There is currently significant interest in policies, regulations and research aiming to reduce aviation’s climate impact. Here we model the effect of these measures on global warming and perform a bottom-up analysis of potential technical improvements, challenging the assumptions of the targets for the sector with a number of scenarios up to 2100. We show that although the emissions targets for aviation are in line with the overall goals of the Paris Agreement, there is a high likelihood that the climate impact of aviation will not meet these goals. Our assessment includes feasible technological advancements and the availability of sustainable aviation fuels. This conclusion is robust for several COVID-19 recovery scenarios, including changes in travel behaviour.Aviation is an important contributor to the global economy, satisfying society’s mobility needs. It contributes to climate change through CO Aviation contributes to climate change and ways to reduce its emissions are widely debated. Here, the authors assess the effects of technology improvements and the use of sustainable aviation fuels and find that even when these are considered aviation is unlikely to meet emissions goals in line with the Paris Agreement. Without any further specific measures this reduction is expected to continue at a similar rate until 20372 in a business as usual scenario.Fuel efficiency of jet aircraft has been increasing right from the dawn of jet aviation in the late ’50 s and early ’60 s. This improvement cannot be attributed to one single source but has been achieved by a combination of factors such as improvements of the airframe aerodynamics, weight reductions due to better engineering, materials and manufacturing techniques, larger engines with a lower specific thrust, higher overall pressure ratios and component efficiencies, lighter structures and lighter on-board systems. Kharina and Rutherford3 predicts in its Global Market Forecast continued annual growth of 4.4% in revenue passenger kilometre (RPK) for the next two decades. Boeing4 expects in its Commercial Market Outlook an annual growth of 4.6%. The effects of the COVID-19 pandemic are expected to only have a temporary effect on this growth.Air transport as a sector has been growing rapidly in most regions of the world. The total number of passengers transported annually passed 4 billion in 2017. The number of flights in all regions of the world has increased , water vapour (H2O), nitrogen oxides (NOx), sulphate aerosols, compounds from incomplete combustion  and particulates (soot). The emitted species are transported in the atmosphere and alter a wide range of atmospheric processes including the formation of contrail-cirrus and ozone and the depletion of methane9.Approximately 5% of the current anthropogenic climate change is attributed to global aviation12. Contrail-cirrus influence the incoming solar radiation and the outgoing infrared radiation emitted by the Earth and its atmosphere. The net change, the radiative forcing (RF), is on average positive and hence contrail-cirrus act to warm the climate13. The emitted nitrogen oxides (NOx) react with hydroxyl radicals (HOx), which eventually form ozone and contribute to the depletion of methane in the atmosphere. Therefore, emissions of nitrogen oxides increase the ozone concentration and decrease the methane concentration . Ozone and methane are greenhouse gases and changes in their concentrations cause changes in the RF, which are in total positive, i.e. leading to warming15. The net direct impact of aerosol emissions on RF (soot: warming and sulphate: cooling) is small7 and are not further regarded in this study, whereas the impact of soot emissions on contrail-cirrus properties are important16 and considered in our calculations (see ‘Methods’). An open question, which is currently under investigation is whether aerosol emissions significantly alter or even induce natural clouds, both low-level and cirrus clouds17.The formation of persistent contrails-cirrus depends on aircraft and fuel parameters as well as atmospheric conditions, as the propensity of contrail formation is higher in the cold and saturated atmosphere18. Among these targets is a reduction of 75% of CO2 and 90% of NOx emission per passenger-km by 2050. The datum for these reductions is a typical new aircraft in the year 2000. These targets are set for the research, with intended outcomes to be realised at a technological readiness level  of 6.The Advisory Council for Aviation Research and Innovation in Europe (ACARE) has set targets for the reduction of emissions in its Flightpath 2050 document2 emissions from international aviation. This scheme is the Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA). According to this scheme, the post-2020 growth in the sector must be offset such that the net carbon emissions do no longer grow. They must either be reduced via more efficient aircraft and/or the use of SAF or must be compensated via offsets. CORSIA starts as a voluntary pilot scheme in 2021 and becomes mandatory, with some exceptions, in 2027 for all member states19. Aviation is a growing sector that has committed to reduce net CO2 emissions and thus contributes to the international goals of limiting climate warming ‘to well below 2.0° C above preindustrial levels and pursuing efforts to limit the temperature increase to 1.5 °C above preindustrial levels’, as stated in the Paris Agreement20. The Paris Agreement does not set emission targets for specific sectors. Furthermore, international aviation and shipping are not included in the national contributions that countries have to make to comply with the agreement. However, we assume that the international aviation community will contribute to the goal of the Paris Agreement. We will investigate the effect of measures and policies on global warming and also assess their feasibility. Thereby we will not distinguish between domestic and international aviation but treat the sector as a whole. There are two bridges to cross between the emission goals set by ACARE and ICAO and the climate targets set by the Paris Agreement: First, how do the emission goals translate into near-surface temperature changes, i.e. climate change. Second, how large are the non-CO2 effects?The ICAO of the United Nations has agreed on a global market-based measure scheme to abate the growth of CO2 effects will have a considerable contribution to aviation’s climate impact, however, they are currently not included in ICAO’s goal of climate neutral growth and only partly addressed in Flightpath 2050. We assess the feasibility of achieving the Flightpath 2050 goals by technological improvements and the availability of sustainable alternative fuels as an ECATS  expert group and reveal the risk of a large discrepancy, leading to an increasing aviation induced global warming effect rather than stabilisation.Here we close these gaps and show that the emissions goals set by Flightpath 2050 very likely will stabilise aviation’s climate impact, though the sector’s contribution to global warming remains considerable. Contrarily, we find that ICAO’s offsetting scheme, CORSIA, will surpass the climate target set to support the 1.5 °C goal between 2025 and 2064 with a 90% likelihood. In both cases non-CO21, which is independent from aircraft manufactures. This scenario was employed within the WeCare project22 and considers worldwide saturation effects of economic growth. This Randers scenario leads to a growth rate of 1.2%/year in 2050 which we extrapolate to 0.8%/year in 2100 . Our industry-independent scenario shows lower estimates of the transportation volume for the coming two decades compared to the Airbus and Boeing forecasts (see above), though still slightly higher than other estimates for 205024. Advances in airline operating efficiency, including changing the type of aircraft, the number of seats and load factor lead to a reduced increase of flown kilometres  and (5) Flightpath 2050 (FP2050 and FP2050-cont), which utilise the targets of FP2050 .We take into account five different scenarios Table : (1) Cur050 Fig. . Note th26 in terms of near-surface temperature change by taking into account effects from CO2 as well as NOx and H2O emissions and contrail-cirrus  show a clear stabilisation of their climate impact, though with an overshoot around 2050. Allowing 5% of the anthropogenic temperature increase to be contributed by the aviation sector, as motivated by the current estimate of aviation to global warming, both scenarios show compliance with a 2 °C target and the scenario FP2050-cont even with the 1.5 °C target. The inertia of the climate system delays the impact of both FP2050 scenarios, which overshoot these targets around the year 2050. However, after 2050, the FP2050 measures are sufficient to cause significant temperature decreases beyond these targets from this point on.We use these five scenarios to calculate their climate impact with the non-linear climate-chemistry response model AirClimrus Fig. . The inc2 emissions . The introduction of the CORSIA scheme further reduces the climate impact of CO2 emissions and that increases the relative importance of contrail-cirrus and NOx. The technological measures from FP2050 have a similar reduction efficiency for CO2 as CORSIA, however, the strong measures for NOx largely reduce the overall climate impact so that the remaining climate impact from aviation is due to CO2 (50–60%) and contrail-cirrus (around 30%).Hence to summarise, the increase in transport volume leads to an increase in the overall climate impact from aviation, which also increases the relative importance of CO2 effects28, which influences not only the absolute change of near-surface temperatures but also the importance of the individual climate agents. In this work, we take into account uncertainties in the atmospheric lifetime of aviation-related species, uncertainties in the RF of individual species and the climate sensitivity parameter, the last of which relates the RF to temperature changes. These parameters are varied in a Monte–Carlo analysis with 10,000 simulations to obtain a range of possible atmospheric responses. The results of the Monte–Carlo analysis provide a basis for estimating a range when the temperature thresholds, 5% of 1.5 °C and 5% of 2 °C, are surpassed. For example, Fig. The climate impact of aviation emissions has a considerable uncertainty range, especially, for the non-COx emissions , we consider one variant for a single-aisle aircraft, while three variants are considered for a future long-range twin-aisle aircraft. These include (1) a conventional tube-and-wing wide-body aircraft (TW), (2) the so-called Flying-V (FV) or multi-fuel blended wing body (MF-BWB). Both have similar aerodynamic characteristics and were developed by TU Delft32 and (3) NASA’s N3-X (N3) blended wing body34. We find that the fuel consumption of a 2035 aircraft might be reduced between 18% and 22% compared to new 2015 aircraft and between 34% and 44% in 2050. Note that though far future technologies, i.e. in 2075 or later, are in principle of interest they do not significantly impact our results, since their diffusion into the fleet delays their impact and more importantly, the impact on global temperatures will mainly occur beyond 2100 due to the inertia of the atmosphere-ocean system in the order of decades. These findings result in 9 ECATS emission scenarios with 3 variants  including a pessimistic base and an optimistic implementation, which differ by ±10%. The scenarios are developed consistently with the top-down scenarios following the same transport volume development and SAF usage as in the scenario CORSIA. Figure x emissions relative to the year 2000, resulting in a roughly fivefold increase in fuel consumption by 2100 and a fourfold increase in NOx emission. The new technologies introduced from 2035 onwards lead to a reduction in fuel use and NOx emission around 2050, which is then offset by the further increase in transport volume, resulting in a slight increase in fuel use and NOx emission until 2100. This analysis shows that an emission pathway better than BAU might be feasible, but that the goals set by Flightpath 2050 are unlikely to be achieved. The fuel use and NOx emission from the FP2050 scenario  and a change in habits due to experiences during the lock-down, for example, a shift towards web conferences instead of face-to-face meetings. Figure The recent COVID-19 pandemic might question the discussed future aviation pathways we analysed so far. To better understand the possible implications of this pandemic on the climate impact of aviation, we altered the BAU scenario in a parametric way to assess three different pathways for the international recovery from the lock-down of nation states and the associated dramatic reduction in air travel, based on reported transport volumes and scenario projections37 and Ghosh38. Future fuel efficiency improvements are based on the ICAO’s environmental report39, with 1%/year in 2018 decreasing to 0.25% in 2100. These two assumptions lead to a fuel consumption of 823 Tg in 2050, which agrees well with the mean of the ICAO scenarios39. The geographical distribution follows the emission inventories developed within the WeCare project22. Two time horizons are taken, one for the recent past ( = 2012) and one representative for the future (2050), describing the geographical and vertical distribution of the emissions. All scenarios are identical between 1940 and 2018, and deviate afterwards, according to scenario assumptions, derived from the basic storylines. Thereby, we obtain 5 scenarios CurTec, BAU, CORSIA, FP2050, FP2050-cont , which enables an improvement of the overall CO2 reduction potential to 80% in 2100. An analysis of the current growth rates and forecasts of the availability of SAF are used to optimistically estimate future availability of SAF and to allow a conservative estimate of the climate impact of the CORSIA scenario. Note that we have not explicitly considered any closed loop demand-supressing effects of increased costs35, such as SAF costs, since EUROCONTROL has indicated that these effects might be marginal40 and there is a high degree of uncertainty in the prediction of these costs. Instead, we have addressed this sensitivity by changing the growth rates (see below) by ±50% as open loop scenarios, which would cover a number of changes in transport volumes including those arising from demand suppressing costs increases. These assumptions lead to a scenario where 1/3 of the fuel used in 2100 is assumed to be SAF. We consider two different pathways of achieving the Flightpath 2050 objectives, late and continuous (FP2050 and FP2050-cont). Both scenarios have the same transport volume as BAU and consider technological improvements by 2050, which are formulated as ‘CO2 emissions per passenger kilometre have been reduced by 75%, NOx emissions by 90% and perceived noise by 65%, all relative to the year 2000.’41.In the top-down scenario building, we combine top-level assumptions on the evolution of aviation  with a detailed description of the air transport system for specific years. Details are given in the Supplementary Material as textual description and EXCEL sheet. Five scenarios are assessed, which all have some common characteristics Table . They haIn addition to these five main scenarios, we introduce three possible development pathways related to the COVID-19 pandemic by varying the timing and degree of recovery (see main text).x emission reduction potentials  with comprehensive knowledge on the possible availability of advanced technologies in future aircraft programmes along with in-house tools and models for engine performance, aircraft design and aircraft performance . We assess a broad spectrum of possible aircraft configurations, technologies, systems and procedures currently under research and development and evaluate their viability and provide best estimates on fuel consumption and NOls Table . Comparix emission evolutions in a bottom-up approach and combine that with the same overall scenario definition as for the top-down scenarios, e.g. with respect to transport volume.In this work, the fuel efficiency and emission analysis are done for both single-aisle and twin-aisle aircraft market segments, as those two segments will account for about 95% of globally available seat kilometres. Single-aisle aircraft serving short and short-to-medium distance routes are responsible for 47% of the worldwide aviation fuel consumption. Single-and twin-aisle aircraft serving the medium and long-range routes are responsible for another 47% of the fuel consumption. Hence, differently to the top-down FP2050 scenarios, we analyse possible future technology developments and derive the expected fuel efficiencies and NO22 for the years 2015–2070, in 5-year steps, for single-aisle and twin-aisle market segments. As a simplification, we assume that for each segment there is one representative aircraft type which can be used to model the entire market segment appropriately, while multiple aircraft generations are considered. The aircraft Airbus A320neo and A350 are selected as best of class for the current generation and serve as reference aircraft types for the single-aisle and twin-aisle markets, respectively. Entry into service year of the current generation is assumed to be around 2015. The next generations of single-aisle aircraft are assumed to be conventional tube-and-wing configurations entering into service in 2035 and 2050 with the fuel consumption and NOx emission improvement factors as shown in Table 46, starting from their respective entry into service (EIS) .We compute emission inventories based on global fleet forecast data developed in the WeCare project47. In a next step, those inventories are multiplied with the improvement factors  to determine the emissions for the respective aircraft generations. Finally, for all years, the corresponding emission inventory is obtained by combining the inventories of the individual aircraft types and generations according to their market share.For the calculation of the reference emission inventories (those based on the reference aircraft types), we apply the GRIDLAB methodology developed in DLR26 to analyse the climate impact of the various scenarios. AirClim is a surrogate model, which relies on a multitude of pre-calculated responses to emissions with a global climate-chemistry model and has been verified against reference models to correctly simulate scenarios, such as flying lower or higher26. AirClim considers changes in concentration of CO2, water vapour, ozone, methane and the formation of contrail-cirrus, and takes their lifetimes, effects on the Earth radiation budget and eventually the changes in the near-surface temperature into account. The spatial resolution of the relation between emission location and response depends on the kind of effect and related atmospheric lifetimes. For CO2, with a very long atmospheric perturbation, the emission location is unimportant and hence CO2 concentration changes are simulated in a box model. The relation between emission location and chemical concentration changes largely depends on the altitude and geographical location of the emission. The lifetime of aviation NOx and aviation ozone is in the order of several weeks and months, respectively48. Accordingly, chemical responses are dependent on emission altitude and latitude, whereas for short-term contrail-cirrus effects, the longitude is also taken into account. As a background atmosphere, we take the RCP2.6 scenario into account, assuming a world which tries to achieve the Paris Agreement. The effect of sustainable aviation fuel on contrail-cirrus properties is taken into account by utilising the results from Moore et al.49 and Burkhardt et al.16: A linear scaling between SAF use and reduction of soot number particle emissions is assumed, taking into account the results from measurements, which indicate that a 50–50 blend reduces the number of emitted soot particulates by 50%49 and the change in contrail-cirrus properties and lifetime changes the contrail-cirrus RF following the results of Burkhardt et al.16 by parameterising their results in their Fig. pn the relative change in particle number emissions . Note that the formula is only valid for ΔpnWe use the non-linear climate-chemistry response model AirClim50. The increase in RF when using SAF in comparison to a kerosene baseline as calculated by Caiazzo et al.50 stems from the increase in the calculated potential contrail-cirrus coverage, which is caused in their calculations by the change in the Schmidt-Appleman criterion.The effect of SAF use on contrail-cirrus properties and lifetime changes are qualitatively in agreement with Caiazzo et al.28 the climate impact of aviation emissions upon the atmosphere is associated with large uncertainties. The approach has been tested in Dahlmann et al.26 and successfully applied to obtain a robust climate impact for the mitigation option Flying slower and lower51. Here we categorise the uncertainties into three groups following Dahlmann et al.26: (1) uncertainty in atmospheric residence time ( ± 20%), (2) strength of RF , and contrail-cirrus), (3) relation between RF and near-surface temperature change ). Hence, we consider 11 uncertainty parameters, which are drawn individually for each simulation. A total of 10,000 simulations are performed to assess the uncertainty ranges, which are displayed in Fig. Uncertainties in climate impact estimates are quantified by using a Monte–Carlo Simulation. As indicated in Lee et al.Supplementary InformationPeer Review File


Follicular Output Rate (FORT) is an efficient quantitative and qualitative marker of ovarian responsiveness to gonadotropins. Transdermal testosterone (TT) has been used as adjuvant therapy to gonadotrophins in order to improve ovarian response in poor responders (PR). The aim of this study was to analyze whether TT can improve follicular sensitivity to gonadotropins using FORT.This retrospective study, held in a tertiary-care university hospital included 90 PR patients, according to the Bologna criteria. Patients in Group 1 (n = 46) received transdermal application of testosterone preceding gonadotrophin ovarian stimulation under pituitary suppression. In Group 2 (n = 44) ovarian stimulation was carried out with high-dose gonadotrophin in association with minidose GnRH agonist protocol. We analyzed ovarian stimulation parameters and IVF outcomes. We determined antral follicle count (AFC) (3-8 mm) before ovarian stimulation, pre-ovulatory follicle count (PFC) (16-22 mm) and the day of hCG administration. We calculated the FORT using the PFCx100/AFC ratio.Baseline characteristics and ovarian reserve parameters were similar in both groups. FORT and oocytes retrieved were significantly higher in group 1 vs group 2. There were no significant differences in pregnancy rates. In group 1 there was a significant correlation between FORT and AFC.This study suggests that the potential beneficial mechanism of TT in poor responder patients may be based on increasing the antral follicle sensitivity to gonadotrophin. FORT is an excellent tool to demonstrate this. The management of poor responders (PR) is a major challenge in IVF. Various stimulation regimens and interventions have been proposed for improving pregnancy outcomes in PR. These also include several adjuvant therapies such as androgen supplements (dehidroepiandrosterone and testosterone) and GH . Most ofAccording to results obtained in animals, it is possible that androgens exert a facilitating role in follicle responsiveness to FSH, which leads to an increase in the number of growing follicles . A simplTo overcome this difficulty, an objective index to assessing antral follicle responsiveness to exogenous FSH, the Follicular Output Rate (FORT) is being developed . FORT isThe aim of this study was precisely to assess whether transdermal testosterone was able to improve FORT in poor responders.This study was performed by a retrospective analysis of our database of women referred to our center for IVF, and was conducted from January 2013 to May 2016 in the Assisted Reproduction Unit of the Hospital Clinic in Barcelona (Spain). Before starting the IVF cycle, the patients were suggested to use Transdermal testosterone (TT) as an adjuvant therapy to ovarian stimulation. Two patients rejected this therapy. Review Board and informed consent was obtained from all individual participants, included in the study (HB-15-EL-RS-C). We recruited 90 poor responder patients according to the Bologna criteria (16-22 mm in diameter) on dhCG x 100/small antral follicle (3-8 mm in diameter) count at baseline (ovarian arrest day) . We evalThere was no perimplantation diagnosis in any of the cyclesWe suppressed the pituitary suppression by s.c administration of leprolide acetate . This treatment was started in the midluteal phase of the previous cycle and given 1 mg daily, then reduced to 0.5 mg after ovarian arrest was confirmed, and continued until the administration of HCG. Group-1 patients started TT on the day when pituitary suppression was confirmed and the therapy was continued for 5 days. Transdermal testosterone treatment was carried out using a daily single patch with a 2.5 mg/day nominal delivery rate of testosterone , which was applied to the thigh at night and removed always at 09:00h in the morning.This transdermal delivery system maintains testosterone levels stable within narrow ranges with little within - and between - subject variation, providing a highly controllable and reliable way of delivering testosterone, and the hormonal dose administered can be modified according to the patch duration . We chosIn Group 2 gonadotropin therapy started after ovarian arrest was confirmed. In both groups controlled ovarian hyperstimulation was performed with 300IU per day of r-hFSH  together with 75IU HMG . The criteria for hCG administration  were the presence of two or more follicles >18 mm in diameter, with >4 follicles measuring >14mm in association with a consistent rise in serum E2 concentration.The cycle was cancelled when there were less than 3 follicles with diameter >14 mm after 8-9 days of gonadotropin therapy, or after 4-5 additional treatment days without attaining, or the imminent prospect of attaining, the criteria for hCG administration.Oocyte aspiration was performed under vaginal ultrasonography 35-36h after hCG administration. Embryo grading was recorded according to published criteria ; embryosPregnancy was diagnosed by a positive serum β-hCG test 12 days after ET. Clinical pregnancy was defined by observation of a fetal heartbeat using transvaginal ultrasonography upon 5-6 weeks of gestation.Sample size was based on two previous studies from our group, showing that: (i) multifollicular development and oocyte retrieval was obtained in 80% of previously low responders receiving pretreatment with TT and gonadotrophin ovarian stimulation as used in patients in Group 1 . We used a t-test to compare the mean values between two different stimulation protocols. Differences in outcome rates were analyzed using an χ2 test or the Fisher’s exact test. p<0.05 was considered statistically significant. The Spearman’s test was used to determine the correlation between FORT and ovarian reserve parameters in patients treated with TT.As summarized in p=0.001). However, this was not demonstrated with age, basal FSH and AMH levels.When we evaluate the correlations between FORT and ovarian reserve parameters in Group-1 patients, there was a significant correlation with AFC  is not a reliable reflection of antral follicle sensitivity to FSH, as it is greatly influenced by the number of the small antral follicles available before treatment. This contingency constitutes a possible explanation for the inconstant relationship between the absolute counting of growing follicles obtained in COH and IVF-ET outcomes , average (42-58%) and high (>58%) in order to analyze the effective response to FSH and ovarian follicular competence (Taking into account the homogeneity of the studied groups, the significantly higher FORT in Group 1 vs 2 of the study has special relevance. This could also be related to a shorter duration on the days of stimulation and an increase in the number of oocytes obtained. This data agrees with those obtained in other studies (In accordance with previous studies, a correlation between FORT and antral follicle count was also shown in our study (TT has been used in poor responders with long GnRH agonist and antagonist protocols, finding no differences in terms of pregnancy rate or live birth rate (The main limitation of this study was its retrospective design and small sample size. However, the poor responder population according to the Bologna criteria represents only a 5 to 10% of patients in most assisted reproduction clinics, which creates logistic problems when performing a prospective study with sufficient power. Although the patients were not randomized, the two populations had similar baseline characteristics, which made it possible to compare IVF outcomes between the groups.Obviously, the findings of this study should be confirmed by other groups in larger randomized trials, which could shed light on the specific aspect of the sensitizing effect of TT pre-treatment in COH of poor responder patients according to the Bologna criteria.Despite moderate evidence regarding the efficacy of TT as an adjuvant treatment in ovarian stimulation, this study suggests that the potential beneficial mechanism of TT in poor responder patients may be based on increasing the antral follicle sensitivity to the action of gonadotrophin treatment. FORT is an excellent tool to demonstrate this.


Hirayama disease is a rare cervical myelopathy characterised by asymmetrical upper limb weakness and muscle atrophy in the forearm and hand. MRI of the cervical spine plays an essential role in diagnosis, however, the characteristic findings are often only seen when the patient is imaged with the neck in flexion.We present a case of a 15-year-old male who presented with left forearm and hand weakness with muscle wasting. An MRI of the cervical spine with the neck in a neutral position demonstrated atrophy of the spinal cord with intrinsic signal abnormality between C5 and C7. Further imaging with the patient’s neck in flexion demonstrated the hallmark features of Hirayama disease. There was anterior displacement of the thecal sac and spinal cord, and an enlarged, crescent-shaped dorsal epidural space which enhanced following i.v. gadolinium administration. The atrophic segment of cord contacted the posterior vertebral bodies when the neck was in full flexion. This case highlights the importance of imaging patients suspected of having this entity with the neck in full flexion in order to make a diagnosis. A 15-year-old male of Asian descent was referred with left forearm and hand weakness as well as associated muscle wasting. Weakness had been present for approximately one year and there was no recalled precipitating trauma or event. His ability to perform fine motor activities had become limited. He had no other significant past medical history. There was no personal or family history of any neurological disorders.On examination, there was visible muscle wasting to the left forearm, thenar and hypothenar eminences. There was reduced power (4/5) in the median and ulnar nerve distributions, including the intrinsic muscles of the hand. There was no altered sensation. Nerve conduction studies confirmed the presence of median and ulnar neuropathy and electromyography demonstrated denervation of the forearm muscles.An initial MRI of the cervical spine in a supine, neutral position demonstrated mild anteroposterior thinning of the cervical spinal cord between C5 and C7, more pronounced on the left side. There was intrinsic T2 signal hyperintensity in the left hemicord at the C6/7 level .Further imaging was performed, firstly with the neck in partial flexion and then in full flexion. The patient actively flexed his neck to establish a comfortable position and a support was then placed to maintain this position for the scan. On full flexion, there was ventral displacement of the thecal sac and cord, with widening of the dorsal epidural space . The venThe patient was referred to the spinal and neurosurgical service and was offered a cervical collar. He was referred to the physiotherapy and occupational therapy services with a view to provide exercises and injury avoidance techniques to reduce the risk of future flexion injuries to the neck.1–5 Weakness is typically unilateral. Less commonly when there is bilateral upper limb involvement, symptoms are usually asymmetrical.5 Patients develop atrophy of the muscles of the hand and forearm with sparing of the brachioradialis muscle.1–3 There is typically no sensory loss or other neurological findings elsewhere in the body.6 Finger weakness is generally exacerbated by cold temperatures .5Hirayama disease, also known as juvenile spinal muscular atrophy of the distal upper limb, is a cervical myelopathy characterised by insidious onset upper limb weakness predominantly involving the C7, C8 and T1 myotomes.et al. in 1959, Hirayama disease is non-progressive and most commonly affects males between 15 and 25 years of age.1–5 Its highest prevalence is in the Asian population, with large case numbers reported in Japan, China and India.4-6 There are, however, an increasing number of cases being reported in North America, Europe and Australia, thought to be largely due to an increasing Asian population throughout the rest of the world.5,7–9First described by Keizo Hirayama 5,7 Normally the spinal thecal sac is only anchored cranially to the foramen magnum and posterior surfaces of C2 and C3, and caudally to the coccyx. Further stability is provided by attachment of the dural sheaths of exiting nerve roots to the borders of the neural foramina.5,7 The remainder of the dura is suspended in the spinal canal, surrounded by epidural fat, an internal vertebral venous plexus and connective tissue.5It is thought that Hirayama disease occurs due to discrepant growth of the vertebral column and spinal canal contents.5 It is thought, however, that in some individuals, a length discrepancy between a longer vertebral column and a shorter thecal sac may result in the spinal cord and meninges being pulled taut during neck flexion. The thecal sac and cord are displaced anteriorly and pushed against the posterior surface of the vertebral bodies.7 This is believed to cause focal ischaemia, presumably due to compression of the anterior cord and anterior spinal artery against the posterior vertebral bodies. This results in chronic microcirculatory changes and/or venous congestion.1,3,6–8 The anterior horn cells are more susceptible to ischaemia than surrounding white matter which may result in cellular necrosis.1,3 The first autopsy case obtained by Hirayama et al. confirmed anteroposterior spinal cord flattening with ischaemic changes and atrophy of the anterior horn cells.5,8When flexing the neck, the slack of the dura is able to compensate for the slight increase in length of the spinal canal.5,7 Peak age of onset is approximately two years after peak longitudinal growth.5A more rapid growth in height seen in males than in females and the growth spurt which occurs in adolescence may account for the young male predominance of Hirayama disease.2T-weighted images.1–3,5,7,10MRI plays a key role in diagnosis. MRI with the neck in a neutral position may demonstrate localised cord atrophy, flattening of the cervical cord between C5 and C7 and when asymmetric, the more flattened side of the cord corresponds to the affected side. Straightening of the normal cervical lordosis is also seen with intramedullary signal abnormality on 1T-weighted images and hyperintense on 2T-weighted images, with enhancement following i.v. gadolinium administration. Small curvilinear flow voids may be seen within the regional thickening. This abnormality disappears when imaging is performed with the neck in neutral position indicating that this represents a temporarily engorged epidural venous plexus. In one study of 45 patients, the mean laminodural width at maximum forward shifting of the posterior thecal sac measured 5.99 mm.3 There may be forward shift on flexion imaging in healthy subjects, although this is limited to between 1.0 and 4.2 mm.3 Intramedullary signal abnormality is also noted to be at the level of maximum forward shift.1–3,5–7,10–13MRI with the neck in flexion demonstrates the hallmark signs including loss of attachment of the posterior thecal sac with anterior displacement of the posterior wall of the thecal sac, a crescent-shaped epidural thickening iso/hyperintense to the cord on 6,7 This case highlights the importance of performing imaging with the neck in full flexion. When imaging in partial flexion, these hallmark findings were not readily apparent, and only on full flexion were they clearly demonstrated  are characteristic of this disease.


Basic life support is foundation to save lives. In contrast to the developed countries, there is still no national standard BLS training module in Nepal. Basic life support training is being provided by various institutions but lack in consistency and coordination. The Nepal basic life support Course is the video based training in Nepali language with reference to recent advances which was intended for all health care personnel of Nepal in urban as well as rural setting. We aimed to describe the features of this video based training module in local language, to analyse the differences of knowledge before and after the training and to find out the participants perception and satisfaction with this course.This is a descriptive cross-sectional study based on data of trainings conducted over the study period. Ethical approval was taken. The post-test score was recorded and compared with the occupational using ANOVA. On the spot and delayed feedbacks from the participants were collected voluntarily and summarized.Total of 576 participants  successfully completed the training. The difference in post test scores (mean = 12.9+1.8) among the different occupational background was not significant (P=0.159). The feedbacks from the participants were mostly positive and encouraging.The knowledge of basic life support improved significantly irrespective of the occupation of the participants. A universal, nationwide video based training module in Nepali language should be developed focusing all health care personnel of urban as well rural Nepal. There are many academic institutions providing the BLS training currently but in silos.The healthcare professionals of any background must know the BLS skills which are fundamental to save lives.4 which was designed for all health care personnel of Nepal in urban as well as rural setting to be able to provide basic life support in a safe, timely and effective manner.The Nepal BLS for Healthcare Providers Course is the video based training in Nepali language with reference to recent American Heart Association (AHA) guidelinesThis descriptive study describes the training module and analyses the differences in post-test score among different occupational group. This study also aims to evaluate the feedbacks given by participants upon completion of the training.In this descriptive cross-sectional study, the data of trainings from November 2014 - May 2018 was analysed. The trainings were conducted at various institutions of Nepal  focusing the health care personnel of different professional background. They were categorized into clinical doctors , non-clinical doctors , nurses/paramedics and interns. The identity of the participants was not disclosed in the analysis of the data. The feedback forms didn't contain the name of the participants, thus the confidentiality of the participants was maintained. The ethical approval was taken. Data of all the participants who completed the training during this period was included.5 with permission and modified according to the 2015 AHA guidelines.4 The questionnaire underwent expert panel consultation and then was validated in the pilot trainings. The questionnaire contains vignette based multiple choice questionnaire with one right option on knowledge and skills of adult BLS, infant BLS and choking. The written pre-tests were not mandatory and depended upon the wish of the course coordinator before the course. Participants had to secure 80% in the post tests to pass the exam and to be certified. If the goal was unreachable in first attempt remediation was done maximum for two times till satisfactory performance. Structured skill test sheets for adult and infant BLS was developed and tested in the pilot study which was used to check the participant's performance in the BLS skills. The box was ticked only if the participant correctly performed the skill. If they did not perform a specific skill correctly, it was noted on the sheet. At the end of the test the student was informed about the skills they needed to practice further. They had opportunity to redo the test at the end of the course during “remediation”.Two pilot training sessions were conducted in initial phase to test the training video, student manual and the testing materials. Appropriate remediation was undertaken after the feedback from these sessions. There were 15 multiple choice questions (MCQ) which were taken from a previously validated studyAt the end of the all training sessions a voluntary “on the spot feedback” on participants' satisfaction was obtained with a predesigned form for qualitative data collection. This form was divided into five sections-general feedbacks, feedbacks on adult BLS, infant BLS, choking using five point Likert's scale and open comments.An online feedback form “delayed feedback” was developed by the authors and disseminated on May 2018 to all the participants who had completed the training via email to explore their perception about the course. The participation was voluntary and anonymous. The form contained demographic date: age, occupation, duration of work experience, date of Nepal BLS training, frequency of involvement in resuscitation of patients; five tier Likert scale to explore the perception about video based training in local language using 7 items; followed by their open opinion about future courses and refreshers training.The demography, occupation, pre-test/post-test scores were recorded in Microsoft Office Excel. Data analysis was performed using the statistical software SPSS Version 23. The difference in post test scores among the different occupational background was analysed with ANOVA. P<0.05 was considered as statistically significant. The feedbacks were recorded, quantitative data were analysed in proportion. Qualitative data were classified based on themes and analysed.There were total 26 training sessions at different institutions and hospitals of Nepal with total of 576 participants during the three and half year period. Among those participants 425 (73.8%) were clinical doctors, 92 (16%) were nurses and paramedics, 18 (3.1%) were non-clinical doctors and 41 (7.1%) were intern doctors.Among the total 576 participants the mean post-test was 12.9±1.8. The difference in post test scores among the different occupational background was not significant when analysing with ANOVA (P = 0.159) .As per participants performance the box in the structured skill testing sheet was ticked. Among the 576 participants 46 (7.9%) required remediation as some critical steps were missed in first attempt. Following further practice and remediation all of them completed the skill testing successfully.As the feedback process was voluntary, the number of responses varied in different sections of the feedback form. Among the total responses (512 out of 576), 339 (97%) participants strongly agreed or agreed that the objectives of the training were met . About 5Some of the open comments in the feedback form by the participants were categorized into positive and constructive. One of their comments from the participant- “I found this training is of high standard and it is very useful in enhancing knowledge about resuscitation and can be applied in practical life”. The specific areas of satisfaction were as follows: videos (289), simulation skill stations (223), training materials (89), trainers' knowledge and friendliness (132), planning of training (69), and skill testing (48). Specific positive phrases used for video were, “impressive”; “clear”, “interesting”; “informative”, “well explained”, “innovative” and “effective”: One of the participants comment -“The training is fruitful to each and every medical personnel specially the presentation style of the training video in Nepali language and simulation is the most effective part.” Constructive feedbacks for video were “needs to be updated”, “needs improvement in sound” and “more practical”. There were many future recommendations in regards to the number of the AED (152). They wanted more number of AED to practice and more skill stations on AED. “In our hospital settings across the country, very few centers have AED facilities, and in clinical practice, it's replaced by conventional defibrillator, demonstrating it would be difficult but adding a short introduction about conventional defibrillator  would help the BLS participants a lot.” There were contrary statements in regards to the duration of the training. Some also expressed their wishes to attain other similar advanced training in resuscitation.The response rate to the delayed online feedback was 106 (18.4%) till end of May 2018. Of the 106 responders, 89 (84%) were clinical doctors, 12 (11.3%) were nurses/paramedics and 5 (4.7%) nonclinical doctors. Out of them 58 (54.7%) were male. The duration of clinical experience was divided into <1 year, 1–3 years, 3–6 years and >6 years which comprised of 2 (1.9%), 74 (69.8%), 23 (21.7%) and 7 (6.6%) participants respectively. The details of the rating to the statements in Likert scale is summarized .When the participants were inquired about any involvement in resuscitation after the Nepal BLS training, 28 (26.4%) of them had claimed they were frequently involved (>10 times per year), 38 (35.8%) were involved sometimes (5–10 per year), 35 (33%) occasionally (<5 times per year) and 5 (4.7%) were never involved. One hundred and four participants (98.1%) of the participants were interested in taking such lifesaving skills in future. When the opinion about the interval of refreshers course was explored, 65 (61.3 %), 36 (34%), 3 (2.8%) and 2 (1.9%) of the participants stated that it should be done annually, every two years, five years and quarterly respectively. The phrases used to comment on the video based training was “good”, “effective”, “great”, “helpful”, “to the point”, “high standard”, “best”, “worth”, “sufficient”, “phenomenal”. Some participants (14) were concerned that the duration was short and advised that the duration be prolonged to at least 2 days with more practical skill stations and inclusion of neonatal life support and Advanced life support. Some (22) also commented on the need of refreshers course and dissemination of the course among all healthcare workers including those in rural areas. Few commented that the quality of video (2) and audio (5) should be improved with updated content (9).4 as new guidelines were introduced. TheThis is the first video based BLS training in local language in Nepal. Google, Google scholar and PubMed based search did not reveal citation of any other video based BLS training in Nepal. The training is conducted at various health institutions targeting different health care professionals in Nepal from 2014. Till date 47 participants of different background including general practitioner, surgeon, orthopaedic surgeon, anaesthesiologist and paramedics have received the training for teachers (TOT) course and are instructors for Nepal BLS. This video was initially based on AHA guidelines 2010 and was subsequently updated to 2015 version7AHA certified BLS is also available in Nepal but may not be affordable, comprehensible and feasible in our part of world. One of the main features of this training module is the use of modern methods of teaching. The modification of the scenarios and dramas according to the local context makes it practical and feasible in real working scenarios in resource limited countries like ours. Up to present, several publications have highlighted and have addressed the current level of awareness and knowledge in this area among the health care professionals and have emphasized the deficiencies in basic life support skills in Nepal. This video based, instructor-led course teaches the practical skills of both single-rescuer and team-based BLS skills for application in both in- and out-of-hospital settings and trains participants to promptly recognize arrest victim, give high-quality chest compressions, deliver appropriate ventilations, relieve choking and also introduces the use of automated external defibrillator (AED). Hundred and four participants (98%) recommended this training to other health care personnel in the delayed feedback. Ninety-three (87.6%) participants claimed that the content was practical to their work and 97 (91.4%) stated that it improved their BLS skills. Hundred and four participants (98%) gave positive response to the statement that such training should be made mandatory to all health care professionals in Nepal.10 “Instructor led, hands on” class format has reinforced skills proficiency in this training. “Practice while watching” technique allowed Instructors to observe the participants, provide feedback and guide them to acquire the skills. This approach is also found to be efficient in other studies.9 Nepali language being officially and universally spoken all over Nepal, the message might be clearly delivered to Nepali health care personnel by using video based learning in local language. Ninety-four (88.6%) agreed positively that the Nepali version of the video will help better understanding for all health care personnel in the delayed feedbackThe video contains dramatized illustration of real life scenarios based on actual context to our part of world, demonstration of the various skills required for resuscitation and uses “practice as you watch” approach. The video based technique ensures consistency in future trainings irrespective of the instructor quality or mood in contrast to the lecture based trainings. The quality of the video was also rated high  by the participants for adult, infant and choking sections of the video respectively. While analysing the open comments there were many positive feedbacks and encouraging words for the video-based training module (289). In the delayed feedback 96 (90.5%) of the participants thought that the video based instructor led training was superior to the traditional lecture based training. There are few literatures which state that video based learning is better than traditional classroom teaching with lectures.11 The adult, infant and choking skill stations were rated positive in 97%, 94.5% and 91% respectively. Positive comments about the simulation based skill stations were mentioned by 223 participants in the open comments and some of them wanted to increase the time and numbers of simulations. Written post-test was done to ensure participant acquired the knowledge of BLS. The written post-test score after the training was similar in each occupational group which demonstrates that the training improved the knowledge of the participants irrespective of their background occupations. While analysing the on the spot feedback, most of the participants agreed or strongly agreed to the statements given in the feedback form. Most of the participants (98.7%) gave positive rating for the statement that Instructors were friendly, knowledgeable and ready to help The reason for relatively constructive feedback was on response for the pre-information  of the training could be that in some training the student's manual couldn't be distributed before the training due to various reasons. Most of the cardiac arrests in adults are due to ventricular fibrillation which is otherwise fatal within minutes though highly reversible with the rapid application of defibrillator.12 Recent developments in automated external defibrillator technology have provided a means of increasing the rate of prompt defibrillation after out-of-hospital cardiac arrest.14 Although AED is not widely available in Nepal, the course introduces and highlights the use of an AED so that its use will be fortified in future. In open comments there were 152 comments on AED. They wanted more practice time, demonstration and number of AED. Therefore the training in AED for future, such trainings are recommended.Following the video based demonstration and “practice while watching” sessions the students were divided into small groups and real life time simulations were practiced to reinforce the skills learnt during the video session. Moreover, the importance of teamwork and coordination was also experienced by the participants in these simulation sessions. Simulation based medical education is a complex educational intervention and is well established as a practical, safe, structured and effective training strategy to train health care professionals in both technical and nontechnical skills which are known to be critical to effective teamwork.14 Due to anonymous feedback we couldn't categorise the feedback according to the background profession. The training is ongoing and this is just a cross-sectional study so generalization is not reliable. The response rate for delayed feedback was low (18%) and mostly clinical doctors and nurses/paramedics responded so the opinions can't be generalized to all cadres.This video based method of training was not compared to other conventional method of teaching so it cannot be proven from this study that video-based training is superior to the other methods. Moreover, the test was not repeated after some interval of the training to check for significant deterioration of knowledge with time.This video based training in BLS in Nepali language significantly improved knowledge of BLS irrespective of the occupational background of the participants. It is recommended that a national, standard BLS training based on recent updates should be a core competency across all health care professional programs. Considering the feedbacks from the participants, video based training method can be considered a useful technique in such educational programs to ensure consistency and quality. Developing video based training module in local language may also increase the access to the BLS training as this should be adopted in a higher scale to cover all level of health care providers of Nepal including rural and urban areas to be able to provide BLS in a safe, timely and effective manner.


The differences in ENSO sea surface temperature (SST) spatial patterns, whether centered in the Eastern Pacific (EP), Central Pacific (CP) or in the eastern-central equatorial region  have been associated to differences in atmospheric teleconnections and global impacts. However, predicting different types of ENSO events has proved challenging, highlighting the need for a deeper understanding of their predictability. Given the key role played by wind variations in the development and evolution of ENSO events, this study examines the relationship between the leading modes of Pacific surface wind speed variability and ENSO diversity using three different state-of-the-art wind products, including satellite observations and atmospheric reanalyses. Although previous studies have associated different ENSO precursors to either EP or CP events, our results indicate that the most prominent of those ENSO precursors are primarily related to canonical and CP events, and show little correlation with EP events. The latter are associated with tropical Pacific conditions favoring equatorial westerly wind and precipitation anomalies that extend all the way to the eastern Pacific. Results over the entire twentieth century period versus those during the satellite era also suggest that the influences from the Southern Hemisphere may be more robust than those from the Northern Hemisphere. Surface winds play a key role in the initiation, growth and demise of ENSO events through both a deterministic wind component arising as a response to sea surface temperature (SST) anomalies4. These differences range from the extreme El Niño event of 1997/1998, which had the largest anomalies in the Eastern Pacific to the weaker events during 2000–2010 with peak anomalies around the dateline. These differences in spatial patterns, which are more pronounced for the warm (El Niño) phase of ENSO than for the cold La Niña conditions5, are associated with different atmospheric teleconnections and large-scale impacts6. For example, while ENSO events are generally viewed as the primary source of predictability for ocean conditions in the California Current System, with important implications for marine ecosystems in that region7, it is the SST anomalies in the central/western equatorial Pacific, like those associated with Central Pacific (CP) ENSO events, that are more influential on SST anomalies along the US West Coast9. SST anomalies in the Eastern equatorial Pacific (as in EP ENSO events), on the other hand, may be more influential on precipitation over California9. Thus, the ability to predict different ENSO types is critical, although, to-date, it has proved very challenging11.ENSO events differ in their amplitude and spatial patterns as emphasized by recent literature12, the Western North Pacific Precursor (WNP)13, and the South Pacific Meridional Mode (SPMM)14. These ENSO precursors have primarily been described in terms of SST anomalies: the PMM is characterized by SST anomalies that extend southwestward from the coast of California to the central equatorial Pacific15; the WNP precursor is defined in terms of SST anomalies in the western North Pacific region (122°–132° E to 18°–28° N)13; and the SPMM exhibits anomalies extending along the west coast of South America toward the eastern equatorial Pacific14. However, these precursors also include important sea level pressure (SLP) and wind signatures, which can influence ENSO events through both thermo-dynamical  and dynamical  processes15. These various precursors have been associated with different types of El Niño events: the PMM has been viewed as a precursor for CP events17, while the WNP and SPMM have been considered more influential on EP El Niño events18. Other studies, however, have emphasized the key discriminating role of the initial/background subsurface ocean conditions, which may themselves result from large-scale wind patterns, for the development of different El Niño types20.Influences from the extra-tropical Pacific have been proposed as possible sources of ENSO predictability. The most prominent of these extra-tropical precursors include the Pacific Meridional Mode (PMM)21), but the large-scale fields needed for climate studies are usually obtained from atmospheric reanalysis products. These, however, may assimilate different observations with different assimilation techniques, use different SST fields as lower boundary conditions, and suffer from model errors, factors that can all introduce inaccuracies and discrepancies among the different data sets22. Satellite data provide large-scale wind observations at a relatively high spatial and temporal resolutions, and are now of sufficient duration and accuracy to allow their utilization for climate studies24. In particular, wind speed has been continuously measured from space since 1988, and carefully inter-calibrated across different satellite missions25, providing an excellent data set for examining ENSO precursors. In this study, we will use these satellite-based wind speed data, complemented by those obtained from two state-of-the-art atmospheric reanalysis products to pursue the following objectives: (1) identify the dominant patterns of wind speed variability in the Pacific basin, their relationship with known ENSO precursors and their association with ENSO diversity; and (2) assess the robustness of these relationships across different products and time periods.These extra-tropical ENSO precursors are not necessarily independent, but they are likely linked by the large-scale atmospheric circulation, as captured by the basin-scale wind field. Thus, large-scale patterns of wind variations could be used to examine extra-tropical influences on ENSO and its diversity. In situ wind observations from moored buoys provide an invaluable “ground truth” where available  the NOAA-20CRv3 atmospheric reanalysis 27. These are very different wind products. The first is an observational dataset obtained by merging satellite microwave retrievals from several inter-calibrated radiometers , the second is an atmospheric reanalysis that assimilates a broad range of observations, and the third is a 179-year atmospheric reanalysis that only assimilates SLP, in addition to prescribing SST from the Simple Ocean Data Assimilation with sparse input version 3 (SODAsi.328) and HadISST2.229, and prescribing sea ice concentration from HadISST2.330, as lower boundary conditions27. The latter reanalysis is used for comparison with the two other products over the overlapping period 1988–2015 (20CR-1988 hereafter) as well as during 1900–2015 (20CR-1900 hereafter) to examine the robustness of the results over a century-long period. To more fully characterize the atmospheric conditions associated with the leading wind speed patterns we also use SLP, vector winds and precipitation, which are available from both atmospheric reanalyses. Since ECMWF-ERA5 and NOAA-20CRv3 are ensembles , we use the ensemble mean wind speed, which is computed from sub-daily values of each ensemble member. Our SST dataset is the Extended Reconstructed SST version 5 (ERSSTv5)31, and sea surface height (SSH), a quantity dynamically-related to upper-ocean heat content, is obtained from the ECMWF Ocean Reanalysis System 5 (ORAS5)32 available to us from 1979 to 2017.We use three different wind speed (WS) datasets at monthly time resolution: (1) satellite ocean surface winds, from the 1° monthly merged radiometers climate data record available from 1988 to present (referred to as SAT in the graphics); (2) the ECMWF-ERA5 atmospheric reanalysis 33, as:N is the total sample size, and r1 and r2 are the lag-1 autocorrelations for each of the time series.This study makes use of correlation and regression analysis, whose statistical significance is assessed using a two-tailed student-t test. To account for the temporal autocorrelation of the time series, we computed an effective number of degrees of freedom N* following Bretherton et al.4. Here, we characterize ENSO diversity using the indices proposed by Takahashi et al.34. This approach relies on the two leading empirical orthogonal functions (EOFs) of SST anomalies in the equatorial Pacific (10° S–10° N), which explain a large fraction (~ 83%) of the SST variance in this region. The leading EOF exhibits a “canonical” ENSO pattern35, with positive anomalies that achieve their largest values in the central-eastern Pacific, while the second EOF displays a dipole pattern along the equator, with negative anomalies in the eastern Pacific, and positive anomalies in the central Pacific  at time to + t to the Pacific conditions at the initial time to, as indicated by the state vector x, through the operator H such that:To determine the basin-wide patterns of SST and SSH that are most conducive to either EP or CP events (“sensitivity patterns”) at some later time we use the same approach of Capotondi and Sardeshmukhx includes SST and SSH information. The inclusion of SSH was shown to be essential for capturing ENSO diversity20. The SST and SSH fields are smoothed with a 3-month running mean and linearly detrended before projecting them onto their leading EOFs, a step adopted to reduce the number of degrees of freedom. We retain 20 SST EOFs and 20 SSH EOFs, accounting for 80% and 66% of the corresponding field variance. H(t) is computed through multiple linear regressions, and the initial state most conducive to y (t + to) is determined as the leading right singular vector of H.The state vector 36, where the number of independent realizations is estimated as outlined by Quadrelli et al.37. This leading pattern of variability can account for larger fractions of variance locally. For example, since 1988, this pattern explains more than 20% of the variance around 20° S and 50°–60° S in all three datasets, and as much as 40% and 60% of the variance in the eastern and central-western equatorial Pacific, respectively. The spatial patterns of EOF2 and EOF3 for the different datasets are displayed in Figs. We start by examining the dominant patterns of wind speed variability over the Pacific basin  using EOF analysis. Wind speed anomalies have been smoothed with a 3-month running mean and linearly detrended prior to the EOF calculation. The leading patterns are shown in Fig. 39. A similar SLP structure, obtained through EOF analysis over a region in the eastern South Pacific, has been termed South Pacific Oscillation (SPO)40. In the Northern Hemisphere, SLP anomalies associated with our leading WS mode, exhibit a negative SLP center around 40° N, 160° W, which is consistent with a deepening and eastward extension of the Aleutian Low. These SLP anomalies are associated with a weakening of the off-equatorial trade winds and a strengthening of the far-western Pacific equatorward winds in both Hemispheres.To understand the connection between these patterns of wind speed variability and atmospheric circulation, we regress SLP and vector winds on the standardized principal components (PCs) associated with the patterns in Fig. 40, and with the lag between sub-seasonal equatorial wind variations and the ENSO peak2, the deepening of the Aleutian Low in the Northern Hemisphere is more typical of the mature phase of ENSO events. Since wind variations in the Northern Hemisphere typically peak during the boreal winter-spring season15, unlike the Southern Hemisphere winds40, the EOF calculation over the entire Pacific basin may confound the different hemispheric seasonalities.The leading PCs of wind speed show a very good correspondence with the canonical ENSO index Fig. e with co42, whose equatorward pole is responsible for a weakening of the Northern Hemisphere trade winds during the phase displayed in Fig. 38 for PSA-1.Thus, we repeat the EOF calculation in the two Hemispheres separately, using regions poleward of 5° to avoid the inclusion of equatorial wind signals. Results from the satellite merged winds are compared with those from 20CR-1900 in Fig. 14 for both SAT and 20CR-1900. However, while the satellite winds show SST anomalies extending from Baja California to the central equatorial Pacific .20 used SST and SSH to identify precursors of ENSO diversity, and demonstrated the key role played by subsurface conditions, as encapsulated by SSH, in the selection of the ENSO type. Here, we extend that approach to the full Pacific basin  analysis. One of the reanalysis products extends back to the mid-1800s, allowing a comparison of wind variability over recent decades with those occurred over a century-long period. Pacific surface winds are a key component of most of the proposed extra-tropical ENSO precursors, as they promote formation of sea surface temperature (SST) anomalies through either thermo-dynamical or dynamical processes, but their specific role as ENSO precursors had never been previously investigated. Here we find that the dominant pattern of surface wind speed variability over the entire Pacific basin is similar among the different products and significantly correlated with ENSO variability at a lead time of 2–3 months. Locally, this pattern accounts for larger fractions of variance in some parts of the South Pacific and especially along the equator.53. In addition, the linear detrending applied to all the variables used in this study is likely inadequate to remove the climate change signal, which may be more pronounced in recent decades and may also manifest itself in the form of low-frequency decadal variations54 rather than a linear trend. A study based on the Community Earth System Model (CESM) Large Ensemble55 detected a strengthening of the North Pacific Meridional Mode with climate change, which could explain a more prominent influence of the Northern Hemisphere on ENSO in the recent period. Disentangling these issues is beyond the scope of the present study, but an in-depth analysis of low-frequency ENSO variations using the century-long atmosphere and coupled reanalyses that are becoming available may illuminate the evolving nature of ENSO precursors, and will be considered in future studies. It will also be important to repeat similar analyses in climate models that provide a “realistic” simulation of ENSO diversity, using long model simulations to verify the present results with a higher degree of statistical significance, and scenario simulations to examine the influence of climate change on ENSO precursors and their relationship with ENSO diversity.Hemispheric patterns of wind speed variability that exclude the equatorial band capture the leading SST and sea level pressure precursors proposed in the literature, including the Pacific Meridional Mode and North Pacific Oscillation in the Northern Hemisphere and the South Pacific Meridional Mode and South Pacific Oscillation in the Southern Hemisphere. These precursors are very similar among the three different datasets over the post-1988 period, but differences are detected in the structure of the Northern Hemisphere wind speed and SST precursors over the 1900–2015 period, suggesting a lower degree of stationarity of the Northern Hemisphere wind patterns prior to 1988. While these differences may be partly associated with a larger degree of sparseness and uncertainty in the data assimilated in the 20CRv3 reanalysis during the earlier part of the twentieth century, natural and/or anthropogenically-forced variations of the atmosphere–ocean system can also be expected to play an important role. ENSO characteristics, including the frequency of occurrence of EP and CP events, appear to vary on decadal timescales in both observations and long model simulations56, implying a relevant role for both Hemispheres in the model context, and suggesting the need for further investigations of the relative role of Northern and Southern Hemisphere precursors in observations.The leading patterns of wind speed variability are significantly correlated with “canonical” and CP-type ENSO events after 1988, but correlations for the Northern Hemisphere patterns are barely significant over the century-long period, again suggesting a possibly less robust role for Northern Hemisphere wind precursors, with the caveats noted above. Patterns of SST and SSH similar to those detected with this analysis also emerge as optimal precursors of canonical ENSO events in a millennium-long integration of the National Center for atmospheric Research (NCAR) Community Earth System Model version 2 (CESM2)20 to determine the SST and sea surface height (SSH) structures that are most conducive to either EP or CP event types three seasons later, and then determine the associated wind, sea level pressure and precipitation patterns through linear regression. The indices associated with these SST and SSH initial conditions for each event type appear to be well correlated with the EP and CP indices at the later time. The wind speed and sea level pressure fields obtained with this approach are very similar to those obtained through EOF analysis for CP events, confirming the key role played by extra-tropical SLP and wind precursors for this type of events. The main wind anomalies for EP events are found along the equator, and are associated with a penetration of the anomalous equatorial westerlies to the eastern part of the basin.A novel result of this study is that the patterns of Northern and Southern Hemisphere wind speed variability show no statistically significant correlation with EP ENSO events during the satellite era. While the post-1988 period was predominantly characterized by CP ENSO events, the results obtained using the 20CRv3 reanalysis over the 1900–2015 period also show correlations of the wind patterns with EP events that are statistically insignificant or only marginally significant, supporting the results obtained during the satellite era. To gain insight in the nature of EP precursors, we use the statistical approach of Capotondi and Sardeshmukh57. Our results confirm that the CP events detected with this approach capture the larger cluster of moderate events discussed in Takahashi and Dewitte57. These events appear to be related to well-known extra-tropical precursors, and their exact longitudinal location and spatial pattern may be modulated by the initial zonal thermocline slope. As in Takahashi and Dewitte57, EP events are rarer and appear to be associated with conditions that allow the equatorial wind (and convection/precipitation) anomalies to extend to the eastern Pacific. These conditions may occur during positive phases of the Pacific Decadal Oscillation, which is associated with a reduced zonal thermocline slope58 and may be favored by enhanced stochastic wind activity in the form of Westerly Wind Events59. Influences from other oceans, as recently suggested for the Atlantic60, may also play a role.We note that the indices used to characterize ENSO diversity emphasize the distinction between moderate (CP) and extreme (EP) event typesThis study has demonstrated that surface wind speed data from satellite retrievals are now of sufficient duration and accuracy to be suitable for climate studies, and may provide an excellent benchmark for reanalysis products that do not assimilate them . The continuation of satellite missions, together with sustained in situ wind observations for calibration and validation of the satellite retrievals, will be of paramount importance for an increasingly robust assessment of ENSO wind forcing in the context of a changing climate.Supplementary Figures.


To the Editor: We were pleased to read Landau et al’s,A healthy 26-year-old woman with no medical history and 2 prior episodes of BTX A injections at another facility presented to our office with concerns of lesions on her side of the forehead that appeared after the injection of onabotulinumtoxin A by an outside physician. Three weeks prior, she had received injections in her frontalis and glabellar muscles to treat rhytids. Within days, she noticed discolored skin depressions along the side of the forehead at the injection sites. She returned to her physician for consultation, but the physician could not alleviate the depressions despite 2 follow-up office visits. She then came to our office for further management.On physical examination, an atrophic plaque with an underlying blue-green color change was noted . The injA 27-year-old woman with no medical history presented to our office with lesions on the central aspect of the forehead that appeared after the glabellar and frontalis injection of abobotulinumtoxin A by a physician assistant 4 weeks prior. Within days after the initial injection, she noticed soft-tissue swelling in the central aspect of the forehead area. Her injector was unsure how to proceed with the treatment, so she came to our office for further management.On physical examination, there was a large central linear cutaneous depression, best appreciated on tangential lighting . We admiBoth of our patients had resolution of the cutaneous depressions within 1 month of the standard duration of BTX A, which is around 3 to 6 months.,Given the similar duration of BTX A and the cutaneous depressions, it seems as though aberrant muscle contraction may be the underlying mechanism for this adverse effect. Since the frontalis muscle has cutaneous insertions, changes in the contractility of its fibers may lead to superficial skin changes.There are 2 variants of cutaneous depressions after BTX A injection: 1 with well-defined circular depressions and 1 that appears more linear, following the orientation of the frontalis muscle. Linear depressions, such as ours, are more likely due to aberrant frontalis muscle contraction, given the underlying anatomy.Linear cutaneous depression after BTX A injection was demonstrated in 1 previous report, in which the patient was biopsied for concern of coup de sabre, but this biopsy showed no abnormalities.None disclosed.


The positive impact that physical activity has on patients with cancer has been shown in several studies over recent years. However, supervised physical activity programs have several limitations, including costs and availability. Therefore, our study proposes a novel approach for the implementation of a patient-executed, activity tracker–guided exercise program to bridge this gap.Our trial aims to investigate the impact that an activity tracker–guided, patient-executed exercise program for patients undergoing radiotherapy has on cancer-related fatigue, health-related quality of life, and preoperative health status.Patients receiving postoperative radiotherapy for breast cancer  or neoadjuvant, definitive, or postoperative treatment for other types of solid tumors  will be randomized (1:1:1) into 3-arm studies. Target accrual is 201 patients in each trial (50 patients per year). After providing informed consent, patients will be randomized into a standard care arm (arm A) or 1 of 2 interventional arms (arms B and C). Patients in arms B and C will wear an activity tracker and record their daily step count in a diary. Patients in arm C will receive personalized weekly targets for their physical activity. No further instructions will be given to patients in arm B. The target daily step goals for patients in arm C will be adjusted weekly and will be increased by 10% of the average daily step count of the past week until they reach a maximum of 6000 steps per day. Patients in arm A will not be provided with an activity tracker. The primary end point of the OnkoFit I trial is cancer-related fatigue at 3 months after the completion of radiotherapy. This will be measured by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. For the OnkoFit II trial, the primary end point is the overall quality of life, which will be assessed with the Functional Assessment of Cancer Therapy-General sum score at 6 months after treatment to allow for recovery after possible surgery. In parallel, blood samples from before, during, and after treatment will be collected in order to assess inflammatory markers.Recruitment for both trials started on August 1, 2020, and to date, 49 and 12 patients have been included in the OnkoFit I and OnkoFit II trials, respectively. Both trials were approved by the institutional review board prior to their initiation.The OnkoFit trials test an innovative, personalized approach for the implementation of an activity tracker–guided training program for patients with cancer during radiotherapy. The program requires only a limited amount of resources.ClinicalTrials.gov NCT04506476; https://clinicaltrials.gov/ct2/show/NCT04506476. ClinicalTrials.gov NCT04517019; https://clinicaltrials.gov/ct2/show/NCT04517019.DERR1-10.2196/28524 Radiotherapy is a key treatment modality for the curative treatment of various tumor entities. Despite continuous technical improvements in facilitating increasingly precise dose delivery, side effects are inevitable in many cases . Among pwearables, have been used by a growing population to record physical activity and biodata, such as pulse and sleep patterns. Although fitness wristbands were initially considered purely as lifestyle products, in recent years, the scientific benefits of these products have increasingly come to the fore [Activity trackers, which are also called the fore -19. HoweIn the presented OnkoFit studies, we aim to investigate whether an activity tracker–based fitness program can reduce CRF and improve the quality of life and preoperative health status of patients undergoing radiotherapy.The OnkoFit trials are two independent, single-center, randomized prospective phase III trials that have been certified by the working group radiological oncology of the German Cancer Society. After providing informed consent, patients will be randomized to a standard arm (arm A) or 1 of 2 interventional arms (arm B and C) in a 1:1:1 ratio . All patThe OnkoFit I trial is exclusively designed for patients with breast cancer, while the OnkoFit II trial is open to patients undergoing preoperative, definitive, or postoperative radiotherapy for various tumor sites. The separation of the tumor entities in two different trials allows for two different end points. Although the end point of the OnkoFit I trial—fatigue at 3 months after radiotherapy—has been evaluated in a pilot trial that was conducted in our department , it was A summary of key inclusion and exclusion criteria is provided in Inclusion criteriaOnkoFit I trialInformed consentAge>18 yearsHistologically confirmed breast cancerEaster Cooperative Oncology Group score of 0-2Indication for postoperative radiotherapy after breast-conserving surgery or mastectomyOnkoFit II trialInformed consentAge>18 yearsDiagnosis of lung cancer, esophageal cancer, brain tumors, head and neck tumors, pancreatic cancer, rectal cancer, sarcoma, and uterus cervix cancerEaster Cooperative Oncology Group score of 0-2Indication for preoperative, definitive, or postoperative radiochemotherapyPlanned duration of treatment of at least 4 weeksExclusion criteriaOnkoFit I trialParticipation in other interventional trialsHistory of using an activity trackerPregnancyRecent cardiovascular events Easter Cooperative Oncology Group score of 3-4Comorbidities with impairments of mobility, such as paraplegiaOnkoFit II trialParticipation in other interventional trialsHistory of using an activity trackerPregnancyRecent cardiovascular events Easter Cooperative Oncology Group score of 3-4Comorbidities with impairments of mobility, such as paraplegiaAfter providing informed consent, patients will be included into either the OnkoFit I trial or OnkoFit II trial and randomized into 1 of the 3 arms of the studies . Both stIn this arm, patients will be advised to conduct at least 1.5 hours of moderate physical activity or 75 minutes of strenuous physical activity per week. Patients will receive an educational patient brochure (written in the German language) about the rational and potential benefits of physical activity during cancer treatment. Activity trackers will not be provided to the patients .As in arm A, patients in arm B will be advised to conduct 1.5 hours of moderate physical activity or 75 minutes of strenuous physical activity per week and will receive the previously mentioned patient brochure. In addition, patients will be given an activity tracker. They will be instructed to wear it throughout the day and document the daily step count in a patient activity diary, which will be provided to each patient. No instructions will be provided with regard to daily or weekly goals for step counts .As in the other arms, patients will be counseled about conducting 1.5 hours of moderate physical activity or 75 minutes of strenuous exercise and will receive the patient brochure. The same activity tracker as that in arm B will be given to patients. However, in arm C, patients will receive weekly goals for their average step counts during treatment. The baseline step count will be assessed from the time of informed consent provision until the time of computed tomography simulation . This period usually amounts to approximately 7 days. The patients will document daily step counts in a patient activity diary. At the time of computed tomography simulation, the mean daily step count will be calculated; this will constitute the basis for the upcoming week’s goal for step counts. If the average step count is 6000 or higher, the new goal will be to not fall under this value. If the average step count is less than 6000, the new goal will be calculated by increasing the past week’s step count average by 10%. If, for instance, the average step count is 3000 steps, the new target will be 3300 steps. The last change to the target step count will take place during the last week of radiotherapy. The highest possible target step count is 6000. This means that an average of 5800 steps in 1 week will result in a new goal of 6000 steps. We chose this 6000-step threshold based on a literature search we conducted, which suggested that a sedentary lifestyle is defined by threshold  Figure .In all arms, blood samples will be taken at baseline, at the end of radiotherapy, and at 6 months after the end of treatment. The activity trackers that will be used in this trial are commercially available accelerometers.For the OnkoFit I trial, the primary end point will be fatigue, which will be scored according to the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale. The end point will be assessed 3 months after the completion of radiotherapy. The FACIT-F questionnaire, which consists of 40 questions, was validated to assess fatigue in patients with cancer among our own patient cohort in a pilot project, which was conducted prior to the OnkoFit trials , as wellFor the OnkoFit II trial, the primary end point will be the overall HRQoL, which will be assessed by the Functional Assessment of Cancer Therapy-General sum score. This end point will be measured 6 months after the end of treatment in order to account for possible surgical interventions and possible recovery thereafter. In addition to the secondary end points listed for the OnkoFit I trial, we will assess the frequency of unplanned inpatient treatments for patients planned for ambulatory treatments and the frequency of postoperative complications (which will be assessed by using the Clavien-Dindo classification system)  in patieTreatment-related toxicities will be scored by using the German translation of the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE), which were developed by the National Cancer Institute. Briefly, the assessment of the severity and frequency of symptoms will be based on a 5-tier scale that ranges from “none” to “very severe” or from “never” to “almost always.” Depending on the treated site , specific sets of questions were created. The patient-reported outcome measurement questionnaires for patients with head and neck cancer as well as patients with thoracic and abdominal tumor lesions have been used in our department ,24. In oTo further expand our knowledge on the possible pathomechanisms behind CRF and the potential effects that exercise has on the course and severity of CRF, blood samples will be taken from patients before radiotherapy, at the end of radiotherapy, and at 6 months after radiotherapy for the evaluation of inflammatory markers, such as neutrophil counts and interleukin-6 and C-reactive protein levels.Based on patients’ preferences, patients can keep the activity tracker after the completion of treatment. Independent of this decision, patients will be seen for follow-up at 3, 6, and 12 months after the completion of radiotherapy. Thereafter, follow-ups will take place yearly for up to 5 years.f=0.25) with an α error of 5% and a power of 80%, a one-way independent sample analysis of variance was conducted. Per the results of this analysis, 201 patients (67 patients per arm) will be recruited for each trial [Previous studies were able to demonstrate a medium to high effect size with regard to the influence that physical activity has on the fatigue and HRQoL of patients with cancer. Based on a medium effect size  and are registered on ClinicalTrials.gov . The recruitment of patients started on August 1, 2020. The results will be published in a peer-reviewed journal upon the completion of the trial. As of June 2021, we have recruited 49 patients in the OnkoFit I trial and 12 patients in the OnkoFit II trial. Per our recruitment plan, 50 patients are expected to be recruited in both OnkoFit I and OnkoFit II trials per year. The reasons for the more rapid recruitment in the OnkoFit I trial than in the OnkoFit II trial are manifold. One reason is the prioritization of the OnkoFit I trial over the OnkoFit II trial during the COVID-19 pandemic. Another reason is the decline of the number of patients who are eligible for the OnkoFit II trial during the pandemic. However, we expect that the recruitment rate in the OnkoFit II will accelerate soon.The benefit of physical activity both during and after various kinds of cancer treatments has been shown in several randomized trials. Physical activity not only improves HRQoL but also has the capability to reduce the severity of negative treatment effects. With regard to patients undergoing radiotherapy, the feasibility and positive impact of combining radiotherapy with physical activity has been observed, and further clinical studies are currently being conducted  . HoweverWe see several advantages in an activity tracker–based training program. First, most activity tracker devices are easy to use and can be intuitively used by most older patients without any previous experience with such devices. Second, these devices provide real-time feedback to patients, which results in self-awareness and motivation. Third, the quantitative measures of physical activity levels can be remotely shared with caregivers, thereby providing an objective view on a patient’s constitution and whether activity goals have been met . The OnkSince acute and long-term side effects vary widely between patients with breast cancer undergoing radiotherapy and patients receiving preoperative or definitive radiotherapy, different end points were defined for the OnkoFit I and OnkoFit II trials. Additionally, the time points for assessment vary. In the OnkoFit II trial, the end point will be assessed 6 months after the end of radiotherapy and therefore later than in the OnkoFit I trial (the assessment will be conducted at 3 months), since patients receiving preoperative radiotherapy may still be in reconvalescence from surgery 3 months after the end of radiotherapy.Patients undergoing radiochemotherapy in a neoadjuvant setting are at risk of increased side effects during and after concomitant surgery if they experience (severe) toxicity after the completion of radiation treatment. The concept of prehabilitation, which is defined as a rehabilitation program that is initiated before treatment, has gained more and more recognition in the field of oncology in recent years . In two One of the limitations of the proposed study is the lack of a supervised preintervention and postintervention fitness test , which would provide a more objective perspective on the fitness levels of patients than the fitness questionnaire—the one that will be used in our trials—alone. Furthermore, the trials were designed as monocenter trials that will be conducted at a single institution, which might limit the generalizability of the data.The randomized OnkoFit I and II trials will investigate a unique approach to conducting a patient-executed fitness program during and after radiation therapy. In these trials, activity trackers will be used to improve HRQoL; reduce the severity of treatment side effects, including CRF; and improve the preoperative health status of patients. The findings of these trials will help to further our knowledge on combining exercise therapy with radiation treatment that focuses on the patient point of view.