IMiD resistance in multiple myeloma: current understanding of the underpinning biology and clinical impact.

Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with multiple myeloma. IMiDs are used in therapeutic combinations at all stages of disease and are approved as a single-agent maintenance treatment after autologous stem cell transplantation. However, patients become resistant to ongoing therapy over time and inevitably relapse. It is only in the last decade that the mechanism of IMiD action has been elucidated; through binding to the cereblon component of the CRL4CRBN E3 ubiquitin ligase, a set of neosubstrates is designated for degradation by the proteasome. In myeloma cells, this includes the zinc-finger B-cell transcription factors Ikaros and Aiolos, which, in turn, lead to decreased levels of IRF4 and c-MYC and cell death. As our knowledge of IMiD mechanism of action has advanced, the ability to study resistance mechanisms has also developed. This review explores the existing work on IMiD resistance and proposes areas of future research that may advance our understanding and management of this common clinical condition.

A large cryptosporidiosis outbreak associated with an animal contact event in England: a retrospective cohort study, 2023.

Development of gastrointestinal illness after animal contact at petting farms is well described, as are factors such as handwashing and facility design that may modify transmission risk. However, further field evidence on other behaviours and interventions in the context of Cryptosporidium outbreaks linked to animal contact events is needed. Here, we describe a large outbreak of Cryptosporidium parvum (C. parvum) associated with a multi-day lamb petting event in the south-west of England in 2023 and present findings from a cohort study undertaken to investigate factors associated with illness. Detailed exposure questionnaires were distributed to email addresses of 647 single or multiple ticket bookings, and 157 complete responses were received. The outbreak investigation identified 23 laboratory-confirmed primary C. parvum cases. Separately, the cohort study identified 83 cases of cryptosporidiosis-like illness. Associations between illness and entering a lamb petting pen (compared to observing from outside the pen; odds ratio (OR) = 2.28, 95 per cent confidence interval (95% CI) 1.17 to 4.53) and self-reported awareness of diarrhoeal and vomiting disease transmission risk on farm sites at the time of visit (OR = 0.40, 95% CI 0.19 to 0.84) were observed. In a multivariable model adjusted for household clustering, awareness of disease transmission risk remained a significant protective factor (adjusted OR (aOR) = 0.07, 95% CI 0.01 to 0.78). The study demonstrates the likely under-ascertainment of cryptosporidiosis through laboratory surveillance and provides evidence of the impact that public health messaging could have.

Short-term outcomes of 43 dogs treated with arthroscopic suturing for meniscal tears associated with cranial cruciate ligament disease.

OBJECTIVE: To describe short-term outcomes and complications in dogs receiving meniscal suturing and concurrent tibial plateau leveling osteotomy (TPLO) with or without augmentation with an extracapsular suture. STUDY DESIGN: Retrospective case series. ANIMALS: Forty-three client-owned dogs submitted for cruciate ligament disease. METHODS: Dogs were included if meniscal suturing was performed during or after a TPLO procedure. Criteria included an unstable medial meniscus without evidence of a tear, a caudal vertical longitudinal tear with or without displacement, or if a bucket-handle tear was debrided and the remaining rim was unstable. Stifle stabilization was performed by either a standard TPLO or an augmented TPLO (TPLO + internal brace [IB]). Outcome measures included physical examination findings, radiographs, subjective gait examination, Liverpool Osteoarthritis in Dogs (LOAD) scores, and second-look arthroscopy. RESULTS: Forty-four meniscal repairs were performed in 43 dogs. Five types of meniscal tears were treated employing eight suture materials. Complications were documented in 15 cases (34%). The stabilization technique had a significant impact on the outcome (p = .049): TPLO + IB had a 93.3% success rate and the success rate was 71.4% in the TPLO-only group. CONCLUSION: Five types of meniscal pathology were addressed successfully in the study, indicating that currently accepted criteria for meniscal suturing in dogs may be overly conservative. The majority of complications were not related to the meniscal suturing itself and did not compromise the outcome. The stifle stabilization technique had an impact on outcome. CLINICAL SIGNIFICANCE: The authors found arthroscopic meniscal suturing to be practical and successful in this patient population. Postoperative stifle stability had an impact on successful treatment.

Enhanced Recovery After Surgery Patients Are Prescribed Fewer Opioids at Discharge: A Propensity-score Matched Analysis.

OBJECTIVE: We aimed to compare discharge opioid prescriptions pre- and post-ERAS implementation. SUMMARY OF BACKGROUND DATA: ERAS programs decrease inpatient opioid use, but their relationship with postdischarge opioids remains unclear. METHODS: All patients undergoing hysterectomy between October 2016 and November 2020 and pancreatectomy or hepatectomy between April 2017 and November 2020 at 1 tertiary care center were included. For each procedure, ERAS was implemented during the study period. PSM was performed to compare pre - versus post-ERAS patients on discharge opioids (number of pills and oral morphine equivalents). Patients were matched on age, sex, race, payor, American Society of Anesthesiologists score, prior opioid use, and procedure. Sensitivity analyses in open versus minimally invasive surgery cohorts were performed. RESULTS: A total of 3983 patients were included (1929 pre-ERAS; 2054 post-ERAS). Post-ERAS patients were younger (56.0 vs 58.4 years; P < 0.001), more often female (95.8% vs 78.1%; P < 0.001), less often white (77.2% vs 82.0%; P < 0.001), less often had prior opioid use (20.1% vs 28.1%; P < 0.001), and more often underwent hysterectomy (91.1% vs 55.7%; P < 0.001). After PSM, there were no significant differences between cohorts in baseline characteristics. Matched post-ERAS patients were prescribed fewer opioid pills (17.4 pills vs 22.0 pills; P < 0.001) and lower oral morphine equivalents (129.4 mg vs 167.6 mg; P < 0.001) than pre-ERAS patients. Sensitivity analyses confirmed these findings [open (18.8 pills vs 25.4 pills; P < 0.001 \ 138.9 mg vs 198.7 mg; P < 0.001); minimally invasive surgery (17.2 pills vs 21.1 pills; P < 0.001 \ 127.1 mg vs 160.1 mg; P < 0.001). CONCLUSIONS: Post-ERAS patients were prescribed significantly fewer opioids at discharge compared to matched pre-ERAS patients.

Truth in Reporting: How Data Capture Methods Obfuscate Actual Surgical Site Infection Rates within a Health Care Network System.

BACKGROUND: Two systems measure surgical site infection rates following colorectal surgeries: the American College of Surgeons National Surgical Quality Improvement Program and the Centers for Disease Control and Prevention National Healthcare Safety Network. The Centers for Medicare & Medicaid Services pay-for-performance initiatives use National Healthcare Safety Network data for hospital comparisons. OBJECTIVE: This study aimed to compare database concordance. DESIGN: This is a multi-institution cohort study of systemwide Colorectal Surgery Collaborative. The National Surgical Quality Improvement Program requires rigorous, standardized data capture techniques; National Healthcare Safety Network allows 5 data capture techniques. Standardized surgical site infection rates were compared between databases. The Cohen κ-coefficient was calculated. SETTING: This study was conducted at Boston-area hospitals. PATIENTS: National Healthcare Safety Network or National Surgical Quality Improvement Program patients undergoing colorectal surgery were included. MAIN OUTCOME MEASURES: Standardized surgical site infection rates were the primary outcomes of interest. RESULTS: Thirty-day surgical site infection rates of 3547 (National Surgical Quality Improvement Program) vs 5179 (National Healthcare Safety Network) colorectal procedures (2012-2014). Discrepancies appeared: National Surgical Quality Improvement Program database of hospital 1 (N = 1480 patients) routinely found surgical site infection rates of approximately 10%, routinely deemed rate "exemplary" or "as expected" (100%). National Healthcare Safety Network data from the same hospital and time period (N = 1881) revealed a similar overall surgical site infection rate (10%), but standardized rates were deemed "worse than national average" 80% of the time. Overall, hospitals using less rigorous capture methods had improved surgical site infection rates for National Healthcare Safety Network compared with standardized National Surgical Quality Improvement Program reports. The correlation coefficient between standardized infection rates was 0.03 (p = 0.88). During 25 site-time period observations, National Surgical Quality Improvement Program and National Healthcare Safety Network data matched for 52% of observations (13/25). κ = 0.10 (95% CI, -0.1366 to 0.3402; p = 0.403), indicating poor agreement. LIMITATIONS: This study investigated hospitals located in the Northeastern United States only. CONCLUSIONS: Variation in Centers for Medicare & Medicaid Services-mandated National Healthcare Safety Network infection surveillance methodology leads to unreliable results, which is apparent when these results are compared with standardized data. High-quality data would improve care quality and compare outcomes among institutions.

The signs, symptoms and help-seeking experiences of neutropenic sepsis patients before they reach hospital: a qualitative study.

PURPOSE: Neutropenic sepsis (NS) is a medical emergency in which urgent treatment with antibiotics is known to improve outcomes, yet there are minimal data about what happens to patients with NS before they reach hospital. We aimed to examine the pre-hospital experiences of patients with NS, identifying its early presenting features and exploring the factors potentially delaying patients' arrival at hospital. METHODS: We conducted in-depth, qualitative interviews with 22 cancer patients admitted to hospital for treatment of NS and 10 patient carers. The setting was a tertiary referral centre in Southern England. RESULTS: Thirty seven percent of patients took over 12 h to present to hospital after symptom onset. The mean delay in presentation was 11 h (range 0-68 h). Thematic analysis of the interviews, using grounded theory, revealed wide-ranging, potentially modifiable factors delaying patients' presentation to hospital. For example, information provided to patients about NS from different sources was inconsistent, with 'mixed messages' about urgency triggering delays. All patients self-monitored their temperature and understood the implication of a fever but few appreciated the potential significance of feeling unwell in the absence of fever. Attempts to obtain treatment were sometimes thwarted by nonspecialists' failure to recognise possible neutropenia in a patient with apparently mild signs, and several patients with NS were discharged without treatment. Some patients denied their symptoms to themselves and others to avoid hospital admission; palliative patients seemed particularly prone to these attitudes, while their carers were keen to seek medical attention. CONCLUSIONS: This investigation of patients' and carers' experiences of NS identifies numerous strategies for improving patient education, support and pre-hospital management, all of which may reduce pre-hospital delays and consequently decrease morbidity and mortality from NS.

Zolmitriptan for acute migraine attacks in adults.

BACKGROUND: Migraine is a common, disabling condition and a burden for the individual, health services, and society. Zolmitriptan is an abortive medication for migraine attacks, belonging to the triptan family. These medicines work in a different way to analgesics such as paracetamol and ibuprofen. OBJECTIVES: To determine the efficacy and tolerability of zolmitriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and the Oxford Pain Relief Database, together with three online databases (www.astrazenecaclinicaltrials.com, www.clinicaltrials.gov, and apps.who.int/trialsearch) for studies to 12 March 2014. We also searched the reference lists of included studies and relevant reviews. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using zolmitriptan to treat a migraine headache episode. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratios and numbers needed to treat for an additional beneficial effect (NNT) or harmful effect (NNH) compared with placebo or a different active treatment. MAIN RESULTS: Twenty-five studies (20,162 participants) compared zolmitriptan with placebo or an active comparator. The evidence from placebo-controlled studies was of high quality for all outcomes except 24 hour outcomes and serious adverse events where only limited data were available. The majority of included studies were at a low risk of performance, detection and attrition biases, but did not adequately describe methods of randomisation and concealment.Most of the data were for the 2.5 mg and 5 mg doses compared with placebo, for treatment of moderate to severe pain. For all efficacy outcomes, zolmitriptan surpassed placebo. For oral zolmitriptan 2.5 mg versus placebo, the NNTs were 5.0, 3.2, 7.7, and 4.1 for pain-free at two hours, headache relief at two hours, sustained pain-free during the 24 hours postdose, and sustained headache relief during the 24 hours postdose, respectively. Results for the oral 5 mg dose were similar to the 2.5 mg dose, while zolmitriptan 10 mg was significantly more effective than 5 mg for pain-free and headache relief at two hours. For headache relief at one and two hours and sustained headache relief during the 24 hours postdose, but not pain-free at two hours, zolmitriptan 5 mg nasal spray was significantly more effective than the 5 mg oral tablet.For the most part, adverse events were transient and mild and were more common with zolmitriptan than placebo, with a clear dose response relationship (1 mg to 10 mg).High quality evidence from two studies showed that oral zolmitriptan 2.5 mg and 5 mg provided headache relief at two hours to the same proportion of people as oral sumatriptan 50 mg (66%, 67%, and 68% respectively), although not necessarily the same individuals. There was no significant difference in numbers experiencing adverse events. Single studies reported on other active treatment comparisons but are not described further because of the small amount of data. AUTHORS' CONCLUSIONS: Zolmitriptan is effective as an abortive treatment for migraine attacks for some people, but is associated with increased adverse events compared to placebo. Zolmitriptan 2.5 mg and 5 mg benefited the same proportion of people as sumatriptan 50 mg, although not necessarily the same individuals, for headache relief at two hours.

Predictors of anxiety and depression in operating room nurses during the COVID-19 pandemic: A multi-center cross-sectional study.

BACKGROUND: Operating room nurses (ORNs) who directly deal with the treatment and care of COVID-19 patients during the pandemic are at risk in terms of psychological stress and other mental health problems. OBJECTIVE: The aim of the study was to compare the anxiety and depression levels of ORNs working in different countries in the COVID-19 outbreak, and to determine the predictors and the difference between countries. METHODS: This was a descriptive and cross-sectional study. Data were collected online using a google form between February 2021-February 2022. The universe of the research is nurses who are members of national Perioperative Nurses Association (USA, Türkiye, Australia, England, India, Israel) and 1127 ORNs participated the study. In multivariate analysis, independent predictors of anxiety and depression status were examined by binary logistic regression analysis. RESULTS: The rate of anxiety is 5.46 times higher in nurses in the USA, 5.07 times higher among nurses in Australia, and 4.49 times higher for nurses in England. It was determined that the rate of depression in ORNs working in Türkiye was 5.97 times higher. It was found that the rate of depression is 1.59 times higher in ORNs living away from the family after care of COVID-19 patient. CONCLUSION: Despite some differences between countries in terms of health system, patient potential, economic and the opportunities offered, generally high levels of anxiety and/or depression indicate that all ORNs need urgent support. Identifying risk factors will help recognize anxiety and depression in ORNs and take measures to protect their mental health during the pandemic.

A better performing algorithm for identification of implausible growth data from longitudinal pediatric medical records.

Tracking trajectories of body size in children provides insight into chronic disease risk. One measure of pediatric body size is body mass index (BMI), a function of height and weight. Errors in measuring height or weight may lead to incorrect assessment of BMI. Yet childhood measures of height and weight extracted from electronic medical records often include values which seem biologically implausible in the context of a growth trajectory. Removing biologically implausible values reduces noise in the data, and thus increases the ease of modeling associations between exposures and childhood BMI trajectories, or between childhood BMI trajectories and subsequent health conditions. We developed open-source algorithms (available on github) for detecting and removing biologically implausible values in pediatric trajectories of height and weight. A Monte Carlo simulation experiment compared the sensitivity, specificity and speed of our algorithms to three published algorithms. The comparator algorithms were selected because they used trajectory information, had open-source code, and had published verification studies. Simulation inputs were derived from longitudinal epidemiological cohorts. Our algorithms had higher specificity, with similar sensitivity and speed, when compared to the three published algorithms. The results suggest that our algorithms should be adopted for cleaning longitudinal pediatric growth data.

Combined effects of agitation, macromolecular crowding, and interfaces on amyloidogenesis.

Amyloid formation and accumulation is a hallmark of protein misfolding diseases and is associated with diverse pathologies including type II diabetes and Alzheimer's disease (AD). In vitro, amyloidogenesis is widely studied in conditions that do not simulate the crowded and viscous in vivo environment. A high volume fraction of most biological fluids is occupied by various macromolecules, a phenomenon known as macromolecular crowding. For some amyloid systems (e.g. α-synuclein) and under shaking condition, the excluded volume effect of macromolecular crowding favors aggregation, whereas increased viscosity reduces the kinetics of these reactions. Amyloidogenesis can also be catalyzed by hydrophobic-hydrophilic interfaces, represented by the air-water interface in vitro and diverse heterogeneous interfaces in vivo (e.g. membranes). In this study, we investigated the effects of two different crowding polymers (dextran and Ficoll) and two different experimental conditions (with and without shaking) on the fibrilization of amyloid-ß peptide, a major player in AD pathogenesis. Specifically, we demonstrate that, during macromolecular crowding, viscosity dominates over the excluded volume effect only when the system is spatially non homogeneous (i.e. an air-water interface is present). We also show that the surfactant activity of the crowding agents can critically influence the outcome of macromolecular crowding and that the structure of the amyloid species formed may depend on the polymer used. This suggests that, in vivo, the outcome of amyloidogenesis may be affected by both macromolecular crowding and spatial heterogeneity (e.g. membrane turn-over). More generally, our work suggests that any factors causing changes in crowding may be susceptibility factors in AD.

Patterns of genetic divergence among populations of the common dormouse, Muscardinus avellanarius in the UK.

Quantitative descriptions of population genetic structure allows the delineation of population units and is therefore of primary importance in population management and wildlife conservation. Yet, predicting factors that influence the gene flow patterns in populations particularly at landscape scales remains a major challenge in evolutionary biology. Here we report a population genetic study of the common dormouse, Muscardinus avellanarius, a species that is seriously threatened due to anthropogenic factors, in two regions, Bontuchel (Denbighshire) and Afonwen (Gwynedd), both in Wales, UK. Ten microsatellite loci were used to characterize patterns of genetic diversity of M. avellanarius within both regions. While the population differentiation between both regions is apparent through geographical scale separating them, by using Bayesian clustering analyses, we identified the occurrence of genetic division among populations of M. avellanarius in Bontuchel region, but no significant evidence of differentiation in Afonwen. We found a strong significant isolation-by-distance (IBD) pattern at a fine-scale (less than 1 km) within continuous habitat and between habitat patches in both regions. Overall, analyses suggest that small-scale dispersal associated with the social structure and dispersal tendencies of this species is reflected in the genetic structure of populations. These findings then provide useful baseline data for supporting local management strategies.

Four-dimensional computed tomography (4D-CT) for preoperative parathyroid localization: A good study but are we using it?

BACKGROUND: Four-dimensional computed tomography (4D-CT) scan to localize abnormal parathyroid glands is diagnostically superior to ultrasound (US) and sestamibi. The implementation of 4D-CT imaging is unknown. METHODS: The Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) database from 2014 to 2018 was utilized. Patients with hyperparathyroidism undergoing an initial operation were included. The rate of US, sestamibi and 4D-CT performance was calculated for the entire study population, and for each institution. RESULTS: 7,959 patients were included. In 311(3.9%) patients, no preoperative imaging was recorded. Of patients with imaging, US was performed in 6,872(86.3%), sestamibi in 5,094(64.0%), and 4D-CT in 1,630(20.4%). The combination of US and sestamibi was most frequent (3,855, 48.4%). Institutional rates of 4D-CT performance varied from 0.1% to 88.7%. CONCLUSIONS: Of the imaging modalities, 4D-CT was utilized least frequently and with greatest variability. Given the high accuracy of 4D-CT, efforts to reduce this variation may improve overall preoperative localization in patients with hyperparathyroidism.

Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial.

BACKGROUND: Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored. PATIENTS AND METHODS: We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. RESULTS: Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population. CONCLUSION: Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.

Ixazomib, lenalidomide, and dexamethasone is effective and well tolerated in multiply relapsed (≥2nd relapse) refractory myeloma: a multicenter real world UK experience.

There are limited real world data on ixazomib, lenalidomide, and dexamethasone (IRd) in multiply relapsed myeloma. We analyzed outcomes of 116 patients who received IRd predominantly at second and subsequent relapse including those refractory to proteasome inhibitors (PIs). With a median follow up 16.3 months, the overall response rate was 66.9%; median progression-free survival (PFS) was 17.7 months with median overall survival (OS) not reached (NR). PFS and OS were significantly shorter in advanced disease (PFS; 12.6 vs. 21.2 months (p = .01), OS; 15.9 months vs. NR (p = .01) for ISS3 vs. ISS 1&2, respectively). PFS and OS were significantly shorter in clinical high risk (CHR) compared to standard risk (SR) patients (PFS; 9.3 months vs. NR (p = .001), OS; 11.5 months vs. NR (p < .001), respectively). There was a trend toward shorter PFS in PI-refractory patients 13.7 vs. 19.6 months for non-PI refractory (p = .2). The triplet combination was generally well tolerated.

Maintenance Strategies Post-Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma.

Multiple myeloma, the second most common hematological malignancy worldwide, has demonstrated dramatic improvements in outcome in the last decade. In newly diagnosed patients, induction chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care. After ASCT, the majority of patients experience disease remission but, despite recent therapeutic developments, most will eventually relapse. In this review we consider clinical aspects of maintenance therapies that can be used post-ASCT to prolong remission duration. We discuss the evidence for the effectiveness of each of these drugs as a maintenance therapy, alongside other benefits and drawbacks to their use, for example, route of administration and potential toxicities. We discuss questions which remain unanswered around the optimal use of currently available maintenance therapies and review newer agents being considered for use as maintenance such as emerging immunotherapies.

Normocalcemic hyperparathyroidism: A Collaborative Endocrine Surgery Quality Improvement Program analysis.

BACKGROUND: Normocalcemic primary hyperparathyroidism may be more challenging to cure compared with classical primary hyperparathyroidism. The aim of this study was to utilize a multi-institutional database to better characterize this condition. METHODS: The Collaborative Endocrine Surgery Quality Improvement Program database was queried for all patients who underwent parathyroidectomy for sporadic primary hyperparathyroidism. Patient characteristics, operative details, pathology, and outcomes data were compared between patients with normocalcemic primary hyperparathyroidism and those with hypercalcemia. RESULTS: Among 7,569 patients, 9.7% (733) were normocalcemic primary hyperparathyroidism. Mean age at surgery and sex were similar for normocalcemic primary hyperparathyroidism and primary hyperparathyroidism with hypercalcemia. The primary hyperparathyroidism with hypercalcemia cohort had a single parathyroid resected more frequently than the normocalcemic primary hyperparathyroidism group (73.3%% vs 47.5%, P < .05). Patients with normocalcemic primary hyperparathyroidism had a higher rate of subtotal (3.5 gland) resection (10.0% vs 4.7%, P < .05). Pathology reported a higher frequency of multigland hyperplasia in the normocalcemic primary hyperparathyroidism cohort (43.1% vs 21.9%, P <.05). In the normocalcemic primary hyperparathyroidism cohort, 47 patients (6.4%) underwent remedial surgery compared with 307 patients (4.5%) with primary hyperparathyroidism with hypercalcemia (P < .05). The rate of clinical concern for persistent hyperparathyroidism was similar between the 2 groups (P = .09) but not reported in 25% overall. CONCLUSION: Patients with normocalcemic primary hyperparathyroidism have higher rates of multigland disease and remedial surgery compared with primary hyperparathyroidism with hypercalcemia.

Children who read words accurately despite language impairment: who are they and how do they do it?

Some children learn to read accurately despite language impairments (LI). Nine- to 10-year-olds were categorized as having LI only (n = 35), dyslexia (DX) only (n = 73), LI + DX (n = 54), or as typically developing (TD; n = 176). The LI-only group had mild to moderate deficits in reading comprehension. They were similar to the LI + DX group on most language measures, but rapid serial naming was superior to the LI + DX group and comparable to the TD. For a subset of children seen at 4 and 6 years, early phonological skills were equally poor in those later classified as LI or LI + DX. Poor language need not hinder acquisition of decoding, so long as rapid serial naming is intact; reading comprehension, however, is constrained by LI.

Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP.

Pericellular degradation of interstitial collagens is a crucial event for cells to migrate through the dense connective tissue matrices, where collagens exist as insoluble fibers. A key proteinase that participates in this process is considered to be membrane-type 1 matrix metalloproteinase (MT1-MMP or MMP-14), but little is known about the mechanism by which it cleaves the insoluble collagen. Here we report that homodimerization of MT1-MMP through its hemopexin (Hpx) domain is essential for cleaving type I collagen fibers at the cell surface. When dimerization was blocked by coexpressing either a membrane-bound or a soluble form of the Hpx domain, cell surface collagenolytic activity was inhibited in a dose-dependent manner. When MMP-13, a soluble collagenase active as a monomer in solution, was expressed as a membrane-anchored form on the cell surface, homodimerization was also required to cleave collagen. Our results introduce a new concept in that pericellular collagenolysis is regulated by correct molecular assembly of the membrane-anchored collagenase, thereby governing the directionality of the cell to migrate in tissue.