Mapping the Iceberg of Autonomic Recovery: Mechanistic Underpinnings of Neuromodulation following Spinal Cord Injury

Spinal cord injury leads to disruption in autonomic control resulting in cardiovascular, bowel, and lower urinary tract dysfunctions, all of which significantly reduce health-related quality of life. Although spinal cord stimulation shows promise for promoting autonomic recovery, the underlying mechanisms are unclear. Based on current preclinical and clinical evidence, this narrative review provides the most plausible mechanisms underlying the effects of spinal cord stimulation for autonomic recovery, including activation of the somatoautonomic reflex and induction of neuroplastic changes in the spinal cord. Areas where evidence is limited are highlighted in an effort to guide the scientific community to further explore these mechanisms and advance the clinical translation of spinal cord stimulation for autonomic recovery

,Anders als alle anderen Egils sagas‘: Zum Konnex von Einzelverfasserschaft und anderer Ästhetik im spätvormodernen Island

In the long-lasting Icelandic manuscript culture, the production and reception of sagas was situated in a narrative tradition characterised by the absence of notions of an author genius and a high degree of mouvance and variance: from the 13th to the 19th century Icelandic saga literature was transmitted anony-mously and in handwritten form in ever new retextualisations, accompanied by reiterating changes of medium (oral / written) and genre (prose / verse). It is therefore less the absence than the more or less sudden appearance of attributions of authorship for these kinds of texts in the course of the 18th century that is remarkable in the Icelandic case. In a first generation of Icelandic literary histories and philological treatises in this period, not only new saga narratives, but also new versions of medieval texts were ascribed to individual authors. The identification of text (versions) with authors often came along with negative assessments of the literary quality of these texts. This conjunction indicates that particular texts that do not meet the aesthetic conventions of saga literature were singled out as works of individuals and that identifiable authorship thus reflects notions of aberration from the literary tra-dition in the Icelandic case. The humanistic treatises exhibit at the same time a high awareness of and nuanced terminology for the complex processes of rewriting and plural authorship of the handwritten Icelandic narrative tradition. This chapter will discuss prominent examples of this protophilological discourse as to their reflection of and relation to Icelandic textual and literary culture in the late pre-modern period

Management of uncomplicated UTI in the post-antibiotic era (II): select non-antibiotic approaches

BACKGROUND Given the high frequency of patients presenting with urinary tract infections (UTIs) and the ensuing high degree of antibiotic prescription, UTI is a critical point of intervention for non-antibiotic treatments in order to curb the further development of antimicrobial resistance and provide risk-appropriate care for patients. OBJECTIVES To highlight several select non-antibiotic therapies for the treatment of uncomplicated UTI and relevant indications (prevention, complicated UTI) from recent literature. SOURCES Pubmed, Google Scholar, &clinicaltrials.gov were searched for clinical trials published in the English language corresponding to non-antibiotic treatments for UTI. CONTENT The focus of this narrative review centers on a limited number of non-antibiotic therapies for the treatment of UTI based on (1) herbal extracts or (2) antibacterial strategies (e.g. bacteriophage therapy, D-mannose). The experience of treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is also used to fuel discussion on the risk of developing pyelonephritis without antibiotics - compared to the projected harms of continuing their widespread use. IMPLICATIONS Non-antibiotic treatment strategies for UTI have shown varying results in clinical trials, and the current evidence does not yet indicate a clear, better alternative to antibiotics. However, the collective experience with non-antibiotic treatments suggests there is a need to weigh the actual benefits/risks of unfettered, non-culture confirmed antibiotic use in uUTI. Given the different mechanisms of action of proposed alternatives, more in depth knowledge on microbiological and pathophysiological factors influencing UTI susceptibility and prognostic indicators are highly needed to stratify patients most likely to benefit. The feasibility of alternatives in clinical practice should also be considered

European guidelines for the diagnosis, treatment and follow-up of breast lesions with uncertain malignant potential (B3 lesions) developed jointly by EUSOMA, EUSOBI, ESP (BWG) and ESSO

Introduction: Breast lesions of uncertain malignant potential (B3) include atypical ductal and lobular hyperplasias, lobular carcinoma in situ, flat epithelial atypia, papillary lesions, radial scars and fibroepithelial lesions as well as other rare miscellaneous lesions. They are challenging to categorise histologically, requiring specialist training and multidisciplinary input. They may coexist with in situ or invasive breast cancer (BC) and increase the risk of subsequent BC development. Management should focus on adequate classification and management whilst avoiding overtreatment. The aim of these guidelines is to provide updated information regarding the diagnosis and management of B3 lesions, according to updated literature review evidence. Methods: These guidelines provide practical recommendations which can be applied in clinical practice which include recommendation grade and level of evidence. All sections were written according to an updated literature review and discussed at a consensus meeting. Critical appraisal by the expert writing committee adhered to the 23 items in the international Appraisal of Guidelines, Research and Evaluation (AGREE) tool. Results: Recommendations for further management after core-needle biopsy (CNB) or vacuum-assisted biopsy (VAB) diagnosis of a B3 lesion reported in this guideline, vary depending on the presence of atypia, size of lesion, sampling size, and patient preferences. After CNB or VAB, the option of vacuum-assisted excision or surgical excision should be evaluated by a multidisciplinary team and shared decision-making with the patient is crucial for personalizing further treatment. De-escalation of surgical intervention for B3 breast lesions is ongoing, and the inclusion of vacuum-assisted excision (VAE) will decrease the need for surgical intervention in further approaches. Communication with patients may be different according to histological diagnosis, presence or absence of atypia, or risk of upgrade due to discordant imaging. Written information resources to help patients understand these issues alongside with verbal communication is recommended. Lifestyle interventions have a significant impact on BC incidence so lifestyle interventions need to be suggested to women at increased BC risk as a result of a diagnosis of a B3 lesion. Conclusions: These guidelines provide a state-of-the-art overview of the diagnosis, management and prognosis of B3 lesions in modern multidisciplinary breast practice

The Surgical Algorithm for the AO Spine Sacral Injury Classification System

Study design: Global cross-sectional survey. Objective: To establish a surgical algorithm for sacral fractures based on the AO Spine Sacral Injury Classification System. Summary of background data: Although the AO Spine Sacral Injury Classification has been validated across an international audience of surgeons, a consensus on a surgical algorithm has yet to be developed for sacral fractures by using the Sacral AO Spine Injury Score (Sacral AOSIS). Methods: A survey was sent to general orthopedic surgeons, orthopedic spine surgeons, and neurosurgeons across the five AO Spine regions of the world. Descriptions of controversial sacral injuries based on different fracture subtypes were given and surgeons were asked whether the patient should undergo operative or non-operative management. The results of the survey were used to create a surgical algorithm based on each subtypes' Sacral AOSIS. Results: International agreement of 70% was decided on by the AO Spine Knowledge Forum Trauma experts to indicate a recommendation of initial operative intervention. Using this, sacral fracture subtypes of AOSIS 5 or greater were considered operative while those with AOSIS 4 or less were generally non-operative. For subtypes with an AOSIS of 3 or 4, if the sacral fracture was associated with an anterior pelvic ring injury (M3 case-specific modifier), intervention should be left to the surgeons' discretion. Conclusion: The AO Spine Sacral Injury Classification System offers a validated hierarchical system to approach sacral injuries. Through multi-specialty and global surgeon input, a surgical algorithm was developed to determine appropriate operative indications for sacral trauma. Further validation is required, but this algorithm provides surgeons across the world with the basis for discussion and the development of standard of care treatment. Level of evidence: Level IV

Clinical and radiographic long-term outcome of hemiarthroplasty for complex proximal humerus fractures

BACKGROUND: Hemiarthroplasty (HA) is a treatment option for complex proximal humerus fractures not suitable for conservative treatment or open reduction and internal fixation (ORIF). Long-term outcomes using a large metaphyseal volume prosthesis in the management of fractures of the proximal humerus have not been reported thus far. METHODS: Between 2006 and 2010, 41 patients with a proximal humerus fracture were treated with HA (average age: 62 years: range, 38-85) at our institution. Nine patients underwent revision surgery, three patients were lost to follow-up and seven died unrelated to the index surgery. Twenty-two patients were reviewed clinically and radiographically at a mean period of 10.4 years (range, 9-13 years). RESULTS: Seven out of nine failures of HA occurred within the first 2 postoperative years: 2 infections and 5 greater tuberosity non-/mal-unions. The other two patients underwent revision for rotator cuff deficiency more than 5 years after initial surgery. Of those patients available for final follow-up, the implant survival rate was 71% (22 out of 31 patients). Their mean relative Constant score was 76 % (range, 49-96), the mean active elevation was 116° (range, 60-170) and the mean external rotation was 28° (range, 0-55), at the final follow-up. The majority had a good/excellent internal rotation, with 13 patients (59%) to the 12th thoracic vertebra and 7 patients (31%) to the 8th thoracic vertebra. The mean Subjective Shoulder Value was 76% (range, 40-100). Clinical outcomes did not significantly deteriorate over a period of 10 years, except for flexion (p<0.001) and internal rotation (p=0.002). Analyzing greater tuberosity healing, one patient had a non-union, 10 (45%) had a mal-union, and in 12 patients (55%) the greater tuberosity healed in an anatomical position. Patients with a displaced mal-union of the greater tuberosity did not have inferior clinical results at last follow-up. Only two patients showed glenoid erosion and in no patient stem loosening could be identified at the final follow-up. CONCLUSION: The revision rate following large metaphyseal volume HA to treat a proximal humerus fracture was 29% after 10 years postoperatively, with failure within 2 years largely related to greater tuberosity non-/mal-union and later related to rotator cuff insufficiency. Patients with a retained implant showed good clinical and radiographic long-term results, without relevant deterioration over time even when the greater tuberosity healed in a non-anatomical position

Concentration-effect relationships of plasma caffeine on EEG delta power and cardiac autonomic activity during human sleep

Acute caffeine intake affects brain and cardiovascular physiology, yet the concentration-effect relationships on the electroencephalogram and cardiac autonomic activity during sleep are poorly understood. To tackle this question, we simultaneously quantified the plasma caffeine concentration with ultra-high-performance liquid chromatography, as well as the electroencephalogram, heart rate and high-frequency (0.15-0.4 Hz) spectral power in heart rate variability, representing parasympathetic activity, with standard polysomnography during undisturbed human sleep. Twenty-one healthy young men in randomized, double-blind, crossover fashion, ingested 160 mg caffeine or placebo in a delayed, pulsatile-release caffeine formula at their habitual bedtime, and initiated a 4-hr sleep opportunity 4.5 hr later. The mean caffeine levels during sleep exhibited high individual variability between 0.2 and 18.4 μmol L$^{-1}$ . Across the first two non-rapid-eye-movement (NREM)-rapid-eye-movement sleep cycles, electroencephalogram delta (0.75-2.5 Hz) activity and heart rate were reliably modulated by waking and sleep states. Caffeine dose-dependently reduced delta activity and heart rate, and increased high-frequency heart rate variability in NREM sleep when compared with placebo. The average reduction in heart rate equalled 3.24 ± 0.77 beats per minute. Non-linear statistical models suggest that caffeine levels above ~7.4 μmol L$^{-1}$ decreased electroencephalogram delta activity, whereas concentrations above ~4.3 μmol L$^{-1}$ and ~ 4.9 μmol L$^{-1}$ , respectively, reduced heart rate and increased high-frequency heart rate variability. These findings provide quantitative concentration-effect relationships of caffeine, electroencephalogram delta power and cardiac autonomic activity, and suggest increased parasympathetic activity during sleep after intake of caffeine

Pulmonary hemodynamics before and after pediatric heart transplantation

BACKGROUND Pulmonary hypertension (PH) may limit the outcome of pediatric heart transplantation (pHTx). We evaluated pulmonary hemodynamics in children undergoing pHTx. METHODS Cross-sectional, single-center, observational study analyzing pulmonary hemodynamics in children undergoing pHTx. RESULTS Twenty-three children (female 15) underwent pHTx at median (IQR) age of 3.9 (.9-8.2) years with a time interval between first clinical signs and pHTx of 1.1 (.4-3.2) years. Indications for pHTx included cardiomyopathy (CMP) (n = 17, 74%), congenital heart disease (CHD) (n = 5, 22%), and intracardiac tumor (n = 1, 4%). Before pHTx, pulmonary hemodynamics included elevated pulmonary artery pressure (PAP) 26 (18.5-30) mmHg, pulmonary capillary wedge pressure (PCWP) 19 (14-21) mmHg, left ventricular enddiastolic pressure (LVEDP) 17 (13-22) mmHg. Transpulmonary pressure gradient (TPG) was 6.5 (3.5-10) mmHg and pulmonary vascular resistance (Rp) 2.65 WU*m$^{2}$ (1.87-3.19). After pHTx, at immediate evaluation 2 weeks after pHTx PAP decreased to 20.5 (17-24) mmHg, PCWP 14.5 (10.5-18) mmHg (p < .05), LVEDP 16 (12.5-18) mmHg, TPG 6.5 (4-12) mmHg, Rp 1.49 (1.08-2.74) WU*m$^{2}$ resp.at last invasive follow up 4.0 (1.4-6) years after pHTx, to PAP 19.5 (17-21) mmHg (p < .05), PCWP 13 (10.5-14.5) mmHg (p < .05), LVEDP 13 (10.5-14) mmHg, TPG 7 (5-9.5) mmHg, Rp 1.58 (1.38-2.19) WU*m$^{2}$ (p < .05). In CHD patients PAP increased (p < .05) after pHTx at immediate evaluation and decreased until last follow-up (p < .05), while in CMP patients there was a continuous decline of mean PAP values immediately after HTx (p < .05). CONCLUSIONS While PH before pHTx is frequent, after pHTx the normalization of PH starts immediately in CMP patients but is delayed in CHD patients