Lipid Levels and Risk of Diabetic Polyneuropathy in 2 Danish Type 2 Diabetes Cohorts.

BACKGROUND AND OBJECTIVES: Reduction of blood lipids may aid in preventing diabetic polyneuropathy (DPN), but evidence remains conflicting. We investigated the association between lipid parameters and DPN risk in individuals with type 2 diabetes mellitus (T2DM). METHODS: We conducted a population-based cohort study of individuals with newly diagnosed T2DM and a cross-sectional study using a clinically recruited T2DM cohort. Triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and non-HDL cholesterol were measured in routine diabetes care. Each lipid parameter was categorized according to the latest cutoffs in clinical guidelines on dyslipidemia. DPN was assessed with validated hospital diagnosis codes in the population-based cohort and with the Michigan Neuropathy Screening Instrument questionnaire in the clinical cohort. We calculated hazard ratios (HRs) using Cox regression and prevalence ratios (PRs) using Poisson regression. RESULTS: We included 61,853 individuals in the population-based cohort (median age 63 [quartiles 54-72] years) and 4,823 in the clinical cohort (median age 65 [quartiles 57-72] years). The incidence rate of hospital-diagnosed DPN in the population-based cohort was 3.6 per 1000 person-years during a median follow-up of 7.3 years. Achieving guideline targets for HDL, LDL, and non-HDL cholesterol showed no association with DPN risk. By contrast, adjusted HRs (95% CI) for DPN were 1.02 (0.89-1.18) for triglyceride levels between 150 and 204 mg/dL (1.7-2.3 mmol/L) and 1.28 (1.13-1.45) for levels >204 mg/dL (2.3 mmol/L). In the clinical cohort with a DPN prevalence of 18%, DPN associated strongly with triglycerides >204 mg/dL (2.3 mmol/L) with an adjusted PR (95% CI) of 1.40 (1.21-1.62). The prevalence of DPN was modestly elevated for individuals with HDL cholesterol <39 mg/dL (1.0/1.3 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women (PR 1.13 [0.99-1.28]) and for individuals with non-HDL cholesterol >131 mg/dL (3.4 mmol/L) (PR 1.27 [1.05-1.52]). In both cohorts, spline models showed an increasing risk of DPN starting from triglyceride levels >124 mg/dL (1.4 mmol/L). All results were similar among statin users. DISCUSSION: High triglyceride levels are a strong DPN risk factor. Future intervention studies shall determine whether triglyceride reduction is more important for DPN prevention than reduction of other lipids.

Short notice cancellations - an insight into Irish surgical waiting lists.

BACKGROUND: The reasons underlying prolonged waiting lists for surgery in Ireland are multifactorial. Patient-related factors including non-attendances contribute in part to the current waiting times. AIMS: To determine the rate of short notice cancellation for day case surgery in a model 2 HSE hospital over a 1-month period and to implement an intervention to try and reduce the rate of cancellation. METHODS: The cancellation rate was documented over a 1-month period in the hospital. An intervention was then implemented, involving a phone call to the patient from a member of the surgical team to attempt to reduce the cancellation rate. Cancellations were re-audited after the implementation of the phone intervention. RESULTS: The initial audit revealed a cancellation rate of 39.7% during the first month prior to implementation of the phone intervention. A phone call intervention from a member of the surgical team was associated with a decrease in cancellations from 39.7 to 14.6% (p < 0.01). CONCLUSIONS: While cancellations remained high even after our intervention, a simple phone call was effective and more than halved our cancellation rate. Future efforts need to focus on increasing awareness of patient responsibility for attending scheduled appointments and procedures.

Subthalamic Deep Brain Stimulation Lead Asymmetry Impacts the Parkinsonian Gait Disorder.

Background: The preferable position of Deep Brain Stimulation (DBS) electrodes is proposed to be located in the dorsolateral subthalamic nucleus (STN) to improve general motor performance. The optimal DBS electrode localization for the post-operative improvement of balance and gait is unknown. Methods: In this single-center, retrospective analyses, 66 Parkinson's disease (PD) patients (24 female, age 63 ± 7 years) were assessed pre- and post-operatively (8.45 ± 4.2 months after surgery) by using MDS-UPDRS, freezing of gait (FoG) score, Giladi's gait and falls questionnaire and Berg balance scale. The clinical outcome was related to the DBS electrode coordinates in x, y, z plane as revealed by image-based reconstruction (SureTune™). Binomial generalized linear mixed models with fixed-effect variables electrode asymmetry, parkinsonian subtype, medication, age class and clinical DBS induced changes were analyzed. Results: Subthalamic nucleus-deep brain stimulation improved all motor, balance and FoG scores in MED OFF condition, however there were heterogeneous results in MED ON condition. DBS electrode reconstructed coordinates impacted the responsiveness of axial symptoms. FoG and balance responders showed slightly more medially located STN electrode coordinates and less medio-lateral asymmetry of the electrode reconstructed coordinates across hemispheres compared to non-responders. Conclusion: Deep brain stimulation electrode reconstructed coordinates, particularly electrode asymmetry on the medio-lateral axis affected the post-operative responsiveness of balance and FoG symptoms in PD patients.

Incidence of Chronic Pulmonary Aspergillosis in Patients with Suspected or Confirmed NTM and TB-A Population-Based Retrospective Cohort Study.

Chronic pulmonary aspergillosis (CPA) is a severe and underdiagnosed pulmonary fungal infection with a significant overlap in symptoms and imaging findings of mycobacterium tuberculosis (TB) and non-tuberculous mycobacterium (NTM). Infection with TB or NTM is a predisposing underlying condition for CPA in approximately one-third of patients. A previously published study from Uganda showed increased incidence and complication rate of CPA with respect to pre-existing radiographic cavitation in a post-treatment TB population. The aim of this study was to investigate the incidence of CPA in a low-endemic population of confirmed or suspected TB and NTM patients. We manually reviewed 172 patients referred on suspicion or for treatment of TB or NTM at the Department of Respiratory Medicine, Odense University Hospital during the period of 1 January 2018 to 31 December 2020. We found no CPA amongst TB patients as opposed to an incidence of 8.2% (n = 4) in NTM-infected patients. We identified possible investigatory differences in Aspergillus blood sample screening protocols depending on NTM or TB, initiated at the Department of Respiratory Medicine at Odense University Hospital. A focused screening and investigatory protocol in NTM patients with persisting or developing symptoms is warranted in relation to suspected CPA.

Four-year HbA1c and LDL-cholesterol trajectories among individuals with mental disorders and newly developed type 2 diabetes.

The impact of different types of mental disorders on long-term glycemic and lipid trajectories following newly diagnosed type 2 diabetes (T2D) remains unknown. We used real-world clinical data in a population-based cohort to fill this knowledge gap. We found that individuals with new T2D and preexisting personality, anxiety, unipolar depression, or psychotic disorder had higher mean HbA1c levels over 4 years following the onset of T2D, whereas no differences were found regarding LDL-C levels. This knowledge should be considered in the management of T2D in these vulnerable groups.

Evidence from South Africa for a protracted end-Permian extinction on land.

Earth's largest biotic crisis occurred during the Permo-Triassic Transition (PTT). On land, this event witnessed a turnover from synapsid- to archosauromorph-dominated assemblages and a restructuring of terrestrial ecosystems. However, understanding extinction patterns has been limited by a lack of high-precision fossil occurrence data to resolve events on submillion-year timescales. We analyzed a unique database of 588 fossil tetrapod specimens from South Africa's Karoo Basin, spanning ∼4 My, and 13 stratigraphic bin intervals averaging 300,000 y each. Using sample-standardized methods, we characterized faunal assemblage dynamics during the PTT. High regional extinction rates occurred through a protracted interval of ∼1 Ma, initially co-occurring with low origination rates. This resulted in declining diversity up to the acme of extinction near the Daptocephalus-Lystrosaurus declivis Assemblage Zone boundary. Regional origination rates increased abruptly above this boundary, co-occurring with high extinction rates to drive rapid turnover and an assemblage of short-lived species symptomatic of ecosystem instability. The "disaster taxon" Lystrosaurus shows a long-term trend of increasing abundance initiated in the latest Permian. Lystrosaurus comprised 54% of all specimens by the onset of mass extinction and 70% in the extinction aftermath. This early Lystrosaurus abundance suggests its expansion was facilitated by environmental changes rather than by ecological opportunity following the extinctions of other species as commonly assumed for disaster taxa. Our findings conservatively place the Karoo extinction interval closer in time, but not coeval with, the more rapid marine event and reveal key differences between the PTT extinctions on land and in the oceans.

Surgical Strategies to Reduce Postoperative Recurrence of Crohn's Disease After Ileocolic Resection.

Postoperative recurrence after ileocaecal resection for fibrostenotic terminal ileal Crohn's disease is a significant issue for patients as it can result in symptom recurrence and requirement for further surgery. There are very few modifiable factors, aside from smoking cessation, that can reduce the risk of postoperative recurrence. Until relatively recently, the surgical technique used for resection and anastomosis had little or no impact on postoperative recurrence rates. Novel surgical techniques such as the Kono-S anastomosis and extended mesenteric excision have shown promise as ways to reduce postoperative recurrence rates. This manuscript will review and discuss the evidence regarding a range of surgical techniques and their potential role in reducing disease recurrence. Some of the techniques have been shown to be associated with significant benefits for patients and have already been integrated into the routine clinical practice of some surgeons, while other techniques remain under investigation. Current techniques such as resection of the mesentery close to the intestine and stapled side to side anastomosis are being challenged. It is looking more likely that surgeons will have a major role to play when it comes to reducing recurrence rates for patients undergoing ileocaecal resection for Crohn's disease.

Statin Therapy and Risk of Polyneuropathy in Type 2 Diabetes: A Danish Cohort Study.

OBJECTIVE: Statins may reduce the risk of diabetic polyneuropathy (DPN) as a result of lipid-lowering and anti-inflammatory effects, but statins have also been associated with neurotoxicity. We examined whether statin therapy affects the risk of DPN. RESEARCH DESIGN AND METHODS: We identified all Danish patients with incident type 2 diabetes during 2002-2016. New users initiated statins between 180 days before and 180 days after their first diabetes record, while prevalent users had initiated statins before that period. Patients were followed for incident DPN using validated hospital diagnosis codes, starting 180 days after their first diabetes record. Cox proportional hazard analysis was used to compute adjusted hazard ratios (aHRs) for DPN. RESULTS: The study cohort comprised 59,255 (23%) new users, 75,528 (29%) prevalent users, and 124,842 (48%) nonusers; median follow-up time was 6.2 years (interquartile range 3.4-9.6). The incidence rate of DPN events per 1,000 person-years was similar in new users (4.0 [95% CI 3.8-4.2]), prevalent users (3.8 [3.6-3.9]), and nonusers (3.8 [3.7-4.0]). The aHR for DPN was 1.05 (0.98-1.11) in new users and 0.97 (0.91-1.04) in prevalent users compared with statin nonusers. New users had a slightly increased DPN risk during the first year (1.31 [1.12-1.53]), which vanished after >2 years of follow-up. Findings were similar in on-treatment and propensity score-matched analyses and with additional adjustment for pretreatment blood lipid levels. CONCLUSIONS: Statin therapy is unlikely to increase or mitigate DPN risk in patients with type 2 diabetes, although a small acute risk of harm cannot be excluded.

The craniomandibular anatomy of the early archosauriform Euparkeria capensis and the dawn of the archosaur skull.

Archosauria (birds, crocodilians and their extinct relatives) form a major part of terrestrial ecosystems today, with over 10 000 living species, and came to dominate the land for most of the Mesozoic (over 150 Myr) after radiating following the Permian-Triassic extinction. The archosaur skull has been essential to this diversification, itself diversified into myriad forms. The archosauriform Euparkeria capensis from the Middle Triassic (Anisian) of South Africa has been of great interest since its initial description in 1913, because its anatomy shed light on the origins and early evolution of crown Archosauria and potentially approached that of the archosaur common ancestor. Euparkeria has been widely used as an outgroup in phylogenetic analyses and when investigating patterns of trait evolution among archosaurs. Although described monographically in 1965, subsequent years have seen great advances in the understanding of early archosaurs and in imaging techniques. Here, the cranium and mandible of Euparkeria are fully redescribed and documented using all fossil material and computed tomographic data. Details previously unclear are fully described, including vomerine dentition, the epiptergoid, number of premaxillary teeth and palatal arrangement. A new diagnosis and cranial and braincase reconstruction is provided, and an anatomical network analysis is performed on the skull of Euparkeria and compared with other amniotes. The modular composition of the cranium suggests a flexible skull well adapted to feeding on agile food, but with a clear tendency towards more carnivorous behaviour, placing the taxon at the interface between ancestral diapsid and crown archosaur ecomorphology, corresponding to increases in brain size, visual sensitivity, upright locomotion and metabolism around this point in archosauriform evolution. The skull of Euparkeria epitomizes a major evolutionary transition, and places crown archosaur morphology in an evolutionary context.

Ex vivo-expanded autologous adipose tissue-derived stromal cells ensure enhanced fat graft retention in breast augmentation: A randomized controlled clinical trial.

Autologous fat grafting and implant surgery are used for volume restoration in plastic surgery. With the aim of producing a treatment superior to current solutions, we report a randomized, controlled, data assessor-blinded clinical trial comparing fat grafts enriched with ex vivo-expanded autologous adipose-derived stromal cells (ASCs) to nonenriched fat grafts in breast augmentation. The intervention group received ASC-enriched fat grafts (≥20 × 106 viable ex vivo-expanded ASCs per milliliter fat), and the control group received conventional nonenriched fat grafts. Volume retention was measured by magnetic resonance imaging, and clinical photographs were taken simultaneously for outcome evaluation. ASC-enriched fat grafts had significantly higher retention rates (mean = 80.2%) compared with conventional fat grafts (mean = 45.1%). Clinical photos showed statistically significant superior results in the intervention group, assessed by independent clinical experts. These results improve the prospects for using culture-expanded ASCs in both reconstructive and cosmetic volume restoration and make the procedure an attractive alternative to conventional fat grafting and implants. This study is registered at www.ClinicalTrials.gov, number H-16046960.

Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12.

On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.

A narrative review of potential measures of dynamic stability to be used during outdoor locomotion on different surfaces.

Dynamic stability of locomotion plays an important role in running injuries, particularly during trail running where ankle injuries occur frequently. Several studies have investigated dynamic stability of locomotion using wearable accelerometer measurements. However, no study has reviewed how dynamic stability of locomotion is quantified using accelerometry. Therefore, the present review aims to synthetise the methods and findings of studies investigating stability related parameters measured by accelerometry, during locomotion on various surfaces, and among asymptomatic participants. A systematic search of studies associated with locomotion was conducted. Only studies including assessment of dynamic stability parameters based on accelerometry, including at least one group of asymptomatic participants, and conditions that occur during trail running were considered relevant for this review. Consequently, all retrieved studies used a non-obstructive portable accelerometer or an inertial measurement unit. Fifteen studies used a single tri-axial accelerometer placed above the lumbar region allowing outdoor recordings. From trunk accelerations, a combination of index of cycle repeatability and signal dispersion can adequately be used to assess dynamic stability. However, as most studies included indoor conditions, studies addressing the biomechanics of trail running in outdoor conditions are warranted.

Hyperspasticity After Partial Neurectomy for Treatment of Myospasms Following Subpectoral Breast Reconstruction.

Breast reconstruction using tissue expander is a frequently used method of reconstruction after mastectomy. We describe a rare complication of myospasms after subpectoral tissue expander reconstruction with acellular dermal matrix. The patient gradually developed disturbing pectoral muscle spasms lasting almost a year. Botulinum toxin A was undesired due to its transient effect. Selective denervation of the medial pectoral nerve branches was performed and resulted in worse spasms where the breast bounced at a rapid speed. Complete denervation of the pectoral nerves led to immediate liberation. We recommend a cranial denervation of both medial and lateral pectoral nerves to secure complete denervation leading to permanent relief of involuntary spasms where selective denervation may lead to hyperspasticity.

Correction: Platelet-independent adhesion of calcium-loaded erythrocytes to von Willebrand factor.

[This corrects the article DOI: 10.1371/journal.pone.0173077.].

Platelet-independent adhesion of calcium-loaded erythrocytes to von Willebrand factor.

Adhesion of erythrocytes to endothelial cells lining the vascular wall can cause vaso-occlusive events that impair blood flow which in turn may result in ischemia and tissue damage. Adhesion of erythrocytes to vascular endothelial cells has been described in multiple hemolytic disorders, especially in sickle cell disease, but the adhesion of normal erythrocytes to endothelial cells has hardly been described. It was shown that calcium-loaded erythrocytes can adhere to endothelial cells. Because sickle erythrocyte adhesion to ECs can be enhanced by ultra-large von Willebrand factor multimers, we investigated whether calcium loading of erythrocytes could promote binding to endothelial cells via ultra-large von Willebrand factor multimers. We used (immunofluorescent) live-cell imaging of washed erythrocytes perfused over primary endothelial cells at venular flow rate. Using this approach, we show that calcium-loaded erythrocytes strongly adhere to histamine-stimulated primary human endothelial cells. This adhesion is mediated by ultra-large von Willebrand factor multimers. Von Willebrand factor knockdown or ADAMTS13 cleavage abolished the binding of erythrocytes to activated endothelial cells under flow. Platelet depletion did not interfere with erythrocyte binding to von Willebrand factor. Our results reveal platelet-independent adhesion of calcium-loaded erythrocytes to endothelium-derived von Willebrand factor. Erythrocyte adhesion to von Willebrand factor may be particularly relevant for venous thrombosis, which is characterized by the formation of erythrocyte-rich thrombi.

Three-dimensional position changes of the midface following Le Fort III advancement in syndromic craniosynostosis.

Little is known about the positional change of the Le Fort III segment following advancement. To study this, pre- and postoperative computed tomography scans of 18 craniosynosthosis patients were analyzed. The Le Fort III segment movement was measured by creating a reference coordinate system and by superpositioning the postoperative over the preoperative scan. On both the pre- and postoperative scans, four anatomical landmarks were marked: the most anterior point of the left and right foramen infraorbitale, the nasion, and the anterior nasal spine. A significant anterior movement of the four reference points was observed. No significant transversal differences were found. A significant difference between the anterior movement of the nasion and anterior nasal spine was found. In vertical dimension, there was a significant cranial movement of nasion in the study group. In addition, from all patients standardized lateral X-rays were viewed to determine the location and direction of force application that were linked to the outcomes of the three-dimensional movement of the nasion and anterior nasal spine (ANS) and the surgical technique. Conclusively, a significant advancement of the midface can be achieved with Le Fort III distraction osteogenesis in this specific patient group. Counterclockwise movement seemed to be the most dominant movement despite different modes of anchorage.

Rapid, accurate, and on-site detection of C. difficile in stool samples.

OBJECTIVES: A rapid test to diagnose Clostridium difficile infection (CDI) on hospital wards could minimize common but critical diagnostic delay. Field asymmetric ion mobility spectrometry (FAIMS) is a portable mass spectrometry instrument that quickly analyses the chemical composition of gaseous mixtures (e.g., above a stool sample). Can FAIMS accurately distinguish C. difficile-positive from -negative stool samples? METHODS: We analyzed 213 stool samples with FAIMS, of which 71 were C. difficile positive by microbiological analysis. The samples were divided into training, test, and validation samples. We used the training and test samples (n=135) to identify which sample characteristics discriminate between positive and negative samples, and to build machine learning algorithms interpreting these characteristics. The best performing algorithm was then prospectively validated on new, blinded validation samples (n=78). The predicted probability of CDI (as calculated by the algorithm) was compared with the microbiological test results (direct toxin test and culture). RESULTS: Using a Random Forest classification algorithm, FAIMS had a high discriminatory ability on the training and test samples (C-statistic 0.91 (95% confidence interval (CI): 0.86-0.97)). When applied to the blinded validation samples, the C-statistic was 0.86 (0.75-0.97). For samples analyzed ≤7 days of collection (n=76), diagnostic accuracy was even higher (C-statistic: 0.93 (0.85-1.00)). A cutoff value of 0.32 for predicted probability corresponded with a sensitivity of 92.3% (95% CI: 77.4-98.6%) and specificity of 86.0% (78.3-89.3%). For even fresher samples, discriminatory ability further increased. CONCLUSIONS: FAIMS analysis of unprocessed stool samples can differentiate between C. difficile-positive and -negative samples with high diagnostic accuracy.

Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration.

Chronic vascular inflammation is driven by interactions between activated leukocytes and the endothelium. Leukocyte ß2-integrins bind to endothelial intercellular adhesion molecule 1 (ICAM-1), which allows leukocyte spreading, crawling and transendothelial migration. Leukocytes scan the vascular endothelium for permissive sites to transmigrate, which suggests that there is apical membrane heterogeneity within the endothelium. However, the molecular basis for this heterogeneity is unknown. Leukocyte adhesion induces ICAM-1 clustering, which promotes its association to the actin-binding proteins filamin B, α-actinin-4 and cortactin. We show that these endothelial proteins differentially control adhesion, spreading and transmigration of neutrophils. Loss of filamin B, α-actinin-4 and cortactin revealed adaptor-specific effects on a nuclear-to-peripheral gradient of endothelial cell stiffness. By contrast, increasing endothelial cell stiffness stimulates ICAM-1 function. We identify endothelial α-actinin-4 as a key regulator of endothelial cell stiffness and of ICAM-1-mediated neutrophil transmigration. Finally, we found that the endothelial lining of human and murine atherosclerotic plaques shows elevated levels of α-actinin-4. These results identify endothelial cell stiffness as an important regulator of endothelial surface heterogeneity and of ICAM-1 function, which in turn controls the adhesion and transmigration of neutrophils.

Three-dimensional airway changes after Le Fort III advancement in syndromic craniosynostosis patients.

BACKGROUND: To investigate the changes of upper airway volume in syndromic craniosynostosis patients following Le Fort III advancement, computed tomographic scans were analyzed and related to the amount of advancement. METHODS: In this retrospective study, the preoperative and postoperative computed tomographic scans of 19 patients with syndromic craniosynostosis who underwent Le Fort III advancement were analyzed. In four cases, preoperative polysomnography demonstrated obstructive sleep apnea. The airway was segmented using a semiautomatic region growing method with a fixed Hounsfield threshold value. Airway volumes of hypopharynx and oropharynx (compartment A) and nasopharynx and nasal cavity (compartment B) were analyzed separately, as was the total airway volume. Advancement of the midface was recorded using lateral skull radiographs. Data were analyzed for all patients together and for patients with Crouzon/Pfeiffer and Apert syndromes separately. RESULTS: Airway volume increased significantly in compartment A (20 percent; p = 0.044) and compartment B (48 percent; p < 0.001), as did total airway volume in (37 percent; p < 0.001) in the total study group. No significant differences in volume changes were found comparing Apert with Crouzon/Pfeiffer patients. No distinct relation could be found between advancement of the midface and volume gain either in the total study group or in Apert and Crouzon/Pfeiffer patient groups separately. Postoperative polysomnography showed significant improvement of obstructive sleep apnea in all four patients. CONCLUSIONS: A significant improvement of the upper airway after Le Fort III advancement in syndromic craniosynostosis patients is demonstrated. No distinct relation could be observed between advancement and airway volume changes.

[A baby with a white lesion in the upper jaw]. / Een zuigeling met een molaar.

A 6-month-old girl had a floating molar due to Langerhans cell histiocytosis.