Pancreaticoduodenectomy with preoperative total embolization of the hepatic arteries (PD-HAE)-a novel treatment with sacrifice of the hepatic arterial blood supply without the need for arterial reconstruction.

PURPOSE: Tumors with involvement of common hepatic and gastroduodenal arteries (CHA and GDA) or GDA and the proper hepatic artery (PHA) are traditionally considered nonresectable. We have devised a new procedure that includes pancreaticoduodenectomy with preoperative hepatic artery embolization (PD-HAE) to facilitate an R0 resection of tumors involving the hepatic arteries without vascular anastomoses and complete sacrifice of normal hepatic arterial blood supply. METHODS: To allow resection of the hepatic arteries, preoperative embolization of the PHA was performed to induce an increased collateral arterial blood flow from the periphery of the liver, far from the hepatic hilum 10-14 days prior to the operation. Between May 1, 2017 and December 31, 2019, eight patients with ductal adenocarcinoma were operated with the PD-HAE procedure. RESULTS: The embolizations were uneventful apart from a transient marginal elevation of alanine aminotransferase in three patients. All patients had N disease with perineural invasion of tumor cells around the adventitia of the artery and severe perivascular inflammation. An R0 resection (> 1.0 mm to all resection margins) was obtained in six patients (75%). Mean hospital stay was 12 days. Median survival was 23 months (95% CI: 19.5-26.5 months). Six patients (75%) are still alive 11 to 36 months after the operation. There was perioperative fatality, and morbidity was comparable to standard pancreaticoduodenectomy. CONCLUSION: PD-HAE is a safe procedure and may provide the opportunity for curative resection in otherwise unresectable patients. However, larger studies are needed to evaluate this procedure.

Patient-centered management strategy for concurrent musculoskeletal complaints in elbows, shoulders, and neck after an isolated hand/forearm complaint: A prospective interventional study.

The aim was to evaluate patient-reported outcomes before and after a patient-centered management strategy targeting concurrent proximal musculoskeletal complaints (MSCs) in patients with an isolated hand/forearm complaint. A prospective interventional study included 66 patients. Intervention targeting concurrent MSCs was implemented as a patient-centered add-on to standard treatment for primary hand/forearm complaints. The patient-centered management strategy included patient education, individualized exercises, and manual therapy. Patient-reported outcome measures and pain questionnaires regarding the location, frequency, and intensity of pain in hands, elbows, shoulders, and neck were collected at baseline, after the last session of the patient-centered management strategy, and at 3-month follow-up. There were significant improvements in all patient-reported outcomes between baseline and follow-up. DASH scores improved significantly, by 17-29 points on the 3 subscales. There was a significant improvement of 6 points in PCS, 2 points in HADS, and 0.051 points in EQ-5D index. Median pain intensity on NRS decreased from 6 (4-8) to 5 (2.5-7) in hands, 3 (0-6) to 0 (0-3) in elbows, 5 (2-7) to 2.5 (0-5) in shoulders, and 3 (0-6) to 2 (0-3) in the neck, between baseline and discharge. Patients reporting concurrent MSCs in the elbow, shoulder, and neck after an isolated hand/forearm complaint may benefit from patient-centered management comprising patient education, individualized exercises, and manual therapy targeting pain and functional deficits in the upper-limb and neck. LEVEL OF EVIDENCE: IV.

Modulation of Deiodinase Types 2 and 3 during Skeletal Muscle Regeneration.

The muscle stem-cell niche comprises numerous cell types, which coordinate the regeneration process after injury. Thyroid hormones are one of the main factors that regulate genes linked to skeletal muscle. In this way, deiodinase types 2 and 3 are responsible for the fine-tuning regulation of the local T3 amount. Although their expression and activity have already been identified during muscle regeneration, it is of utmost importance to identify the cell type and temporal pattern of expression after injury to thoroughly comprehend their therapeutic potential. Here, we confirmed the expression of Dio2 and Dio3 in the whole tibialis anterior muscle. We identified, on a single-cell basis, that Dio2 is present in paired box 7 (PAX7)-positive cells starting from day 5 after injury. Dio2 is present in platelet derived growth factor subunit A (PDGFA)-expressing fibro-adipogenic progenitor cells between days 7 and 14 after injury. Dio3 is detected in myogenic differentiation (MYOD)-positive stem cells and in macrophages immediately post injury and thereafter. Interestingly, Dio2 and Dio3 RNA do not appear to be present in the same type of cell throughout the process. These results provide further insight into previously unseen aspects of the crosstalk and synchronized regulation of T3 in injured muscle mediated by deiodinases. The set of findings described here further define the role of deiodinases in muscle repair, shedding light on potential new forms of treatment for sarcopenia and other muscular diseases.

Regulation of thyroid hormones and branchial iodothyronine deiodinases during freshwater acclimation in tilapia.

Euryhaline fishes are capable of maintaining osmotic homeostasis in a wide range of environmental salinities. Several pleiotropic hormones, including prolactin, growth hormone, and thyroid hormones (THs) are mediators of salinity acclimation. It is unclear, however, the extent to which THs and the pituitary-thyroid axis promote the adaptive responses of key osmoregulatory organs to freshwater (FW) environments. In the current study, we characterized circulating thyroxine (T4) and 3-3'-5-triiodothyronine (T3) levels in parallel with the outer ring deiodination (ORD) activities of deiodinases (dios) and mRNA expression of dio1, dio2, and dio3 in gill during the acclimation of Mozambique tilapia (Oreochromis mossambicus) to FW. Tilapia transferred from seawater (SW) to FW exhibited reduced plasma T4 and T3 levels at 6 h. These reductions coincided with an increase in branchial dio2-like activity and decreased branchial dio1 gene expression. To assess whether dios respond to osmotic conditions and/or systemic signals, gill filaments were exposed to osmolalities ranging from 280 to 450 mOsm/kg in an in vitro incubation system. Gene expression of branchial dio1, dio2, and dio3 was not directly affected by extracellular osmotic conditions. Lastly, we observed that dio1 and dio2 expression was stimulated by thyroid-stimulating hormone in hypophysectomized tilapia, suggesting that branchial TH metabolism is regulated by systemic signals. Our collective findings suggest that THs are involved in the FW acclimation of Mozambique tilapia through their interactions with branchial deiodinases that modulate their activities in a key osmoregulatory organ.

Preoperative high-dose glucocorticoids for early recovery after liver resection: randomized double-blinded trial.

BACKGROUND: Glucocorticoids modulate the surgical stress response. Previous studies showed that high-dose preoperative glucocorticoids reduce levels of postoperative inflammatory markers and specific biomarkers of liver damage compared with placebo, and suggested a reduced complication rate and shorter hospital stay after liver surgery. However, there are no studies with a clinical primary outcome or of early recovery outcomes. The aim of this study was to investigate whether a single high dose of preoperative glucocorticoid reduces complications in the immediate postoperative phase after liver surgery. METHODS: This was a single-centre, double-blinded, parallel-group RCT investigating preoperative methylprednisolone 10 mg/kg (high dose) versus dexamethasone 8 mg (standard-dose postoperative nausea prophylaxis) in patients scheduled for open liver resection. The primary outcome was number of patients with a complication in the postanaesthesia care unit; secondary outcomes included duration of hospital stay, pain and nausea during admission, and 30-day morbidity. RESULTS: A total of 174 patients (88 in high-dose group, 86 in standard-dose group) were randomized and analysed (mean(s.d.) age 65(12) years, 67.2 per cent men); 31.6 per cent had no serious co-morbidities and 25.3 per cent underwent major liver resection. Complications occurred in the postanaesthesia care unit in 51 patients (58 per cent) in the high-dose group and 58 (67 per cent) in the standard-dose group (risk ratio 0.86, 95 per cent c.i. 0.68 to 1.08; P = 0.213). Median duration of hospital stay was 4 days in both groups (P = 0.160). Thirty-day morbidity and mortality rates were similar in the two groups. CONCLUSION: A high dose of preoperative glucocorticoids did not reduce acute postoperative complications after open liver resection compared with a standard dose. Registration number: NCT03403517 (http://www.clinicaltrials.gov); EudraCT 2017-002652-81 (https://eudract.ema.europa.eu/).

The Deiodinases: Their Identification and Cloning of Their Genes.

In this minireview, we provide a historical outline of the events that led to the identification and characterization of the deiodinases, the recognition that deiodination plays a major role in thyroid hormone action, and the cloning of the 3 deiodinase genes. The story starts in 1820, when it was first determined that elemental iodine was important for normal thyroid function. Almost 100 years later, it was found that the primary active principle of the gland, T4, contains iodine. Once radioactive iodine became available in the 1940s, it was demonstrated that the metabolism of T4 included deiodination, but at the time it was assumed to be merely a degradative process. However, this view was questioned after the discovery of T3 in 1952. We discuss in some detail the events of the next 20 years, which included some failures followed by the successful demonstration that deiodination is indeed essential to normal thyroid hormone action. Finally, we describe how the 3 deiodinases were identified and characterized and their genes cloned.

Preoperative Hypoalbuminemia Predicts Early Mortality Following Open Abdominal Surgery in Patients Above 60 Years of Age.

BACKGROUND: Major abdominal surgery in older and frail patients is associated with considerable morbidity and mortality. Plasma albumin is routinely measured in the clinic and has been proposed as an indicator of frailty. This study aimed to investigate if plasma albumin is a predictor of mortality in older patients undergoing open abdominal surgery. MATERIALS AND METHODS: We conducted a single-center, register-based retrospective study of patients, aged ⩾60 years who underwent one of 81 open abdominal surgical procedures. Patients operated on during the period from January 1st, 2000 to May 31st, 2013 were consecutively identified in the Danish National Patient Registry. Plasma albumin was measured within 30 days prior to surgery and the primary endpoint was 30-day postoperative mortality. RESULTS: 3,639 patients were included of whom 68.2% underwent emergency surgery. The rate of severe hypoalbuminemia (plasma albumin < 28 g/L) was 43.4%. Preoperative plasma albumin was lower in patients with a fatal 30-day outcome (mean 20.6 g/L vs 30.1 g/L in survivors, p < 0.0001). Other independent predictive parameters of 30-day mortality were age, male sex, and emergency surgery. We present an algorithm including these four variables for the prediction of 30-day mortality for patients aged ⩾60 years undergoing open abdominal surgery. CONCLUSION: Preoperative plasma albumin is a predictor of 30-day mortality in patients above 60 years of age following open abdominal surgery. Assessment of plasma albumin in conjunction with other risk factors such as age, sex, and surgical priority may improve preoperative decision-making.

A Type 2 Deiodinase-Dependent Increase in Vegfa Mediates Myoblast-Endothelial Cell Crosstalk During Skeletal Muscle Regeneration.

Background: The type 2 deiodinase (DIO2) converts thyroxine to 3,3',5-triiodothyronine (T3), modulating intracellular T3. An increase in DIO2 within muscle stem cells during skeletal muscle regeneration leads to T3-dependent potentiation of differentiation. The muscle stem cell niche comprises numerous cell types, which coordinate the regeneration process. For example, muscle stem cells provide secretory signals stimulating endothelial cell-mediated vascular repair, and, in turn, endothelial cells promote muscle stem differentiation. We hypothesized that Dio2 loss in muscle stem cells directly impairs muscle stem cell-endothelial cell communication, leading to downstream disruption of endothelial cell function. Methods: We assessed the production of proangiogenic factors in differentiated C2C12 cells and in a C2C12 cell line without Dio2 (D2KO C2C12) by real-time quantitative-polymerase chain reaction and enzyme-linked immunosorbent assay. Conditioned medium (CM) was collected daily in parallel to evaluate its effects on human umbilical vein endothelial cell (HUVEC) proliferation, migration and chemotaxis, and vascular network formation. The effects of T3-treatment on vascular endothelial growth factor (Vegfa) mRNA expression in C2C12 cells and mouse muscle were assessed. Chromatin immunoprecipitation (ChIP) identified thyroid hormone receptor (TR) binding to the Vegfa gene. Using mice with a targeted disruption of Dio2 (D2KO mice), we determined endothelial cell number by immunohistochemistry/flow cytometry and evaluated related gene expression in both uninjured and injured skeletal muscle. Results: In differentiated D2KO C2C12 cells, Vegfa expression was 46% of wildtype (WT) C2C12 cells, while secreted VEGF was 45%. D2KO C2C12 CM exhibited significantly less proangiogenic effects on HUVECs. In vitro and in vivo T3 treatment of C2C12 cells and WT mice, and ChIP using antibodies against TRα, indicated that Vegfa is a direct genomic T3 target. In uninjured D2KO soleus muscle, Vegfa expression was decreased by 28% compared with WT mice, while endothelial cell numbers were decreased by 48%. Seven days after skeletal muscle injury, D2KO mice had 36% fewer endothelial cells, coinciding with an 83% decrease in Vegfa expression in fluorescence-activated cell sorting purified muscle stem cells. Conclusion:Dio2 loss in the muscle stem cell impairs muscle stem cell-endothelial cell crosstalk via changes in the T3-responsive gene Vegfa, leading to downstream impairment of endothelial cell function both in vitro and in vivo.

A Cohort Analysis of Clinical and Ultrasound Variables Predicting Cancer Risk in 20,001 Consecutive Thyroid Nodules.

CONTEXT: Assessing thyroid nodules for malignancy is complex. The impact of patient and nodule factors on cancer evaluation is uncertain. OBJECTIVES: To determine precise estimates of cancer risk associated with clinical and sonographic variables obtained during thyroid nodule assessment. DESIGN: Analysis of consecutive adult patients evaluated with ultrasound-guided fine-needle aspiration for a thyroid nodule ≥1 cm between 1995 and 2017. Demographics, nodule sonographic appearance, and pathologic findings were collected. MAIN OUTCOME MEASURES: Estimated risk for thyroid nodule malignancy for patient and sonographic variables using mixed-effect logistic regression. RESULTS: In 9967 patients [84% women, median age 53 years (range 18 to 95)], thyroid cancer was confirmed in 1974 of 20,001 thyroid nodules (9.9%). Significant ORs for malignancy were demonstrated for patient age <52 years [OR: 1.82, 95% CI (1.63 to 2.05), P < 0.0001], male sex [OR: 1.68 (1.45 to 1.93), P < 0.0001], nodule size [OR: 1.30 (1.14 to 1.49) for 20 to 19 mm, OR: 1.59 (1.34 to 1.88) for 30 to 39 mm, and OR: 1.71 (1.43 to 2.04) for ≥40 mm compared with 10 to 19 mm, P < 0.0001 for all], cystic content [OR: 0.43 (0.37 to 0.50) for 25% to 75% cystic and OR: 0.21 (0.15 to 0.28) for >75% compared with predominantly solid, P < 0.0001 for both], and the presence of additional nodules ≥1 cm [OR: 0.69 (0.60 to 0.79) for two nodules, OR: 0.41 (0.34 to 0.49) for three nodules, and OR: 0.19 (0.16 to 0.22) for greater than or equal to four nodules compared with one nodule, P < 0.0001 for all]. A free online calculator was constructed to provide malignancy-risk estimates based on these variables. CONCLUSIONS: Patient and nodule characteristics enable more precise thyroid nodule risk assessment. These variables are obtained during routine initial thyroid nodule evaluation and provide new insights into individualized thyroid nodule care.

A Global Loss of Dio2 Leads to Unexpected Changes in Function and Fiber Types of Slow Skeletal Muscle in Male Mice.

The type 2 iodothyronine-deiodinase (D2) enzyme converts T4 to T3, and mice deficient in this enzyme [D2 knockout (D2KO) mice] have decreased T3 derived from T4 in skeletal muscle despite normal circulating T3 levels. Because slow skeletal muscle is particularly susceptible to changes in T3 levels, we expected D2 inactivation to result in more pronounced slow-muscle characteristics in the soleus muscle, mirroring hypothyroidism. However, ex vivo studies of D2KO soleus revealed higher rates of twitch contraction and relaxation and reduced resistance to fatigue. Immunostaining of D2KO soleus showed that these properties were associated with changes in muscle fiber type composition, including a marked increase in the number of fast, glycolytic type IIB fibers. D2KO soleus muscle fibers had a larger cross-sectional area, and this correlated with increased myonuclear accretion in myotubes formed from D2KO skeletal muscle precursor cells differentiated in vitro. Consistent with our functional findings, D2KO soleus gene expression was markedly different from that in hypothyroid wild-type (WT) mice. Comparison of gene expression between euthyroid WT and D2KO mice indicated that PGC-1α, a T3-dependent regulator of slow muscle fiber type, was decreased by ∼50% in D2KO soleus. Disruption of Dio2 in the C2C12 myoblast cell line led to a significant decrease in PGC-1α expression and a faster muscle phenotype upon differentiation. These results indicate that D2 loss leads to significant changes in soleus contractile function and fiber type composition that are inconsistent with local hypothyroidism and suggest that reduced levels of PCG-1α may contribute to the observed phenotypical changes.

[Epidemiology of severe visual impairment and blindness of old people in Germany]. / Epidemiologie hochgradiger Sehbehinderungen und Blindheit älterer Menschen in Deutschland.

Approximately 500,000 blind and 1 million visually impaired persons live in Germany, which lacks a national blind registry. Therefore data from social welfare agencies and population-based studies are used to estimate prevalence and incidence. Main causes for severe visual impairment and blindness are age-related macular degeneration, glaucoma and diabetic eye diseases. We observed a relative decline of the incidence of severe visual impairment and blindness over the last decades, which is primarily due to improved ophthalmic care and better treatment options. However, the absolute number of subjects with severe visual impairment and blindness increases due to population ageing. This will cause significant social and economic challenges in the future.

Sex and racial/ethnic differences in the association between childhood attention-deficit/hyperactivity disorder symptom subtypes and body mass index in the transition from adolescence to adulthood in the United States.

BACKGROUND: While attention-deficit/hyperactivity disorder (ADHD) has been associated with higher body mass index (BMI), little research has focused on how this association differs by sex or race/ethnicity. OBJECTIVE: To investigate the association between ADHD and BMI by sex and race/ethnicity (ie, European [EA], African [AA], and Hispanic American [HA]). METHODS: Data came from the National Longitudinal Survey of Adolescent to Adult Health Waves II to IV (n = 13 332, age: 12-34 years). On the basis of self-reported childhood ADHD symptoms between the ages of 5 and 12 years, participants were categorized into: ADHD predominantly hyperactive/impulsive (ADHD-HI); ADHD predominantly inattentive (ADHD-I); ADHD combined (ADHD-C; a combination of ADHD-HI and ADHD-I symptoms); and non-ADHD. RESULTS: The patterns of ADHD-BMI associations in the transition period between adolescence and young adulthood differed by sex and race/ethnicity. Compared with non-ADHD, ADHD-HI was associated with higher BMI among EA males and females, while ADHD-I was associated with higher BMI among EA females. ADHD-C was associated with higher BMI for HA females. We found no evidence of an association among AA males and females and HA males. CONCLUSION: These study results suggest that the association between ADHD subtypes and BMI might differ across population subgroups in the United States.

Tibial plateau fractures are associated with a long-lasting increased risk of total knee arthroplasty a matched cohort study of 7,950 tibial plateau fractures.

OBJECTIVE: This study aims to investigate the risk of total knee replacement (TKR) following tibia plateau fractures. Secondary the study aims to investigate the risk of knee arthroscopy following tibial plateau fractures. METHOD: The study was designed as a matched cohort study. All patients who sustained a tibial plateau fracture in Denmark between January 1, 1996, and December 31, 2000, were included and followed until December 31, 2015. For each patient with a tibial plateau fracture, 10 matched citizens without a tibial plateau fracture were included as a reference group. RESULTS: 7,950 patients sustained a tibial plateau fracture in Denmark during the study period. The median age of patients was 52.6 (IQR: 32.4-71.5) years. The mean observational period was 13.9 years. 5.7% were treated with a TKR (N = 452), and 2.0% of patients from the reference group were treated with a TKR (N = 1,623). Patients with a tibial plateau fracture had a 3.5 (95%CI: 3.1-3.9) times higher hazard ratio (HR) compared to patients from the reference group. 7.6% of patients with a tibial plateau fracture were treated with a secondary knee arthroscopy (N = 603) and 2.0% of patients from the reference group were treated with a knee arthroscopy (N = 1,565). Patients with a tibial plateau fracture presented with a 5.0 (95%CI: 4.5-5.6)) times higher HR compared to patients in the reference group. CONCLUSIONS: Tibial plateau fractures are associated with a 3.5 times increased risk of TKR compared with an age- and gender-matched reference group with a mean follow-up of 13.9 years.

[Pro re nata anti-VEGF treatment results for neovascular age-related macular degeneration in routine clinical treatment: comparison of single with triple injections]. / Pro-re-nata-anti-VEGF-Behandlungsergebnisse bei neovaskulärer altersabhängiger Makuladegeneration in der klinischen Routineversorgung: Vergleich von Einzel- mit 3er-Injektionen.

BACKGROUND: Different injection regimens from continuous to pro re nata (PRN) have been proposed for treatment of neovascular age-related macular degeneration (nAMD). So far the PRN single injection on reactivation regimen has not been compared to the PRN triple injection on reactivation regimen (IVAN scheme). OBJECTIVE: Comparison of the two nAMD PRN injection regimens with single and triple injections on reactivation in a real-world setting in a retrospective case series in two German treatment centers. MATERIAL AND METHODS: Naïve nAMD patients, who started treatment according to either the single or triple injection regimen were included. Endpoints were best corrected visual acuity (LogMAR), central retinal thickness on optical coherence tomography (µm) and number of injections, all at 3, 6, 12, 18 and 24 months after treatment initiation. RESULTS: A total of 146 patients with single injection and 148 patients with triple injection regimens were included. There were no significant differences between the two treatment regimens in best corrected visual acuity (single vs. triple injection scheme: 0.50 ± 0.42 vs. 0.56 ± 0.42, p = 0.14), central retinal thickness (303 ± 76.2 vs. 306 ± 110, p = 0.79) and number of injections (13 ± 4.4 vs. 12 ± 5.4, p = 0.31). This was the case for all analyzed time points. CONCLUSION: There were no significant functional or morphological differences between the two PRN injection regimens with single and triple injections on reactivation after 24 months. For evaluation of long-term therapy results further studies are warranted.

Functional Analysis of Genetic Variation in the SECIS Element of Thyroid Hormone Activating Type 2 Deiodinase.

CONTEXT: Thyroid hormone is important for normal brain development. The type 2 deiodinase (D2) controls thyroid hormone action in the brain by activating T4 to T3. The enzymatic activity of D2 depends on the incorporation of selenocysteine for which the selenocysteine-insertion sequence (SECIS) element located in the 3' untranslated region is indispensable. We hypothesized that mutations in the SECIS element could affect D2 function, resulting in a neurocognitive phenotype. OBJECTIVE: To identify mutations in the SECIS element of DIO2 in patients with intellectual disability and to test their functional consequences. DESIGN, SETTING, AND PATIENTS: The SECIS element of DIO2 was sequenced in 387 patients with unexplained intellectual disability using a predefined pattern of thyroid function tests. SECIS element read-through in wild-type or mutant D2 was quantified by a luciferase reporter system in transfected cells. Functional consequences were assessed by quantifying D2 activity in cell lysate or intact cell metabolism studies. RESULTS: Sequence analysis revealed 2 heterozygous mutations: c.5703C>T and c.5730A>T, which were also present in the unaffected family members. The functional evaluation showed that both mutations did not affect D2 enzyme activity in cell lysates or intact cells, although the 5730A>T mutation decreased SECIS element read-through by 75%. In the patient harboring the c.5730A>T variant, whole genome sequencing revealed a pathogenic deletion of the STXBP1 gene. CONCLUSIONS: We report on two families with mutations in the SECIS element of D2. Although functional analysis showed that nucleotide 5730 is important for normal SECIS element read-through, the two variants did not segregate with a distinct phenotype.

Patellar fractures are associated with an increased risk of total knee arthroplasty: A Matched Cohort Study of 6096 Patellar Fractures with a mean follow-up of 14.3 Years.

AIMS: The aim of this study was to investigate the incidence of knee arthroplasty and arthroscopy following patellar fractures, and to compare this with an age- and gender-matched group without a prior patellar fracture. PATIENTS AND METHODS: A national matched cohort study based on the Danish National Patient Register including all citizens of Denmark (approximately 5.3 million) was undertaken. A total of 6096 patients who sustained a patellar fracture in Denmark between 1 January 1996 and 31 December 2000 were included. The median age of these patients was 50.6 years (interquartile range (IQR) 28.5 to 68.9); 49.1% were women. Patients were followed-up until 31 December 2015, with regard to treatment with knee arthroplasty and/or knee arthroscopy. RESULTS: Patients with a patellar fracture had an increased risk of knee arthroplasty (hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.57 to 2.13) compared with citizens without a patellar fracture, and the effect was strongest during the first five years (HR 3.02, 95% CI 2.26 to 4.03). Patients with a patellar fracture also had a higher risk of knee arthroscopy (HR 3.94, 95% CI 3.49 to 4.46), and the effect was highest during the first five years after the fracture (HR 7.40, 95% CI 6.32 to 8.66). CONCLUSION: Patellar fractures are associated with an increased risk of knee arthroplasty and knee arthroscopy. The consequences of a patellar fracture may be more severe than previously considered, and patients must expect a lifelong increased risk of knee arthroplasty. Cite this article: Bone Joint J 2018;100-B:1477-81.

Diet quality and its association with type 2 diabetes and major cardiometabolic risk factors among adults in China.

AIM: We examined the association between diet quality and diabetes and major cardiometabolic risks among adults in China. METHODS AND RESULTS: We developed the China Dietary Guideline Index (CDGI) based on the 2007 Chinese dietary guidelines and tailored the Alternate Healthy Eating Index 2010 (which we call the tAHEI) to assess diet quality. Our analysis linked the dietary intake and covariates measured in 2006 with CM risk factors measured in 2009. We used diet data the longitudinal China Health and Nutrition Survey 2006 collected in 3 consecutive 24-h recalls from 4440 adults aged 18 to 65 to calculate both the tAHEI and the CDGI scores. We performed multivariable logistic regressions to analyze the association of each 2006 score with diabetes, abdominal obesity, elevated blood pressure, and lipid-related cardiometabolic risk factors in 2009. After we adjusted for potential confounders, adults in the top quintile compared with the bottom quintile of the tAHEI scores showed 36% lower odds of high low-density lipoprotein cholesterol (LDL-C) (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.46, 0.90] in men and 33% lower odds (OR 0.67; 95% CI 0.49, 0.91) in women, while the CDGI scores showed 35% lower odds of high LDL-C (OR 0.65; 95% CI 0.46, 0.92) in men only. Further, the CDGI scores indicated 55% lower odds of diabetes in the top versus the bottom quintile (OR 0.45; 95% CI 0.23, 0.87) in men only, whereas a null association was observed for the tAHEI scores for both sexes. Both index scores showed null associations with other cardiometabolic risk factors. CONCLUSIONS: Chinese diets that scored high on both the CDGI and the tAHEI showed similarly negative associations with high LDL-C risk, whereas only CDGI score was negatively related to diabetes risk in men.

Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified. METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software. RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes. CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers.

BACKGROUND: Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction is recognized as a common adverse effect of treatment, but the importance of incident hypothyroidism during TKI therapy remains unclear. This study analyzed the prognostic significance of hypothyroidism during TKI therapy in cancer patients. METHODS: This was a retrospective cohort study of adult patients with advanced nonthyroidal cancer treated with TKI and available thyroid function testing at three affiliated academic hospitals from 2000 to 2017. Patients with preexisting thyroid disease were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid status with TKI treatment was determined from thyroid function testing and initiation of thyroid medication, and classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (SCH; TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (OH; TSH >10 mIU/L, low free thyroxine, or requiring replacement). Multivariate models were used to evaluate the effect of TKI-related hypothyroidism on overall survival (OS). RESULTS: Of 1120 initial patients, 538 remained after exclusion criteria. SCH occurred in 72 (13%) and OH in 144 (27%) patients with TKI therapy. Patients with hypothyroidism had significantly longer OS, with median OS in euthyroid patients of 685 days [confidence interval (CI) 523-851] compared to 1005 days [CI 634-1528] in SCH and 1643 days [CI 1215-1991] in OH patients (p < 0.0001). After adjustment for age, sex, race/ethnicity, cancer type, cancer stage, ECOG performance status, and checkpoint inhibitor therapy, OH remained significantly associated with OS (hazard ratio = 0.561; p < 0.0001), whereas SCH did not (hazard ratio = 0.796; p = 0.165). Analysis of hypothyroid patients (SCH and OH) with TSH >5 and <10 mIU/L stratified by hormone replacement status showed improved survival associated with hormone replacement. CONCLUSIONS: New hypothyroidism in cancer patients treated with TKI is associated with significantly improved OS, should not necessitate TKI dose reduction or discontinuation, and may provide independent prognostic information.

Risk Factors for New Hypothyroidism During Tyrosine Kinase Inhibitor Therapy in Advanced Nonthyroidal Cancer Patients.

BACKGROUND: Thyroid dysfunction during tyrosine kinase inhibitor (TKI) cancer treatment is common, but predisposing risk factors have not been determined. Recommendations for monitoring patients treated with one or multiple TKI and in conjunction with other relevant cancer therapies could be improved. The study objective was to assess the risk factors for new thyroid dysfunction in TKI-treated previously euthyroid cancer patients. METHODS: A retrospective cohort study of patients with advanced nonthyroidal cancer treated with TKI from 2000 to 2017, having available thyroid function tests showing initial euthyroid status, excluding patients with preexisting thyroid disease or lack of follow-up thyroid function tests. During TKI treatment, patients were classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (TSH >10 mIU/L, low free thyroxine, or requiring thyroid hormone replacement). The timing of thyroid dysfunction and TKI used were assessed. Risk factors for incident hypothyroidism were evaluated using multivariate models. RESULTS: In 538 adult patients included, subclinical hypothyroidism occurred in 71 (13.2%) and overt hypothyroidism occurred in 144 (26.8%) patients with TKI therapy, following a median cumulative TKI exposure of 196 days (interquartile range [IQR] 63.5-518.5 days). The odds of hypothyroidism were greatest during the first six months on a TKI. Median exposure time on the TKI concurrent with thyroid dysfunction in patients treated with only one TKI was 85 days (IQR 38-293.5 days) and was similar to the 74 days (IQR 38-133.3 days) in patients treated previously with other TKI (p = 0.41). Patients who developed hypothyroidism compared to those who remained euthyroid had greater odds of being female (odds ratio = 1.99 [confidence interval 1.35-2.93], p < 0.01), but greater cumulative TKI exposure and greater number of TKI received were not associated with thyroid dysfunction. CONCLUSIONS: Thyroid dysfunction occurred in 40% of euthyroid patients. Monitoring thyroid function in TKI-treated patients is recommended, with particular attention to female patients and within the first six months of exposure to a new TKI.