Future emergence of new ecosystems caused by glacial retreat.

Glacier shrinkage and the development of post-glacial ecosystems related to anthropogenic climate change are some of the fastest ongoing ecosystem shifts, with marked ecological and societal cascading consequences1-6. Yet, no complete spatial analysis exists, to our knowledge, to quantify or anticipate this important changeover7,8. Here we show that by 2100, the decline of all glaciers outside the Antarctic and Greenland ice sheets may produce new terrestrial, marine and freshwater ecosystems over an area ranging from the size of Nepal (149,000 ± 55,000 km2) to that of Finland (339,000 ± 99,000 km2). Our analysis shows that the loss of glacier area will range from 22 ± 8% to 51 ± 15%, depending on the climate scenario. In deglaciated areas, the emerging ecosystems will be characterized by extreme to mild ecological conditions, offering refuge for cold-adapted species or favouring primary productivity and generalist species. Exploring the future of glacierized areas highlights the importance of glaciers and emerging post-glacial ecosystems in the face of climate change, biodiversity loss and freshwater scarcity. We find that less than half of glacial areas are located in protected areas. Echoing the recent United Nations resolution declaring 2025 as the International Year of Glaciers' Preservation9 and the Global Biodiversity Framework10, we emphasize the need to urgently and simultaneously enhance climate-change mitigation and the in situ protection of these ecosystems to secure their existence, functioning and values.

THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT: A NEW TREATMENT OUTCOME AND NATURAL HISTORY REGISTRY FOR INHERITED RETINAL DISEASE.

PURPOSE: To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases (IRDs). METHODS: A core committee of 6 members was convened to oversee the construction of the FIRB! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets via a consensus approach. RESULTS: The web-based FIRB! registry records baseline demographic, clinical and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the FIRB! architecture to standardise nomenclature. The registry software assigns individual diagnoses to one of 7 broad phenotypic groups, with minimum datasets dependent upon the broad phenotypic group. Additionally, minimum datasets were agreed upon for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes. CONCLUSIONS: Fight Inherited Retinal Blindness! (FIRB!) is an organized, web-based system that uses observational study methods to collect uniform data from IRD patients to track natural history and (uniquely) treatment outcomes. It is free to Users, who have control over their data.

Retention Rates of Genetic Therapies Based on AAV Serotypes 2 and 8 Using Different Drug-Delivery Materials.

The purpose of this study was to compare the retention rate of Adeno-associated viral vector (AAV) gene therapy agents within different subretinal injection systems. The retention of AAV serotype 2-based voretigene neparvovec (VN) and a clinical-grade AAV serotype 8 vector within four different subretinal cannulas from two different manufacturers was quantified. A standardized qPCR using the universal inverted terminal repeats as a target sequence was developed. The instruments compared were the PolyTip® cannula 25 g/38 g by MedOne Surgical, Inc., Sarasota, FL, USA, and three different subretinal injection needles by DORC, Zuidland, The Netherlands (1270.EXT Extendible 41G subretinal injection needle (23G), DORC 1270.06 23G Dual bore injection cannula, DORC 27G Subretinal injection cannula). The retention rate of VN and within the DORC products (10-28%) was comparable to the retention rate (32%) found for the PolyTip® cannula that is mentioned in the FDA-approved prescribing information for VN. For the AAV8 vector, the PolyTip® cannula showed a retention rate of 14%, and a similar retention rate of 3-16% was found for the DORC products (test-retest variability: mean 4.5%, range 2.5-20.2%). As all the instruments tested showed comparable retention rates, they seem to be equally compatible with AAV2- and AAV8-based gene therapy agents.

Choroideremia: The Endpoint Endgame.

Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.

Unveiling Unequivocal Charge Stripe Order in a Prototypical Cuprate Superconductor.

In the cuprates, high-temperature superconductivity, spin-density-wave order, and charge-density-wave (CDW) order are intertwined, and symmetry determination is challenging due to domain formation. We investigated the CDW in the prototypical cuprate La_{1.88}Sr_{0.12}CuO_{4} via x-ray diffraction employing uniaxial pressure as a domain-selective stimulus to establish the unidirectional nature of the CDW unambiguously. A fivefold enhancement of the CDW amplitude is found when homogeneous superconductivity is partially suppressed by magnetic field. This field-induced state provides an ideal search environment for a putative pair-density-wave state.

The EANM guideline for radiosynoviorthesis.

PURPOSE: Radiosynoviorthesis (RSO) using the intraarticular application of beta-particle emitting radiocolloids has for decades been used for the local treatment of inflammatory joint diseases. The injected radiopharmaceuticals are phagocytized by the superficial macrophages of the synovial membrane, resulting in sclerosis and fibrosis of the formerly inflamed tissue, finally leading to reduced joint effusion and alleviation of joint pain. METHODS: The European Association of Nuclear Medicine (EANM) has written and approved these guidelines in tight collaboration with an international team of clinical experts, including rheumatologists. Besides clinical and procedural aspects, different national legislative issues, dosimetric considerations, possible complications, and side effects are addressed. CONCLUSION: These guidelines will assist nuclear medicine physicians in performing radiosynoviorthesis. Since there are differences regarding the radiopharmaceuticals approved for RSO and the official indications between several European countries, this guideline can only give a framework that must be adopted individually.

Gene therapy for inherited retinal disease: long-term durability of effect.

The recent approval of voretigene neparvovec (Luxturna®) for patients with biallelic RPE65 mutation-associated inherited retinal dystrophy with viable retinal cells represents an important step in the development of ocular gene therapies. Herein, we review studies investigating the episomal persistence of different recombinant adeno-associated virus (rAAV) vector genomes and the pre-clinical and clinical evidence of long-term effects of different RPE65 gene replacement therapies. A targeted review of articles published between 1974 and January 2021 in Medline®, Embase®, and other databases, was conducted, followed by a descriptive longitudinal analysis of the clinical trial outcomes of voretigene neparvovec. Following an initial screening, 14 publications examining the episomal persistence of different rAAV genomes and 71 publications evaluating gene therapies in animal models were included. Viral genomes were found to persist for at least 22 months (longest study follow-up) as transcriptionally active episomes. Treatment effects lasting almost a decade were reported in canine disease models, with more pronounced effects the earlier the intervention. The clinical trial outcomes of voretigene neparvovec are consistent with pre-clinical findings and reveal sustained results for up to 7.5 years for the full-field light sensitivity threshold test and 5 years for the multi-luminance mobility test in the Phase I and Phase III trials, respectively. In conclusion, the therapeutic effect of voretigene neparvovec lasts for at least a decade in animal models and 7.5 years in human subjects. Since retinal cells can retain functionality over their lifetime after transduction, these effects may be expected to last even longer in patients with a sufficient number of outer retinal cells at the time of intervention.

National strategy for palliative care of severely ill and dying people and their relatives in pandemics (PallPan) in Germany - study protocol of a mixed-methods project.

BACKGROUND: In the SARS-CoV-2 pandemic, general and specialist Palliative Care (PC) plays an essential role in health care, contributing to symptom control, psycho-social support, and providing support in complex decision making. Numbers of COVID-19 related deaths have recently increased demanding more palliative care input. Also, the pandemic impacts on palliative care for non-COVID-19 patients. Strategies on the care for seriously ill and dying people in pandemic times are lacking. Therefore, the program 'Palliative care in Pandemics' (PallPan) aims to develop and consent a national pandemic plan for the care of seriously ill and dying adults and their informal carers in pandemics including (a) guidance for generalist and specialist palliative care of patients with and without SARS-CoV-2 infections on the micro, meso and macro level, (b) collection and development of information material for an online platform, and (c) identification of variables and research questions on palliative care in pandemics for the national pandemic cohort network (NAPKON). METHODS: Mixed-methods project including ten work packages conducting (online) surveys and qualitative interviews to explore and describe i) experiences and burden of patients (with/without SARS-CoV-2 infection) and their relatives, ii) experiences, challenges and potential solutions of health care professionals, stakeholders and decision makers during the SARS-CoV-2 pandemic. The work package results inform the development of a consensus-based guidance. In addition, best practice examples and relevant literature will be collected and variables for data collection identified. DISCUSSION: For a future "pandemic preparedness" national and international recommendations and concepts for the care of severely ill and dying people are necessary considering both generalist and specialist palliative care in the home care and inpatient setting.

The COVID-19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers.

BACKGROUND: The world has suffered immeasurably during the COVID-19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. METHODS: The University of Pennsylvania COVID-19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. RESULTS: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID-19 had the highest average endorsed worry, whilst currently having COVID-19 had the lowest rated worry. Total COVID-19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID-19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID-19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. CONCLUSIONS: Widespread medical care disruptions and pandemic-related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long-term effects of COVID-19 worries, interruptions to care and hospital avoidance require further study.

Primary stability of single-stage revision reconstruction of the anterior cruciate ligament in case of failure of dynamic intraligamentary stabilization depends on implant position during ACL repair.

INTRODUCTION: The object of this study was to evaluate the primary stability of tibial interference screw (IFS) fixation in single-stage revision surgery of the anterior cruciate ligament (ACL) in the case of recurrent instability after ACL repair with dynamic intraligamentary stabilization (DIS), dependent on the implant position during DIS. MATERIALS AND METHODS: Tibial aperture fixation in ACL reconstruction (ACL-R) was performed in a porcine knee model using an IFS. Native ACL-R was performed in the control group (n = 15). In the intervention groups DIS and subsequent implant removal were performed prior to single-stage revision ACL-R. A distance of 20 mm in group R-DIS1 (n = 15) and 5 mm in group R-DIS2 (n = 15) was left between the joint line and the implant during DIS. Specimens were mounted in a material-testing machine and load-to-failure was applied in a worst-case-scenario. RESULTS: Load to failure was 454 ± 111 N in the R-DIS1 group, 154 ± 71 N in the R-DIS2 group and 405 ± 105 N in the primary ACL-R group. Load-to-failure, stiffness and elongation of the group R-DIS2 were significantly inferior in comparison to R-DIS1 and ACL-R respectively (p < 0.001). No significant difference was found between load-to-failure, stiffness and elongation of R-DIS1 and the control group. CONCLUSION: Primary stability of tibial aperture fixation in single-stage revision ACL-R in case of recurrent instability after DIS depends on monobloc position during ACL repair. Primary stability is comparable to aperture fixation in primary ACL-R, if a bone stock of 20 mm is left between the monobloc and the tibial joint line during the initial procedure.

Benefits and Shortcomings of Laboratory Model Systems in the Development of Genetic Therapies.

Gene therapeutic approaches promise treatment or even a cure of diseases that were previously untreatable. Retinal gene therapies tested in clinical trials comprise a wide range of different strategies, including gene supplementation therapies, in vivo gene editing, modulation of splicing mechanisms, or the suppression of gene expression. To guarantee efficient transfer of genetic material into the respective target cells while avoiding major adverse effects, the development of genetic therapies requires appropriate in vitro model systems that allow tests of efficacy and safety of the gene therapeutic approach. In this review, we introduce various in vitro models of different levels of complexity used in the development of genetic therapies and discuss their respective benefits and shortcomings using the example of adeno-associated virus-based retinal gene therapy.

Challenges to Gene Editing Approaches in the Retina.

Retinal gene therapy has recently been at the cutting edge of clinical development in the diverse field of genetic therapies. The retina is an attractive target for genetic therapies such as gene editing due to the distinctive anatomical and immunological features of the eye, known as immune privilege, so that inherited retinal diseases (IRDs) have been studied in several clinical studies. Thus, rapid strides are being made toward developing targeted treatments for IRDs. Gene editing in the retina faces a group of heterogenous challenges, including editing efficiencies, off-target effects, the anatomy of the target organ, immune responses, inactivation, and identifying optimal application methods. As clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) based technologies are at the forefront of current gene editing advances, their specific editing efficiency challenges and potential off-target effects were assessed. The immune privilege of the eye reduces the likelihood of systemic immune responses following retinal gene therapy, but possible immune responses must not be discounted. Immune responses to gene editing in the retina may be humoral or cell mediated, with immunologically active cells, including microglia, implicated in facilitating possible immune responses to gene editing. Immunogenicity of gene therapeutics may also lead to the inactivation of edited cells, reducing potential therapeutic benefits. This review outlines the broad spectrum of potential challenges currently facing retinal gene editing, with the goal of facilitating further advances in the safety and efficacy of gene editing therapies.

Importance of Nonhuman Primates as a Model System for Gene Therapy Development in Ophthalmology.

Gene therapy is a treatment concept that uses, in most cases, viral vectors to deliver a therapeutic transgene to target cells. Although the idea of gene therapy dates back over 50 years ago, due to the complexity of the treatment concept, it took until the last decade for the responsible agencies like FDA and EMA to recommend the first gene therapy products for clinical use. The development of these therapies relies on molecular engineering of specifically designed vectors and models to test the effectiveness and safety of the treatment. Despite an increasing effort to find effective surrogates, animal models are still irreplaceable in gene therapy development. Rodents are important for exploring pathways and disease mechanisms and identifying potential treatment targets. However, only the primate eye resembles the human eye to a degree where most structures are nearly identical. Some research questions can therefore only be answered using a nonhuman primate (NHP) model. In this review, we want to summarize these key features and highlight the importance of the NHP model for gene therapy development in ophthalmology.

[Effects of the COVID-19 lockdown on physical performance parameters in professional football]. / Auswirkungen des COVID-19-Lockdowns auf physische Leistungsparameter im professionellen Fußball: Eine narrative Literaturübersicht.

Background: Governmental measures in 2020 to contain the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) brought training and competition in professional soccer to a temporary halt in many countries. As a result of the lockdown, training possibilities were mostly limited to nonspecific home-based training methods. It is unclear whether the lack of sport-specific stimuli led to a reduction in the physical performance of soccer players. Methods: For the narrative review, the PubMed, Google Scholar and BISp-Surf databases were selectively searched for studies examining the effects of the lockdown on physical performance parameters in adult professional soccer players. Results: In this review six prospective longitudinal studies were included. In all studies home-based training was performed during quarantine. Of the studies four compared the performance of the soccer players with data from previous seasons and two studies assessed the performance of players immediately before and after the lockdown period. Discussion: While general strength and endurance performances can be maintained through home-based substitute training programs, the studies indicated that the lack of football-specific stimuli could have an impact on the rapid power and speed performances of soccer players. Progressive loading control especially for speed training should be considered when returning to regular training in order to reduce the risk of injuries.

Mapping tree density at a global scale.

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

Effect of intra-operative intravenous lidocaine on opioid consumption after bariatric surgery: a prospective, randomised, blinded, placebo-controlled study.

Peri-operative lidocaine infusion warrants investigation in bariatric surgery because obese patients present different physiological and pharmacological risks. This single-centre, prospective, randomised double-blind placebo-controlled study enrolled obese patients scheduled for laparoscopic bariatric surgery using an enhanced recovery protocol. Patients received either lidocaine (bolus of 1.5 mg.kg-1 , then a continuous infusion of 2 mg.kg-1 .h-1 until the end of the surgery, then 1 mg.kg-1 .h-1 for 1 h in the recovery area) or identical volumes and rates of 0.9% saline. The primary outcome was the consumption of the equivalent of oxycodone consumption over the first 3 postoperative days. Secondary outcomes were: postoperative pain; incidence of nausea and vomiting; bowel function recovery; and lengths of stay in the recovery area and in hospital. Plasma concentrations of lidocaine were measured. On the 178 patients recruited, data were analysed from 176. The median (IQR [range]) equivalent intravenous oxycodone consumption was 3.3 mg (0.0-6.0 [0.0-14.5]) and 5.0 mg (3.3-7.0 [3.3-20.0]) in the lidocaine and saline groups, respectively (difference between medians (95%CI): 1.7 (0.6-3.4) mg; p = 0.004). Length of stay in the recovery area, postoperative pain, nausea and vomiting, day of recovery of bowel function, and length of stay in hospital were not different between groups. Mean (SD) lidocaine plasma concentrations were 2.44 (0.70) µg.ml-1 and 1.77 (0.51) µg.ml-1 at the end of surgery and 1 hour after the end of infusion, respectively. Lidocaine infusion during bariatric surgery resulted in a clinically non-relevant difference in postoperative oxycodone consumption.

[Perioperative stroke]. / Perioperativer Schlaganfall.

Perioperative stroke is defined as an ischemic cerebrovascular event that occurs during or within 30 days after surgery and is associated with an increased perioperative risk of morbidity and mortality. Depending on the type of surgery stroke is diagnosed in up to 11% of all patients in the perioperative period. Patients with a history of ischemic stroke or transitory ischemic attack have an increased risk for perioperative stroke. Therefore, a critical assessment of indications and the timing of surgery are crucial to prevent recurring stroke in this patient population. Importantly, individualized blood pressure management is essential for optimization of cerebral perfusion during the perioperative period.This article provides a summary of the epidemiology, risk factors, and etiology of perioperative stroke. Moreover, possible preventive strategies relevant for the anesthesiologist are reviewed.

Surgical Aspects in Gene Therapy for Inherited Retinal Diseases. / Chirurgische Aspekte der Gentherapie von Netzhautdystrophien.

Inherited retinal dystrophies (IRD) have been studied since their recognition by Franz Donders and Albrecht von Graefe. It nevertheless took 100 years for a causal therapy to take shape in the form of gene therapy: The approval of Voretigen Neparvovec (VN) for the treatment of hereditary retinal dystrophies due to RPE65 mutations was thus a significant milestone - for the era of personalised medicine in general and ophthalmology in particular. The clinical management around gene therapy applications is complex and requires the cooperation of various experts as a multidisciplinary team. This article describes the requirements, challenges, approaches, and open questions regarding the surgical aspects of gene therapy for retinal dystrophies. The first part outlines the standard surgical treatment. Based on this standard, alternative approaches are indicated for each individual step and their value discussed. Knowledge gaps are defined and in the outlook we speculate on future developments.

Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

BACKGROUND: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. PATIENTS AND METHODS: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. RESULTS: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. CONCLUSION: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS. GOV NUMBER: NCT number 03042429.

Spin-transfer torque generated by a topological insulator.

Magnetic devices are a leading contender for the implementation of memory and logic technologies that are non-volatile, that can scale to high density and high speed, and that do not wear out. However, widespread application of magnetic memory and logic devices will require the development of efficient mechanisms for reorienting their magnetization using the least possible current and power. There has been considerable recent progress in this effort; in particular, it has been discovered that spin-orbit interactions in heavy-metal/ferromagnet bilayers can produce strong current-driven torques on the magnetic layer, via the spin Hall effect in the heavy metal or the Rashba-Edelstein effect in the ferromagnet. In the search for materials to provide even more efficient spin-orbit-induced torques, some proposals have suggested topological insulators, which possess a surface state in which the effects of spin-orbit coupling are maximal in the sense that an electron's spin orientation is fixed relative to its propagation direction. Here we report experiments showing that charge current flowing in-plane in a thin film of the topological insulator bismuth selenide (Bi2Se3) at room temperature can indeed exert a strong spin-transfer torque on an adjacent ferromagnetic permalloy (Ni81Fe19) thin film, with a direction consistent with that expected from the topological surface state. We find that the strength of the torque per unit charge current density in Bi2Se3 is greater than for any source of spin-transfer torque measured so far, even for non-ideal topological insulator films in which the surface states coexist with bulk conduction. Our data suggest that topological insulators could enable very efficient electrical manipulation of magnetic materials at room temperature, for memory and logic applications.