Longitudinal Assessment of Blood-Based Inflammatory, Neuromuscular, and Neurovascular Biomarker Profiles in Intensive Care Unit-Acquired Weakness: A Prospective Single-Center Cohort Study.

BACKGROUND: The diagnosis of intensive care unit (ICU)-acquired weakness (ICUAW) and critical illness neuromyopathy (CINM) is frequently hampered in the clinical routine. We evaluated a novel panel of blood-based inflammatory, neuromuscular, and neurovascular biomarkers as an alternative diagnostic approach for ICUAW and CINM. METHODS: Patients admitted to the ICU with a Sequential Organ Failure Assessment score of ≥ 8 on 3 consecutive days within the first 5 days as well as healthy controls were enrolled. The Medical Research Council Sum Score (MRCSS) was calculated, and motor and sensory electroneurography (ENG) for assessment of peripheral nerve function were performed at days 3 and 10. ICUAW was defined by an MRCSS < 48 and CINM by pathological ENG alterations, both at day 10. Blood samples were taken at days 3, 10, and 17 for quantitative analysis of 18 different biomarkers (white blood cell count, C-reactive protein, procalcitonin, C-terminal agrin filament, fatty-acid-binding protein 3, growth and differentiation factor 15, syndecan 1, troponin I, interferon-γ, tumor necrosis factor-α, interleukin-1α [IL-1α], IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, and monocyte chemoattractant protein 1). Results of the biomarker analysis were categorized according to the ICUAW and CINM status. Clinical outcome was assessed after 3 months. RESULTS: Between October 2016 and December 2018, 38 critically ill patients, grouped into ICUAW (18 with and 20 without) and CINM (18 with and 17 without), as well as ten healthy volunteers were included. Biomarkers were significantly elevated in critically ill patients compared to healthy controls and correlated with disease severity and 3-month outcome parameters. However, none of the biomarkers enabled discrimination of patients with and without neuromuscular impairment, irrespective of applied classification. CONCLUSIONS: Blood-based biomarkers are generally elevated in ICU patients but do not identify patients with ICUAW or CINM. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02706314.

Glycemic Variability and the Thickness of Retinal Layers in Cystic Fibrosis Patients with and without Cystic Fibrosis Related Diabetes.

PURPOSE: Patients with cystic fibrosis (CF) are at risk to develop CF related diabetes (CFRD) and subsequently even diabetic neuro- and/or vasculopathy. We sought to determine if there are typical signs of diabetes-related retinal alterations present in CF patients with preserved and impaired glycemic control. METHODS: During routine annual examination CF patients were offered an additional 7-day period of real time continuous glucose monitoring (rtCGM) and an ophthalmological examination including retinal optical coherence tomography (OCT). Patients were categorized according to the glycemic control, i.e. the results of an oral glucose tolerance test (OGTT) and rtCGM were taken into consideration. OCT data was analyzed by our previously published visual analysis software generating dedicated and spatially resolved deviation maps for visualization and quantification of differences in total retinal thickness and thickness of retinal nerve fiber layer (RNFL) as well as ganglion cell layer (GCL) in comparison to age-matched healthy controls and patients with either type 1 or type 2 diabetes mellitus. RESULTS: Results of the rtCGM and/or OGTT enabled discrimination between patients with normal glycemic control (CFNG; n = 6), with abnormal glycemic control (CFAG; n = 6) and overt CFRD (n = 4). OCT data indicates gradually increasing retinal thinning in all 3 groups, depending on the degree of glucose metabolism disorder compared to healthy controls. At the foveal region total retinal thickness and GCL thickness were significantly thinner in CFRD patients compared to CFNG patients (total retinal thickness: 260.4 µm (239.3-270.8) vs. 275.4 µm (254.3-289.5); GCL: 11.82 µm (11.16-15.25) vs. 17.30 µm (13.95-19.82); each p < 0.05). CONCLUSION: Although we investigated a rather small number of patients, we obtained evidence that intraretinal neurodegenerative changes occur in each of our subgroups (CFNG, CFAG, CFRD). Beyond this, our results favor the detrimental role of additional diabetes, as the deviations from healthy controls were most pronounced in the CFRD group and are similar to those seen in patients suffering from type 1 or type 2 diabetes.

Transcutaneous Osseointegrated Prosthesis Systems (TOPS) for Rehabilitation After Lower Limb Loss: Surgical Pearls.

Background: The biology of osseointegration of any intramedullary implant depends on the design, the press-fit anchoring, and the loading history of the endoprosthesis. In particular, the material and surface of the endoprosthetic stem are designed to stimulate on- and in-growth of bone as the prerequisite for stable and long-lasting integration1-8. Relative movement between a metal stem and the bone wall may stimulate the formation of a connective-tissue interface, thereby increasing the risk of peri-implant infections and implant loss9-12. The maximum achievable press-fit (i.e., the force closure between the implant and bone wall) depends on the diameter and length of the residual bone and thus on the amputation level. Beyond this, the skin-penetrating connector creates specific medical and biological challenges, especially the risk of ascending intramedullary infections. On the one hand, bacterial colonization of the skin-penetrating area (i.e., the stoma) with a gram-positive taxon is obligatory and almost impossible to avoid9,10. On the other hand, a direct structural and functional connection between the osseous tissue and the implant, without intervening connective tissue, has been shown to be a key for infection-free osseointegration11,12. Description: We present a 2-step implantation process for the standard Endo-Fix Stem (ESKA Orthopaedic Handels) into the residual femur and describe the osseointegration of the prosthesis13. In addition, we demonstrate the single-step implantation of a custom-made short femoral implant and a custom-made humeral BADAL X implant (OTN Implants) in a patient who experienced a high-voltage injury with the loss of both arms and the left thigh. Apart from the standard preparation procedures (e.g., marking the lines for skin incisions, preparation of the distal part of the residual bone), special attention must be paid when performing the operative steps that are crucial for successful osseointegration and utilization of the prosthesis. These include shortening of the residual bone to the desired length, preparation of the intramedullary cavity for hosting of the prosthetic stem, precise trimming of the soft tissue, and wound closure. Finally, we discuss the similarities and differences between the Endo-Fix Stem and the BADAL X implant in terms of their properties, intramedullary positioning, and the mechanisms leading to successful osseointegration. Alternatives: Socket prostheses for transfemoral or transtibial amputees have been the gold standard for decades. However, such patients face many challenges to recover autonomous mobility, and an estimated 30% of all amputees report unsatisfactory rehabilitation and 10% cannot use a socket prosthesis at all. Rationale: Transcutaneous osseointegrated prosthetic systems especially benefit patients who are unable to tolerate socket suspension systems, such as those with short residual limbs and/or bilateral limb loss. The use of a firmly integrated endoprosthetic stem allows patients and surgeons to avoid many of the limitations associated with conventional socket prostheses, such as the need to continually fit and refit the socket to match an ever-changing stump6,14-19. Discussion between patients who are considering an osseointegrated prosthesis and those who have already received one ("peer patients") has proven to be a powerful tool to prevent unrealistic expectations. Patients with a transhumeral amputation especially benefit from the stable connection between the residual limb and exoprosthesis. Motion of the affected and even the contralateral shoulder is no longer impaired, as straps and belts are dispensable. Furthermore, transmission of myoelectric signals from surrounding muscles to the prosthesis is fundamentally improved. However, comorbidities such as diabetes mellitus or peripheral arterial disease require careful counseling, even if these conditions were not responsible for the loss of the limb. Transcutaneous osseointegrated prosthetic systems for replacement of an upper or lower limb might not be an option in patients who are unable, for any reason, to take adequate care of the stoma. Expected Outcomes: Despite subtle differences between the systems utilized for the intramedullary anchoring of the prosthetic stem, all data indicate that mobility and quality of life significantly increase while the frequency of stoma infections is remarkably low as long as the patient is able to follow simple postoperative care protocols2-5,9,10,13-19. Important Tips: The impaction pressure of the implant depends on the diameter of the implant and the quality of the residual bone (i.e., the time interval between the amputation and the implantation of the prosthetic stem). The extent of reaming of the inner cortex of the residual bone must be adapted to these conditions. The standard Endo-Fix Stem and BADAL X implant are both slightly curved to adapt to the physiological shape of the femur. Thus, the surgeon must be sure to insert the implant in the right position and at the correct rotational alignment. When preparing a short femoral stump, carefully identify the exact transection level in order to obtain enough bone stock to anchor the implant in the correct intramedullary position for an additional locking screw into the femoral neck and head. Depending on the residual length of the humerus and the press-fit stability of the implant, the utilization of locking screws is optional, as a notch at the distal end of the implant guarantees primary rotational stability. Acronyms and Abbreviations: TOPS = transcutaneous osseointegrated prosthesis systemsEEP = endo-exo prosthesisMRSA = methicillin-resistant staphylococcus aureusa.p. = anteroposteriorK-wire = Kirschner wireCT = computed tomographyDCA = double conus adapterOFP = osseointegrated femur prosthesis.

Functional assessment and outcome following surgical treatment of displaced tibial plateau fractures: a retrospective analysis.

PURPOSE: Patients with tibial plateau fractures (TPF) are at risk of long-term hampered bipedal locomotion. A retrospective single-center study using patient-related outcome measures and a sophisticated assessment of walking abilities was conducted. METHODS: Adults receiving surgical treatment of an isolated TPF between January 2012 and December 2016 received the KOOS questionnaire together with the invitation for an extensive follow-up examination on the clinical outcome including standardized assessment of the walking abilities (loadsol® system). Outcome was assessed relative to the severity of the injury or time to follow-up. Fractures were classified according to AO/OTA and Luo, respectively. RESULTS: 58 out of 132 eligible patients filled in the questionnaire and participated at a median follow-up of 3.05 years after injury. For the categories "pain", "mobility", and "daily life activities", all patients were rather satisfied and this was virtually not related to the time between fracture and assessment. Relevant limitations were reported for "sports and recreational activities" and "quality of life". Loading of the previously fractured leg was most evidently changed on stairs and outdoor walking. Outcome was not related to either fracture type severity or time from injury. CONCLUSION: Outcome after an isolated TPF is neither related to fracture type, severity of the fracture nor time from injury. Simple gait analysis techniques relying on different tasks appear to yield a more sophisticated image on functional deficits after TPF than classical exam of ground-level walking and correlate quite well with validated patient-related outcome measures as the KOOS.

Effects of prenatal Doppler ultrasound on the retina of the chick embryo in ovo.

Currently, the effect of prenatal ultrasound on foetal development is intensively discussed and the guidelines for prenatal diagnostics have been changed. However, data supporting these concerns are scarce. Therefore, we used an established in ovo model of the chicken embryo to investigate cell proliferation and apoptosis within the retina. A total of 21 chicken eggs were fenestrated on Day 5 and allocated to either the control (n = 8) or exposition group (n = 13). The exposition group was treated with pulsed-wave Doppler ultrasound (PWD) for 10 min while controls remained without treatment. After subsequent incubation (6-48 h), the eggs were sacrificed, and chicken embryos were examined morphologically (HE-staining) and immunohistochemically. Counting of apoptotic and proliferating cells per retina was performed using antibodies specific for phospho-histone-H3 and active caspase-3 in combination with a biotin-labelled secondary antibody and peroxidase conjugated avidin-biotin complex for chromogenic detection. Due to a rather low number of specimens at each time point after ultrasound exposition, we neglected the effects of incubation time and focused on treatment effects. This approach revealed that the median number of proliferating cells is reduced after 10 min of exposure to PWD (569 vs. 766), while the number of apoptotic cells is fairly comparable between groups (5 vs. 6). Our data contribute to a better understanding of prenatal US on foetal development by suggesting that PWD could have an impact on the number of proliferating cells in the developing chicken retina and therefore justify further investigations.

Development of a testing device for external wrist bridging dynamic fixators used for distal radius fractures.

BACKGROUND: Stabilization of extra-articular distal radius fractures by wrist joint bridging (WB) dynamic fixation allows for early motion of the wrist, but relies on exact positioning of the device. In fact, physiological movement appeared to be compromised with even distinctly aberrant positioning of such device. To investigate this issue in more detail, we developed an in-vitro testing apparatus suitable for assessing the forces required for flexion and extension of the wrist. METHODS: The experimental set-up enables the transmission of the translational movement of the traverse of a universal testing machine into the main physiological movement (flexion and extension) of the wrist. An external WB dynamic fixator was assembled to an artificial saw bone wrist model prior and after performing a wedge-shaped osteotomy on the distal radius about 1.5 cm proximal to the joint line, i.e. generation of a fracture model. The functionality of the fixator was evaluated under either condition and the effect of misalignment of the external WB dynamic fixator was quantified by purposeful violation of the manufacture's instructions. Results were statistically analyzed using the generalized linear mixed model. FINDINGS: Significantly higher loading was noted as the degree of misalignment increased. The normalized force was significantly higher at a misalignment of 20° compared to 10° (10°: 4.13; 20°: 6.93, P < 0.001). INTERPRETATION: The proposed set-up turned out to allow highly reproducible and sensitive recording of the reaction forces during flexion and extension of the wrist and thus is feasible for the evaluation and comparison of different external WB devices.

[Functional rehabilitation after transfemoral amputation : Shaft prosthesis or endo-exo prosthesis?] / Funktionelle Rehabilitation nach Oberschenkelamputation : Schaftprothese oder Endo-Exo-Prothese?

BACKGROUND: After transfemoral amputation a prosthesis is required to restore autonomous standing and bipedal locomotion. Attachment of the prosthesis can be achieved either classically via socket suspension with a shaft in the stump or directly via implantation of an intramedullary transcutaneous femoral prosthesis (osseointegrated prosthesis). AIM: A fully instrumented gait analysis should enable objectification of the anticipated advantages of the EEP with respect to the gait pattern and individual mobility. MATERIAL AND METHODS: In two patients with a unilateral transfemoral amputation a comprehensive gait analysis was carried out prior to and 6 months (patient 1) or 11 and 20 months (patient 2) after switching from a socket prosthesis to an EEP. This was carried out in the Gait Realtime Analysis Interactive Lab (GRAIL), a fully instrumented gait laboratory with virtual reality and enables assessment close to the conditions of daily life. RESULTS: In both cases the gait analysis confirmed the advantages associated with an EEP for the transmission of force to the prosthesis and the accompanying improvement in gait symmetry.

Influence of the flexor digitorum superficialis tendon transfer on grip strength.

The flexor digitorum superficialis tendon of the ring finger can be transferred to the thumb flexor. We followed ten patients after such a transfer for 5-128 months and measured grip strength and force transmission of the fingers and individual phalanges while the patients gripped 10-cm or 20-cm diameter cylinders. The grip strength of the middle, ring and little fingers was reduced when gripping the 10-cm cylinder, with a significantly larger decrease in the ring finger. With the 20-cm cylinder, grip forces of all fingers were almost identical, with slightly lower force of the ring finger and slightly higher forces in the index and small fingers. We conclude that after transfer of flexor digitorum superficialis tendon from a ring finger, grip strength of the ring finger is reduced. Finger forces are more hampered while gripping objects with smaller circumferences than large ones.

Determining the optimal cholecalciferol dosing regimen in children with CKD: a randomized controlled trial.

BACKGROUND: The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2-4. METHODS: An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment. RESULTS: Ninety children were randomized to daily (n = 30), weekly (n = 29) or monthly (n = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity. CONCLUSION: Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease.

Treatment of perioperative swelling by rest, ice, compression, and elevation (RICE) without and with additional application of negative pressure (RICE+) in patients with a unilateral ankle fracture: study protocol for a monocentric, evaluator-blinded randomized controlled pilot trial.

BACKGROUND: Edema is commonly seen after surgical fixation of ankle fractures. Rest, ice, compression, and elevation (RICE) is an established combination to prevent swelling but hardly able to stimulate lymphatic resorption. Recently, an epicutaneously applied negative pressure suction apparatus (LymphaTouch®) has been introduced to stimulate lymphatic flow. While postoperative recovery, soft tissue, and osseous healing as well as functional outcome are probably linked to the amount of postoperative swelling, estimates on this relative to prevention (RICE) or prevention + stimulated resorption (RICE+) of fluid are scarce. METHODS AND ANALYSIS: This is a single-center, evaluator-blinded randomized pilot trial to investigate postoperative swelling in adults requiring surgical fixation of a closed unilateral ankle fracture. A total of 50 patients will be recruited and randomly assigned to RICE or RICE+ prior to surgery. All patients will undergo evaluator-blinded measurements of the ankle volume the day before surgery and subsequently from the evening of the 2nd postoperative day every 24 h until discharge. RICE will be initiated right after surgery and continued until discharge from the hospital in all patients. Additional application of negative pressure therapy (RICE+) will be initiated on the morning of the 2nd postoperative day and repeated every 24 h until the time of discharge from the hospital. Outcome measures are (i) the relative amount and the time course of the postoperative swelling, (ii) the demand for analgesic therapy (type and amount) together with the perception of pain, (iii) the rate of complications, and (iv) mobility of the ankle joint and the recovery of walking abilities during a 12-weeks follow-up period. Serum and urine samples taken prior to sugery and during postoperative recovery will allow to evaluate the ratio of naturally occurring stable calcium isotopes (δ44/42Ca) as a marker of skeletal calcium accrual. ETHICS AND DISSEMINATION: The protocol was approved by the institutional Ethics Committee (Rostock University Medical Center, Rostock, Germany) in accordance with the Declaration of Helsinki (approval number: A 2020-0092). The results of this study will be actively disseminated through scientific publications and conference presentations. TRIAL REGISTRATION: DRKS, DRKS00023739 . Registered on 14 December 2020.

MATLAB-based tools for automated processing of motion tracking data provided by the GRAIL.

BACKGROUND: The ability for independent bipedal locomotion is an important prerequisite for autonomous mobility and participation in everyday life. Walking requires not only a functional musculoskeletal unit but relies on coordinated activation of muscles and may even require cognitive resources. The time-resolved monitoring of the position of joints, feet, legs and other body segments relative to each other alone or in combination with simultaneous recording of ground reaction forces and concurrent measurement of electrical muscle activity, using surface electromyography, are well-established tools for the objective assessment of gait. RESEARCH QUESTION: The Gait Real-time Analysis Interactive Lab (GRAIL) has been introduced for gait analysis in a highly standardized and well-controlled virtual environment. However, apart from high computing capacity and sophisticated software required to run the system, handling of GRAIL data is challenging due to the utilization of different software packages resulting in a huge amount of data stored using different file formats and different sampling rates. These issues make gait analysis even with such a sophisticated instrument rather tedious, especially within the frame of an experimental or clinical study. METHODS: A user-friendly Matlab based toolset for automated processing of motion capturing data recorded using the GRAIL, with the inherent option for batch analysis was developed. RESULTS: The toolset allows the reading, resampling, filtering and synchronization of data stored in different input files recorded with the GRAIL. It includes a coordinate-based algorithm for the detection of initial contact and toe-off events to split and normalize data relative to gait cycles. Batch processing of multiple measurements and automatic detection of outliers is possible. SIGNIFICANCE: The authors hope that the toolset will be useful to the research community and invite everyone to use, modify or implement it in their own work.

Dynamic Manugraphy as a Promising Tool to Assess the Outcome of Limited Aponeurectomy in Patients With Dupuytren's Contracture.

Background: Dupuytren's contractures interfere with physiological gripping. While limited aponeurectomy is an accepted treatment modality to restore finger mobility, methods to objectify functional outcome beyond determination of the range of motion are scarce. Methods: Patients with Dupuytren's contracture being scheduled for unilateral limited aponeurectomy were invited to participate. Clinical data were gathered prospectively by chart review and interview. The DASH-score and flexion contracture for fingers were registered prior to surgery, 3 and 6 months afterwards. At the same time, dynamic manugraphy for simultaneous recording of the grip pattern and forces generated by the affected hand and anatomic areas (i.e., thumb, index finger, middle finger, ring finger, little finger and palm) were performed. All findings obtained during the follow-up period were compared to the situation at baseline. Comparison between paired samples was done using Wilcoxon rank test. All p-values are two-sided and p < 0.05 was considered to be significant. Results: Out of 23 consecutively enrolled patients, 19 (15 men, 4 women) completed follow-up examinations. Manugraphy confirmed the impairment of physiological gripping with concomitant pathological load distribution at base line. Limited aponeurectomy significantly reduced flexion contractures. However, the DASH-score remained at an excellent level in one patient, indicated improvement in 11 and worsening in seven patients. Six patients had lower grip force at t6 compared to the preoperative condition, although the preoperative flexion contracture (≥110°) was considerably improved in all of them. In four of those, the DASH-score improved while it turned worse in two of them. The force of surgically treated fingers remained unchanged in three patients while it was improved and worsened in half of the remaining patients, respectively. Manugraphy revealed physiological gripping by enlargement of contact area and higher force transmission by the fingertips in 10 of 12 patients with constant or even improved DASH-score and in three of seven patients with a worsened DASH-score. Conclusions: Assessing the reduction of flexion contracture and grip force alone is not sufficient to comprehensively reflect the functional outcome of aponeurectomy for Dupuytren's disease. Visualizing physiological grip pattern provides an additional tool to objectify the success of surgical treatment.

Evaluation of fetuin-A as a predictor of outcome after surgery for osteoporotic fracture of the proximal femur.

BACKGROUND: In the elderly, osteoporotic fractures of the femur are associated with high morbidity and mortality. At the time of hospitalization and during pre-operative care identification of patients at risk for poor outcome despite an otherwise good clinical condition is challenging. We hypothesized that the serum concentration of fetuin-A during post-operative recovery might serve as a biomarker. METHODS: During a 15 months period patients admitted to our hospital for treatment of a femur fracture were registered on a voluntary basis and irrespective of age, underlying diseases and therapy. For all patients enrolled in this registry, blood was sampled for additional laboratory analysis. Patients with osteoporotic fractures were invited for follow-up examination about 2 years later. At this time, the functional outcome and clinical performance together with the handgrip strength as a surrogate measure of overall strength were assessed and the occurrence of additional fractures was recorded. Results from these assessments and the absence or presence of subsequent fractures were combined as summary score of outcome (SSO) and overall physical performance (oPP), a score derived by principal component analysis and relying on normally distributed data, only. RESULTS: 39 of 96 eligible patients were deceased during the follow-up period, while 45 consented to participate in the study. Patients with a SSO ≥ 17 pts were younger and had higher fetuin-A serum concentrations (each p < 0.05) during hospitalization compared to those with a SSO below 8 pts. Age at follow-up together with total serum protein and fetuin-A levels during post-operative recovery had significant influence on SSO and oPP. Fetuin-A at time of follow-up examination was not associated with outcome. CONCLUSIONS: Our results are in favor of fetuin-A as an important factor for fracture healing but do not support an association between fetuin-A at time of follow-up examination and either SSO or oPP.

Exhaled nitric oxide can't replace the methacholine challenge in suspected pediatric asthma.

BACKGROUND: In adults, measurement of FENO has been recently suggested as a substitute for the methacholine challenge test (MCT) for diagnosis of asthma. This study aimed to evaluate whether FeNO is a substitute for MCH also in children with suspicious asthma. METHODS: During a single visit steroid naive children (5-17 years) with suspicious asthma underwent skin prick test (SPT), FENO measurement and spirometry prior and during MCT (one concentration procedure). Results of the SPT (atopy/non-atopy) and MCT (asthma/non-asthma) were used for categorization. ROC analysis in atopy non-atopy subgroups yielded sensitivity, specificity, positive and negative predictive value (PPV and NPV) for FENO. RESULTS: The SPT revealed atopy in 134 out of 222 children (age 9.7 ±â€¯3.2 years) investigated and asthma was diagnosed in 114 (77/37 atopy/non-atopy) patients. FENO values in patients with atopic asthma were significantly higher compared to those with either non-atopic asthma or atopia without asthma (18 ppb (5-89) vs 7 ppb (5-36); p < 0.001; 18 ppb (5-89) vs 11 ppb (5-98); p < 0.05). Sensitivity and specificity of FENO for diagnosing atopic asthma (FENO≥15.5 ppb; AUC = 0.635, p < 0.01) were 61.1% and 64.9% and non-atopic asthma (FENO≥ 6.5 ppb; AUC = 0.445, p = 0.382) 54.1% and 39.2%, respectively. The PPV/NPV for FENO were 0.70/0.55 in atopy and 0.39/0.54 in non-atopy patients, respectively. CONCLUSION: In children, FENO is not appropriate to substitute for the MCT. However, in patients with a negative SPT a FENO in the normal range makes the presence of atopic asthma unlikely.

Growth factor-mediated augmentation of long bones: evaluation of a BMP-7 loaded thermoresponsive hydrogel in a murine femoral intramedullary injection model.

BACKGROUND: Due to our aging population, an increase in proximal femur fractures can be expected, which is associated with impaired activities of daily living and a high risk of mortality. These patients are also at a high risk to suffer a secondary osteoporosis-related fracture on the contralateral hip. In this context, growth factors could open the field for regenerative approaches, as it is known that, i.e., the growth factor BMP-7 (bone morphogenetic protein 7) is a potent stimulator of osteogenesis. Local prophylactic augmentation of the proximal femur with a BMP-7 loaded thermoresponsive hydrogel during index surgery of an osteoporotic fracture could be suitable to reduce the risk of further osteoporosis-associated secondary fractures. The present study therefore aims to test the hypothesis if a BMP-7 augmented hydrogel is an applicable carrier for the augmentation of non-fractured proximal femurs. Furthermore, it needs to be shown that the minimally invasive injection of a hydrogel into the mouse femur is technically feasible. METHODS: In this study, male C57BL/6 mice (n = 36) received a unilateral femoral intramedullary injection of either 100 µl saline, 100 µl 1,4 Butan-Diisocyanat (BDI)-hydrogel, or 100 µl hydrogel loaded with 1 µg of bone morphogenetic protein 7. Mice were sacrificed 4 and 12 weeks later. The femora were submitted to high-resolution X-ray tomography and subsequent histological examination. RESULTS: Analysis of normalized CtBMD (Cortical bone mineral density) as obtained by X-ray micro-computed tomography analysis revealed significant differences depending on the duration of treatment (4 vs 12 weeks; p < 0.05). Furthermore, within different anatomically defined regions of interest, significant associations between normalized TbN (trabecular number) and BV/TV (percent bone volume) were noted. Histology indicated no signs of inflammation and no signs of necrosis and there were no cartilage damages, no new bone formations, or new cartilage tissues, while BMP-7 was readily detectable in all of the samples. CONCLUSIONS: In conclusion, the murine femoral intramedullary injection model appears to be feasible and worth to be used in subsequent studies that are directed to examine the therapeutic potential of BMP-7 loaded BDI-hydrogel. Although we were unable to detect any significant osseous effects arising from the mode or duration of treatment in the present trial, the effect of different concentrations and duration of treatment in an osteoporotic model appears of interest for further experiments to reach translation into clinic and open new strategies of growth factor-mediated augmentation.

Deviation Maps for Understanding Thickness Changes of Inner Retinal Layers in Children with Type 1 Diabetes Mellitus.

Purpose: To analyze the use of deviation maps (DevMs) to understand thickness changes of inner retinal layers in optical coherence tomography (OCT) data. To test a new visual analytics (VA) method with reduced complexity of OCT data analysis by comparing the layer thickness of children with type 1 diabetes mellitus (T1DM) to matched controls. Methods: OCT was performed on unilateral eyes of 26 children with T1DM without diabetic retinopathy and 29 healthy children to obtain macular volume scans. Subsequently, segmented inner retinal layers were analyzed using VA. Deviation maps were generated to readily visualize thickness differences between both groups and to investigate thickness changes of individual patients in relation to the control group. Results: In DevMs of the patient group, the total retina (TR) demonstrated localized, irregular areas of thinning (mean ± standard deviation) involving foveal center, inner macula, and inferior-nasal outer macula (-9.31 ± 1.73 µm; p < 0.05). Similarly, retinal nerve fiber layer showed continuous and localized areas of thinning in both inner and outer macula, extending nasally (-5.45 ± 4.31 µm; p < 0.05). In DevMs of individual patients, the TR and inner retinal layers revealed remarkable changes in thickness that were present between patients at both late and early stages of diabetes. Conclusion: The VA method simplifies the in-depth analysis of OCT volume data from different groups and is effective in detecting retinal thickness changes in children with diabetes. It can be easily adopted in a clinical set-up and intuitively used in complex multidisciplinary studies.

Spectral-Domain Optical Coherence Tomography for Determination of Retinal Thickness in Pediatric Patients with Mild-To-Moderate Chronic Kidney Disease: A Cross-Sectional Study.

OBJECTIVE: Children with chronic kidney diseases (CKD) are at risk for neurological diseases at early adulthood. Spectral-domain optical coherence tomography (SD-OCT) of the retina is especially suitable for determination of intraretinal layer thickness. We wonder whether retinal thinning is already present in pediatric patients with mild-to-moderate CKD. PATIENTS AND METHODS: Children (n = 15; 14.9 ± 2.4 years) with mild-to-moderate CKD (median eGFR of 95ml/min/1.73m2; range: 28-187ml/min/1.73m2) due to glomerulopathy, congenital anomalies of kidney and urinary tract (CAKUT), or haemolytic uremic syndrome (HUS) underwent a detailed ophthalmologic examination including high-resolution SD-OCT. Three OCT scans were obtained from the right eyes of all patients. Within each scan, retinal layers were separated and the mean thickness was determined at the foveal, parafoveal, and perifoveal area. The results were compared to those we obtained previously from healthy children. RESULTS: At the parafoveal area, thickness (median, range) of the total retina (ALL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were reduced compared to healthy volunteers (339µm, (288-361µm) vs. 348µm, (320-385µm); 49.8µm (30.5-56.6µm) vs. 53.5µm (49.5-60.5µm) and 41.0µm (29.4-43.7µm) vs. 43.46µm (39.5-46.3µm); each p < 0.05). The intraretinal thickness measurements at the foveal and perifoveal areas revealed no statistically significant differences between patients and controls. CONCLUSION: Distinct changes within the parafoveal area of the total retina, GCL, and IPL are present in children with mild-to-moderate CKD. Prospective studies are required to assess the clinical significance of our findings.

The corneal subbasal nerve plexus and thickness of the retinal layers in pediatric type 1 diabetes and matched controls.

Optical coherence tomography (OCT) of the retina and corneal confocal laser scanning microscopy (CLSM) of the subbasal nerve plexus (SBP) are noninvasive techniques for quantification of the ocular neurodegenerative changes in individuals with type 1 diabetes mellitus (T1DM). In adult T1DM patients these changes are hardly related to T1DM only. Instead, ageing and/or lifestyle associated comorbidities have to be considered as putative confounding variables. Therefore, we investigated pediatric T1DM patients (n = 28; 14.2 ± 2.51 y; duration of disease: 5.39 ± 4.16 y) without clinical signs of diabetic retina disease, neuropathy, vasculopathy or nephropathy and compared our findings with those obtained in healthy controls (n = 46; 14.8 ± 1.89 y). The SBP was characterized by the averaged length, thickness, and tortuosity of nerve fibers as well as the number of branching and connecting points. OCT was used to determine the total thickness of the retina (ALL) and the thickness of each retinal layer. Both methods revealed signs of early neurodegenerative changes, e.g. thinning of distinct retinal layers at the pericentral ring and shortening of corneal nerve fibers that are already present in pediatric T1DM patients. Standardization of instruments and algorithms are urgently required to enable uniform comparison between different groups and define normative values to introduce in the clinical setting.

Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2-5 and on dialysis.

Vitamin D deficiency is widely prevalent and often severe in children and adults with chronic kidney disease (CKD). Although native vitamin D {25-hydroxyvitamin D [25(OH)D]} is thought to have pleiotropic effects on many organ systems, its skeletal effects have been most widely studied. The 25(OH)D deficiency is causally linked with rickets and fractures in healthy children and those with CKD, contributing to the CKD-mineral and bone disorder (MBD) complex. There are few studies to provide evidence for vitamin D therapy or guidelines for its use in CKD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs have developed recommendations for the evaluation, treatment and prevention of vitamin D deficiency in children with CKD. We present clinical practice recommendations for the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2-5 and on dialysis. A parallel document addresses treatment recommendations for active vitamin D analogue therapy. The WG has performed an extensive literature review to include meta-analyses and randomized controlled trials in healthy children as well as children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system has been used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to individual patient needs as appropriate.

Modified step aerobics training and neuromuscular function in osteoporotic patients: a randomized controlled pilot study.

BACKGROUND: Training programs directed to improve neuromuscular and musculoskeletal function of the legs are scarce with respect to older osteoporotic patients. We hypothesized that a modified step aerobics training program might be suitable for this purpose and performed a randomized controlled pilot study to assess the feasibility of conducting a large study. Here we report on the training-related effects on neuromuscular function of the plantar flexors. PATIENTS AND METHODS: Twenty-seven patients with an age of at least 65 years were enrolled and randomized into control and intervention group. The latter received supervised modified step aerobics training (twice weekly, 1 h per session) over a period of 6 months. At baseline, and after 3 and 6 months neuromuscular function of the plantar flexors, i.e., isometric maximum voluntary torque, rate of torque development and twitch torque parameters were determined in detail in all patients of both groups. RESULTS: Twenty-seven patients (median age 75 years; range 66-84 years) were randomized (control group n = 14; intervention group n = 13). After 3 and 6 months of training, maximum voluntary contraction strength in the intervention group was significantly higher by 7.7 Nm (9.1%; 95% CI 3.3-12.2 Nm, P < 0.01) and 12.4 Nm (14.8%; 95% CI 6.4-18.5 Nm, P < 0.01) compared to controls. These changes were most probably due to neural and muscular adaptations. CONCLUSION: It is worthwhile to investigate efficacy of this training program in a large randomized trial. However, a detailed neuromuscular assessment appears feasible only in a subset of participants.