderate- to high-level contractions. Polymorphisms of the collagen type V alpha 1 chain (COL5A1) gene are purported to influence mechanical properties of collagenous tissues. Our purpose was to assess musculotendinous contractile properties of the quadriceps in relationship to the genetic influence of mechanical stiffness. Eighty recreationally active males (aged 19-31 years) were assessed for the presence of three genetic polymorphisms associated with COL5A1 mRNA stability (rs4919510, rs1536482 and rs12722). Genotypes were determined using real-time PCR. Stiffness and contractile properties of the knee musculotendinous complex were assessed by maximal isometric voluntary contractions, ramp isometric voluntary contractions, electrically stimulated contractile events and ultrasonography. All genotype groups were able to activate their knee extensors fully (>97%) as assessed by the interpolated twitch technique and presented no differences in muscle-tendon contractile properties at low submaximal contraction intensities. For the quadriceps muscle-tendon at moderate ramp contractions of 50 and 60% maximal voluntary contraction, the rs12722 CT and TT genotypes had ∼30% greater mean stiffness. The rs1536482 AG and GG genotypes showed a similar trend, but did not achieve statistical significance. Variants of the COL5A1 gene seem to influence quadriceps muscle-tendon stiffness but do not affect low-level contractile properties.

Reduced skeletal muscle quantity and quality in patients with diabetic polyneuropathy assessed by magnetic resonance imaging.

INTRODUCTION: The aim of this study was to determine whether diabetic polyneuropathy (DPN) is associated with reduced muscle quality using MRI. METHODS: MRIs of the tibialis anterior (TA) muscle were recorded from 9 individuals (5 men) with DPN (∼65 years) and 8 (4 men) age- and gender-matched controls. A magnetization transfer ratio (MTR) and T2 relaxation times of the TA were calculated. RESULTS: Despite equal voluntary activation, the DPN group was ∼37% weaker than controls, with a significantly lower proportion (∼8%) of contractile tissue and lower MTR (0.28 ± 0.03 vs. 0.32 ± 0.02 percent units). T2 relaxation time was significantly longer in the DPN group (77 ± 16 ms) compared with controls (63 ± 6 ms). CONCLUSIONS: These findings indicate a reduction in the structural integrity and myocellular protein density in the TA of those with DPN. Thus, muscle weakness in DPN is likely due to both a loss of muscle mass and a reduction in contractile quality.

Prostate cancer cells stimulated by calcium-mediated activation of protein kinase C undergo a refractory period before re-releasing calcium-bearing microvesicles.

MVs are released in response to several stress agents, in an attempt to prevent continued cellular damage. After an initial stimulus of prostate cancer cells with sublytic C5b-9 and activation of MV release through PKC, cells take at least 20 min to fully recover their ability to microvesiculate. This release of MVs through activation of sublytic C5b-9 was inhibited by the PKC inhibitor bisindoylmaleimide I but not the Rho kinase inhibitor, Y27632. After stimulus there is a rise of 79 nMs(-1) over 11 s, reaching a peak [Ca(2+)]i of 920 nM. The concentration of cytosolic calcium then falls steadily at 2.4 nMs(-1) over 109 s reaching baseline levels (50-100 nM) within 10-15 min. In PC3 cells the rate of release of MVs from stimulated cells also reaches a minimum within 10-15 min. Using fura-2 AM-loaded cells, upon stimulation, cells were found to release MVs with a concentration of intravesicular calcium estimated at ∼ 430 nM.

Microvesicles released constitutively from prostate cancer cells differ biochemically and functionally to stimulated microvesicles released through sublytic C5b-9.

We have classified microvesicles into two subtypes: larger MVs released upon stimulation of prostate cancer cells, sMVs, and smaller cMVs, released constitutively. cMVs are released as part of cell metabolism and sMVs, released at 10-fold higher levels, produced upon activation, including sublytic C5b-9. From electron microscopy, nanosight tracking analysis, dynamic light scattering and flow cytometry, cMVs (194-210 nm in diameter) are smaller than sMVs (333-385 nm). Furthermore, using a Quartz Crystal Microbalance measuring changes in resonant frequency (Δf) that equate to mass deposited on a sensor, an sMV and a cMV are estimated at 0.267 and 0.241 pg, respectively. sMVs carry more calcium and protein, express higher levels of lipid rafts, GPI-anchored CD55 and phosphatidylserine including deposited C5b-9 compared to cMVs. This may allude to biological differences such as increased bound C4BP on sMVs inhibiting complement more effectively.

Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease.

BACKGROUND: Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients). METHODS: Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity. RESULTS: Patients were treated with a median of three chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2) /day for 5 days. Cycles were administered every 28 days for a median of six cycles (range: 2-8 cycles). Seventeen of 18 patients are alive. All surviving patients showed demonstrable improvement after two to four cycles of therapy, with 11 (61%) complete responses, 4 (22%) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections. CONCLUSION: Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.

Are we there yet? Management baselines and biodiversity indicators for the protection and restoration of subtidal bivalve shellfish habitats.

Biodiversity loss and degradation of natural habitats is increasing at an unprecedented rate. Of all marine habitats, biogenic reefs created by once-widespread shellfish, are now one of the most imperilled, and globally scarce. Conservation managers seek to protect and restore these habitats, but suitable baselines and indicators are required, and detailed scientific accounts are rare and inconsistent. In the present study the biodiversity of a model subtidal habitat, formed by the keystone horse mussel Modiolus modiolus (L.), was analysed across its Northeast Atlantic biogeographical range. Consistent samples of 'clumped' mussels were collected at 16 locations, covering a wide range of environmental conditions. Analysis of the associated macroscopic biota showed high biodiversity across all sites, cumulatively hosting 924 marine macroinvertebrate and algal taxa. There was a rapid increase in macroinvertebrate biodiversity (H') and community evenness (J) between 2 and 10 mussels per clump, reaching an asymptote at mussel densities of 10 per clump. Diversity declined at more northern latitudes, with depth and in coarser substrata with the fastest tidal flows. Diversity metrics corrected for species abundance were generally high across the habitats sampled, with significant latitudinal variability caused by current, depth and substrate type. Faunal community composition varied significantly between most sites and was difficult to assign to a 'typical' M. modiolus assemblage, being significantly influenced by regional environmental conditions, including the presence of algal turfs. Within the context of the rapid global increase in protection and restoration of bivalve shellfish habitats, site and density-specific values of diversity are probably the best targets for conservation management and upon which to base monitoring programmes.

Implementing Digital Scribes to Reduce Electronic Health Record Documentation Burden Among Cancer Care Clinicians: A Mixed-Methods Pilot Study.

PURPOSE: To address shortcomings of human scribes (eg, turnover), clinicians are considering digital scribes (DSs). To our knowledge, to date, no study has assessed DS implementation or clinician user experience in cancer centers. We assessed the DS's feasibility, acceptability, appropriateness, usability and its preliminary association on clinician well-being in a cancer center. We also identified implementation facilitators and barriers to DS use. METHODS: Using a mixed-methods longitudinal pilot study design, we implemented a DS at a cancer center. Data collection included surveys at baseline and 1 month after DS use and a semistructured interview with clinicians. The survey assessed demographics, Mini Z (workplace stress and burnout), sleep quality, and implementation outcomes (feasibility, acceptability, appropriateness, and usability). The interview assessed how the DS was used and its impacts on workflows and recommendations for future implementations of the DS. We used paired t tests to assess differences in Mini Z and sleep quality measures over time. RESULTS: Across nine survey responses and eight interviews, we found that although feasibility scores were slightly lower than our cutoff point (15.2 v 16.0), clinicians rated the DS as marginally acceptable (16.0) and appropriate (16.3). Usability was considered marginally usable (68.6 v 68.0). Although the DS did not significantly improve burnout (3.6 v 3.9, P = .081), it improved perceptions of having sufficient documentation time (2.1 v 3.6, P = .005). Clinicians identified suggestions for future implementations, including training needs and usability improvements. CONCLUSION: Our preliminary findings suggest that DS implementation is marginally acceptable, appropriate, and usable among cancer care clinicians. Individualized training and on-site support may improve implementation.