The proportion of patients with symptomatic severe aortic stenosis treated by transcatheter aortic valve replacement (TAVR) is increasing, driven by favorable outcomes from randomized trials and current valve guidelines recommendations. Despite device and technique improvements having reduced procedural morbidities, complications during or immediately after TAVR still carries significant mortality risk.We propose a check‐list of essential items to anticipate potentially life‐threatening complications in TAVR.Purpose of this review is to discuss the most common life‐threatening complications during TAVR from a troubleshooting perspective, depicting the minimum required equipment needed in emergency situations.Prevention of complications remains the most important strategy to optimize outcomes in TAVR procedures. Each specialized Center should institute and make easily accessible standardized emergency kits for the most common life‐threatening conditions during TAVR that should be readily available in the cath‐lab or hybrid operating room. COBTcross‐over balloon techniqueCPBcardio‐pulmonary bypassEACTSEuropean Association for Cardio‐Thoracic SurgeryESCEuropean Society of CardiologyEVARendovascular aortic repairPPMpermanent pacemaker implantationSAVRsurgical aortic valve replacementSOVsinus of valsalvaSTJsino‐tubular junctionTAVRtranscatheter aortic valve replacementTHVtranscatheter heart valveViVvalve‐in‐valve1Transcatheter aortic valve replacement (TAVR) has transformed the way to treat patients suffering from severe symptomatic aortic stenosis (AS) and has become the preferred treatment. With evidence from multiple randomized trials, the latest joint European Society of Cardiology/European Association for Cardio‐Thoracic Surgery and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of valvular heart disease,Even though technological improvements and increased operator experience have led to a decrease in major periprocedural complications,2We reviewed the main periprocedural TAVR complications and described the minimum requirements in emergency kits Table  and the 33.1Due to the proximity of the AV node to the aortic valvular complex, postprocedural high‐degree or complete AV block requiring permanent pacemaker implantation are one of the most common complications after TAVR, ranging from 2% to 51% (average 17%).The diagnosis is easily achieved by intraprocedural electrocardiogram monitoring; most frequently the electric disturbances appear after the valve deployment; in a small percentage the blocks are delayed, hours or even days after the procedure.before removing the wire.A bailout strategy for managing high‐degree blocks is crucial, especially in the setting of minimalist TAVR approach with pacing through the left ventricular wire. In the latter case, especially when implanting self‐expanding devices that require guidewire maneuvering to and from the left ventricle, it is important assuring that major heart rhythm disturbances have not developed The bailout strategy involves prompt transvenous pacing. The venous access and 6F sheath introduction are achieved by a classic Seldinger technique. The sheath harbors the passage of a multipolar catheter to be connected to an external pulse generator. The use of a guiding catheter can be useful to navigate the right ventricle in case of super‐acute cavo‐atrial boundary. A VVI setting at the appropriate sensing ad energy output is recommended.If the patient remains temporary pacemaker‐dependent, assure proper fixation of the electrodes to the skin and consider to exchange for an atraumatic pacing catheter, especially in the context of very elderly patients at risk of right ventricular perforation. Check the settings and battery level of the pulse generator. Always have a spare battery to the pulse generator in the patient's room!3.2One of the most fearful complications after TAVR is hemopericardium Figure ; any timThe key for the success is to quickly evacuate the pericardial space due to cardiac tamponade and possibly facilitate the clotting process. The diagnosis is made by clinical and echocardiographic evaluation .Two tools are mandatory in this context: a pericardiocentesis set and a cell saver.3.3The emergent pericardial drainage could be performed under transesophageal, transthoracic and/or fluoroscopic guidance. Full reversal of the anticoagulation state by the infusion of protamine should be pursued on a case‐by‐case basis since it can risk thrombus formation.In the normal TAVR scenario a fluoroscopic‐guided procedure is often performed using the antero‐posterior and lateral projections to remark the pericardial shadow.In case of a more severe bleeding, a direct blood reinfusion through the femoral introducer sheath could be performed after heparin readministration.a full dose of heparin before sternotomy to establish peripheral cardiopulmonary bypass , with a standard set including pump, oxygenator, reservoir and multiple suction lines, because in most occasions the lesion leading to massive bleeding requires full mechanical support and the possibility to reinfuse the aspirated blood drainage. On some occasions the lesion can be repaired on the beating heart, otherwise a cardioplegic arrest is needed to facilitate a complex repair . In case of myocardial lesions from guidewire perforation we recommend using large sutures with large needles and large Teflon pledgets to mattress the ventricular wall, since the bleeding spot appearing on the surface is often larger than it appears.In case of intractable bleeding a prompt sub‐xiphoid surgical drainage or full sternotomy is mandatory. A good rule of thumb is to observe the amount of bleeding in the first 5 min. If the bleeding is more than 300 ml per minute after 2–3 min, or if the patient remains severely unstable, then conversion to surgery is mandatory. In our practice, we deliver 3.3.1Cell savers are instruments that collect and gather blood lost during surgery or complex interventional procedures. The red blood cells (RBCs) are washed with normal saline and concentrated to make an approximate 225 ml unit with a hematocrit of approximately 55% that can be stored or immediately reinfused to the patient. This tool is effective to promptly restore the normotonic volemia.The system works by the connection of the Pigtail catheter draining the hemopericardium to an outflow‐line to the central venous access.The cell saver is useful given its quick setup, reducing the delay in seeking allogenic blood units. Cell saver could be also useful in cases of complex surgical correction.3.4The VARC‐3 3 definesValve embolization refers to the valve prosthesis movement during or after the deployment such that it loses its contact with the aortic annulus.Device embolization is currently a relatively rare complication of TAVR (0.92% in the largest multicenter TRAVEL registry),More than 80% of valve migration is immediately peri‐procedural, 15% within the first hour and only 3% thereafter. The diagnosis is made from fluoroscopy and echocardiogram.In most cases the preferred management is to address the issue via catheter‐based approaches.1.Repositioning the transcatheter heart valve (THV)2.Implanting a second valve or valve‐in‐valve (ViV)3.Conversion to surgeryThree are the main bailout strategies to be pursuit:In case of THV embolization Figure  rule #1 (a)where to place the embolized valve? Snare Figure  and pull(b)in case you decide (or you need) to leave the embolized prosthesis in the ascending aorta, retrieve it distal to the the Sinus of Valsalva (SoV) to avoid coronary occlusion after second THV deployment and, before advancing the second valve, secure it with a snare while you are advancing the delivery system carrying the second THV, to prevent any migration toward the SoV.It is crucial to achieve an additional arterial accessfor the snare to be able to keep the snared valve in position while advancing the second one(c)choose the most appropriate second THV according to the patient's anatomy to reduce the risk of coronary occlusion(d)if the wire position was not lost, proceed with delivering the second device.Here are our proposed management steps:If wire position was lost, the embolized valve must be re‐crossed, using a Pigtail catheter to avoid crossing and getting stuck within stent struts.Once a central position of the guidewire is achieved the native aortic valve must be recrossed and, holding the embolized valve in place with a snare, the second valve can be implanted as usual.Terumo, Shibuya, Tokyo, Japan) across one strut of the THV, and try to catch the wire with the snare.In case one cannot grasp the valve frame with the snare it is useful to get a Terumo glidewire  TAVR, despite the relative low‐profile sheaths of currently available devices, more accurate preprocedural planning and micro‐puncture access along with ultrasound or fluoroscopic‐guided access and preclosure techniques.Pelvic vascular injuries such as bleedings Figure  and dissOn the other hand, injuries of the great vessels  are rarer but can be catastrophic, needing surgical or endovascular bailout strategies but carries a poor prognosis.In case of using radial artery as secondary arterial access to perform bailout strategies,3.6The diagnosis of ileo‐femoral dissection, disruption or pseudoaneurysm is suspected clinically and confirmed by fluoroscopy, typically by digital subtraction angiogram.Cross‐Over Balloon Technique from the contralateral common femoral artery could be performed over a “0.018” or “0.035” guidewire and with a 5Fr IMA , UF  or JR (Judkins right) catheter. An appropriately sized balloon catheter inflated proximally to the lesion allows achieving temporary hemostasis while appropriate final treatment is planned.In small, localized dissection a balloon dilatation for 15 min can be sufficient to achieve vascular sealing. Otherwise, a peripheral stent is required. Consider partial reversal of the heparinization effect to facilitate hemostasis. Peripheral self‐expanding covered stent‐grafts may be needed in case of vessel lacerations. Make sure to apply an oversizing of at least 15% to prevent endoleaks. A preventive crossover wire is a good option in case of complex femoral anatomies with high risk of periprocedural lesions.In case of very challenging cross‐over anatomies , the alternative is to perform a ipsilateral distal access puncturing the superficial femoral artery to place the stent retrogradely. In this case it is fundamental to puncture the distal access at a sufficient distance to allow easy and effective maneuvering.Involving a vascular surgeon early or pre‐emptively may avoid these potential complications and can be life‐saving.3.7This rare by devastating complication is suspected clinically by the rapid onset of profound hypotension, generally soon after valve deployment, or device's introducer insertion or removal.At fluoroscopy, a huge extravasation of contrast medium or an evident intimal flap may appear. The first goal is to avoid exsanguination. An occlusive balloon inflated just proximal to the rupture site may help buy time to provide further interventional treatments such endovascular aortic repair (EVAR) with available endografts.Open surgery can also be an option, particularly dissection of the ascending aorta that may occur either after wire and catheters manipulations or after valve deployment Figure .3.8Acute coronary obstruction after TAVR is a rare but potentially devasting complication, carrying as much as 50% of mortality.In recent years, the development of the interventional technique called BASILICAIt is well‐established that ViV procedures, especially those involving stentless bioprosthesis or stented bioprosthesis with externally mounted leaflets, low‐coronary ostia  and a shallow SoV and sino‐tubular junction (STJ) present a four to sixfold increased risk of coronary obstruction.An accurate preprocedural evaluation, including a planning for adjunctive techniques for coronary protection such as prophylactic chimney snorkel3.9Life‐threatening TAVR complications causing refractory cardiogenic or hemorrhagic shock can be managed by expeditious institution of CPB as a bridge‐to‐decision with temporary cardio‐respiratory support.We do not use ECMO systems unless there is a need for postoperative mechanical circulatory support. The fastest way to institute the mechanical support is using the primary femoral vascular access site as the default entry for cannula placement.The arterial cannula should be advanced to the common iliac artery, not too deep to reduce the risk of ipsilateral hypogastric ischemia (check at fluoroscopy!). Alternatively, if the large‐bore TAVR introducer sheath is already in place in the femoral artery, inserting a venous cannula  directly through the sheath with the cannula tip positioned at the descending aorta reduces the risk of vascular complication by avoiding sheath exchanges, while providing expeditious CPB with adequate flow to stabilize the patient to guide further management decisions. The venous cannula consists of two stages and should be advanced through the cavo‐atrial junction to maximize the blood drainage under fluoroscopic and transesophageal echocardiographic guidance. The de‐airing process while connecting the cannulae to the CPB machine is crucial for the arterial outflow; this can be achieved by a gentle flushing of sterile saline while connecting the tubings to the CPB circuit.Before the patient being transferred, securing the cannula by silk stitches on the skin and proper dressing is mandatory to avoid cannula dislodgment or removal.4Although serious TAVR complications are quite rare in the current era, they still carry significant morbidity and mortality. Prevention remains the most important strategy but when a complication occurs, it is crucial to make a prompt diagnosis and treatment plan. In the absence of international guidelines, each operator normally adopts “personal” protocols that may be not be standardized, leading some delay in the management even within the same Institution.5Each specialized Center should institute and make easily accessible standardized emergency kits for the most common life‐threatening conditions during TAVR that should be readily available in the cath‐lab or hybrid operation room. It may improve the readiness of the team to treat the emergency situation and may help improve the outcome.Gilbert H.L. Tang: physician proctor for Medtronic; is a consultant for Medtronic, Abbott, and NeoChord; and is an advisory board member for Abbott and JenaValve. Maurizio Taramasso: consultant for Abbott Vascular, Boston Scientific, 4tech, CoreMedic. Speaker fees from Edwards Lifesciences. Francesco Maisano: Grant and/or Research Support from Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific Corporation, NVT, Terumo Consulting fees, Honoraria from Abbott, Medtronic, Edwards Lifesciences, Xeltis, Cardiovalve. Royalty Income/IP Rights: Edwards Lifesciences. Shareholder (including share options) of Cardiogard, Magenta, SwissVortex, Transseptalsolutions, Occlufit, 4Tech, Perifect. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Marco Gennari and Gilbert H.L. Tang: conceptualization and writing. Maurizio Taramasso, Marco Barbanti, and Francesco Maisano: supervision. Giulio Russo, Ana Paula Tagliari, and Philipp Haager: data curation.


Oxygenic photosynthesis produces ROS in abundance, which act as a readout of a functional electron transport system and metabolism. The concept that photosynthetic ROS production is a major driving force in chloroplast to nucleus retrograde signalling is embedded in the literature, as is the role of chloroplasts as environmental sensors. The different complexes and components of the photosynthetic electron transport chain (PETC) regulate O2●− production in relation to light energy availability and the redox state of the stromal Cys‐based redox systems. All of the ROS generated in chloroplasts have the potential to act as signals and there are many sulphhydryl‐containing proteins and peptides in chloroplasts that have the potential to act as H2O2 sensors and function in signal transduction. While ROS may directly move out of the chloroplasts to other cellular compartments, ROS signalling pathways can only be triggered if appropriate ROS‐sensing proteins are present at or near the site of ROS production. Chloroplast antioxidant systems serve either to propagate these signals or to remove excess ROS that cannot effectively be harnessed in signalling. The key challenge is to understand how regulated ROS delivery from the PETC to the Cys‐based redox machinery is organised to transmit redox signals from the environment to the nucleus. Redox changes associated with stromal carbohydrate metabolism also play a key role in chloroplast signalling pathways.Reactive oxygen species (ROS) such as singlet oxygen, superoxide (O Chloroplasts are major producers of reactive oxygen species (ROS) that are important signals in the communication between the chloroplasts and the nucleus. The photosynthetic electron transport chain (PETC) has evolved to control ROs production and thus limit collateral damage while facilitating essential signalling functions. We consider current concepts of ROS production and processing in chloroplasts, highlighting new directions and gaps in our current knowledge. In addition, large amounts of H2O2 are generated in peroxisomes as a result of the metabolism of phosphoglycolate, which is produced by and exported from chloroplasts during photorespiration  not only drives photosynthetic carbon assimilation, but it also generates a repertoire of signals that link energy generation to environmental changes and nuclear gene expression. Photosynthetic metabolism is coordinated with daily and seasonal environmental variations and rhythms in physiology and development are matched to carbon availability  processes because they are capable of acting as either electron donors (reductants) or acceptors (oxidants). Within the context of chloroplast redox biology, these include low molecular weight antioxidants such as ascorbate and α‐tocopherol, glutathione (GSH) and thiol proteins such as thioredoxin (TRX) and peroxiredoxins (PRX). In this way they can drive redox regulation and/or redox signalling  complex, by slowing re‐oxidation of plastoquinol (PQH2) when lumen pH is low  of oxidised chlorophyll  to form the highly reactive 1O2. This occurs when excited chlorophyll  drops down to the lower energy triplet state or following a charge recombination reaction at PSII due to the lack of an electron acceptor . H2O2 can then be reduced to water by chloroplast APXs and 2‐Cys PRXs  and the PSI acceptor side (O2●−), but production of free radicals has been measured from several other sites in the light‐harvesting and electron transport apparatus. In some cases, these sites could contribute a significant proportion of ROS generated  is not available in an oxidised state. Moreover, the PhQ molecules at the A1 sites may also reduce oxygen  reductase (FNR) using a flavin (FAD) cofactor. Discrepancies between supply of reduced Fd (a one electron carrier) and NADP+ (a two electron acceptor) can leave this cofactor in a single electron reduced (semiquinone) state, which also readily reduces O2  has recently been solved  has a redox potential capable of reducing O2 in the lipid environment, but it has such a short lifetime it is unlikely to contribute  of the Cyt b6f complex  Mn cofactors within the electron transport chain  in the processes of PSII repair. For example, oxidation can limit the replacement of damaged D1 proteins because the EF‐Tu translation factor, which is required for delivery of aminoacyl‐tRNAs to the ribosomes, is inactivated by oxidation of the susceptible Cys82 residue , as well as 12 nuclear‐encoded PEP‐associated proteins (PAPs)  suggests the possibility of redox control of chloroplast gene expression. However, the phenotype of the 2●− radicals into H2O2, and it is likely that this is their function in the PEP complex. If this is the case, the stromal APXs (sAPXs) may be sufficient to remove the H2O2 produced by these enzymes. Alternatively, TRXz may protect the transcriptional machinery from H2O2‐mediated oxidation  protein is induced by oxidative stress but not by light  that captures light and transfers energy to the reaction centres. The activation state of STN7 is regulated by the Cyt b6f complex, in response to changes in the balance between the oxidised (PQ) and reduced (PQH2) forms of PQ   under high light conditions  are characterised by their relative reactivities and lifetimes. As such they are likely to function as discrete redox signals that trigger different pathways to regulate the expression of specific suites of nuclear genes. O2●− has a relatively low level of reactivity but it can react with ascorbate, plastocyanin and nitric oxide. Crucially, O2●− radicals can inhibit the activities of FeS (4Fe–4S) cluster‐containing proteins by releasing iron. The chemical or enzymatic dismutation of O2●− generates H2O2, which is removed by enzymes such as APX and PRX. However, these enzymes do not serve to completely eliminate H2O2 from the chloroplasts, but rather to prevent excessive accumulation of this oxidant. H2O2 signalling occurs primarily though the oxidation of protein Cys residues. The oxidation of the redox‐sensitive Cys thiols on proteins leads to the reversible formation of sulphenic acid (‐SOH) that is stabilised by forming a disulphide bond (S‐S) with a nearby thiol or a mixed disulphide bond with reduced GSH. ROS‐mediated Cys oxidation occurs on proteins that are located close to the sites of ROS production. ROS can react with diverse protein side chains and they have no specificity for reactive Cys. PTMs of Cys residues may occur either through dithiol–disulphide exchange reactions or through reactions in which particular protein Cys residues are oxidised by ROS, reactive nitrogen species or reactive sulphur species  may play a role in the regulation of retrograde signalling that operates in plant responses to environmental stresses , β‐ionone or dihydroactinidiolide (dhA), some of which are volatile  and UDP‐glycosyltransferases , which negatively regulates 1O2‐mediated stress responses at the grana margins  was recently shown to be a sensor for extracellular H2O2  the oxidised and reduced forms of antioxidants such as ascorbate and tocopherols can themselves contribute to the transmission of signals is largely unexplored. There are many sulphhydryl‐containing proteins and peptides in chloroplasts that have the potential to act as H2+‐permeable channels belonging to the glutamate receptor‐like, mechanosensitive small conductance‐like and cyclic nucleotide‐gated families that amplify the systemic signal in each cell along the path of the systemic ROS wave. In addition, alteration of the plasmodesmatal (PD) pore size through regulation of PD‐localised protein 1 (PDLP1) and PDLP5 is required for the propagation of the systemic ROS signals . These signals are propagated over long distances throughout the plant in a rapid cell to cell communication process called the ‘ROS wave’ (Fichman et al., in vitro chloroplast redox proteomic studies, only about 20 have been characterised in terms of redox regulation in vivo (Geigenberger et al., Recent advances in high throughput thiol redox proteomics are starting to improve our understanding of redox mechanisms in chloroplasts. Of the thousands of potential TRX targets identified through 1Spatio‐temporal control of ROS production is achieved through specific regulation of key PETC components. In some cases, for example the NDH/PSC1 complex, the capacity of these components to contribute to the chloroplast ROS budget remains unknown.22●−, production and signalling remain to be elucidated. The various assembly states of the photosystems and the different PSII forms that are produced in the repair cycle are likely to vary in their capacities to generate ROS. Similarly, it remains to be determined whether thylakoid regulation involves the formation of biomolecular condensates, micron‐scale membraneless compartments formed by liquid–liquid phase separation and other interactions that constrain chemical reactions.The structural aspects of protein–protein interactions that dictate the specificity of O31O2 production suggests the possibility that other metabolites may fulfil similar roles and that primary metabolism may exert feedback control on primary processes.The demonstrated role of photorespiratory metabolites in the control of 4The regulation of fluxes through alternative electron transport pathways that modulate ROS production remains poorly understood and merits further characterisation. Similarly, the specific roles of the different TRX and PRX forms in this regulation remain to clarified.5The redox regulation of the PEP complex remains poorly understood, particularly regarding the functions of components such as TRXz, PAP4/FSD3 and PAP9/FSD2.6Redox control of chloroplast functions involves numerous intersecting pathways that may include specific ROS sensors, whose role is to transmit information concerning the energy status to the nucleus. Depending on environmental conditions, the relative activity of these pathways will vary in ways we are yet to fully understand.7The existence, nature and functions of ROS receptor proteins in chloroplasts remain to be demonstrated, as well as the mechanisms by which transmission of ROS signals from the chloroplasts to the nucleus and other cellular compartments is controlled.8S‐nitrosylation, S‐glutathionylation, S‐sulphhydration and S‐sulphenylation that can influence protein stability and localisation or instigate alternative protein–protein interactions and functions remains to be elucidated.Chloroplasts are rich in protein Cys residues that are able to undergo reversible oxidation. The functional operation of different redox PTMs such as 92O2 production (Guo et al., The redox state of the apoplast that is controlled by the levels of ascorbate and ascorbate oxidase (Karpinska et al., 10Thiol‐based redox regulation plays a central role in determining photosynthesis‐related metabolic fluxes in dark/light transitions and responses to sunflecks and other transitions in irradiance. The relatively slow activation of CBC enzymes in response to such changes is a potential limitation to photosynthesis and hence crop yields. Is it therefore possible to modulate the activities of redox‐related components to ensure more effective activation and deactivation capacities?The following open questions concerning the mechanistic regulation of PETC functions and oxidative signal generation and transduction remain to be addressed. Filling in these gaps in current knowledge will be essential in order to develop new strategies for crop improvement by tailoring reductive and oxidative signal generation and perception to improve photosynthesis in crop plants under suboptimal environmental conditions.


Coronavirus disease 2019 (COVID‐19), the highly contagious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread worldwide with millions of cases and more than 5 million deaths to date. SARS‐CoV‐2 has caused serious damage all over the world with many countries experiencing the third or the fourth wave of the viral disease outbreaks, mainly due to the emergence of mutant variants. Those who unvaccinated remain most vulnerable to COVID‐19 and its variants. COVID‐19 vaccination, along with prevention strategies, is a critical measure to defense against the disease. COVID‐19 vaccination can reduce the spread of virus and help protect susceptible population. Although herd immunity might not be realized solely by vaccination, COVID‐19 vaccines have been proved to be effective in reducing the risk of severe disease, hospitalization, and even death. It is recommended that people get vaccinated as soon as they are eligible. This review summarizes the recent SARS‐CoV‐2 variants that brought challenges for vaccination and herd immunity and discusses promising management strategies. A. Vaccination induces production of protective antibodies to block the receptor binding domain (RBD) of spike protein from binding to the host angiotensin‐converting enzyme‐2 (ACE‐2) receptor; B. Mass vaccination in population establishes immune barrier, while no vaccination or few vaccination is at risk of COVID‐19 spreading. ACE2angiotensin‐converting enzyme 2ARDSacute respiratory distress syndromeCOVID‐19coronavirus disease 2019IPCinfection prevention and controlPHSMpublic health and social measuresRCTsrandomized controlled trialsSARS‐CoV‐2severe acute respiratory syndrome coronavirus 2VOCvariants of concernVOIVariants of InterestVUMvariants under monitoringWHOworld health organization1Coronavirus disease 2019 (COVID‐19), the highly contagious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread worldwide with experiencing many waves of the viral disease outbreaks,2Viruses, like SARS‐CoV‐2,Continuous evolution of SARS‐CoV‐2 mutant variants has brought challenges to global public health. The world health organization (WHO) have been monitoring and assessing the evolution of SARS‐CoV‐2 since January 2020. The emerging variants were classified as the variants of interest (VOI) or variants of concern (VOC) based on their attributes and prevalence Table . If signGlobally, 193 countries, territories, or areas have been reported cases of the alpha variant, while 142 countries reported cases of beta variant, and 96 countries reported cases of gamma variant. For the delta variant, it has been reported in over 185 countries so far.SARS‐CoV‐2 alpha variant was highly transmissible.After alpha, beta variant acquired higher infectiousness by immune escape. The infection rate of beta variant was about 50% higher than that of the original SARS‐CoV‐2 virus, and the risk of hospitalization, severity, and mortality were also higher. Beta variant also increased its transmission by N501Y mutation and avoided the human immune system tracking by E484K mutation.Gamma variant was the biggest threat of epidemic in South America. Patients with the infected variant might have reinfection. There was two times of transmissibility in Gamma variant than the original SARS‐CoV‐2 virus.Delta variant was responsible for the deadly second wave of COVID‐19 in India.Omicron variant has been considered to be the most ferocious new variant by far. There were 32 mutations in omicron variant, which is twice that of delta variant, and the number of spike protein mutations is the largest. Ten mutants were found in the RBD of omicron variant and only two in delta variants. These mutations in spike proteins had been found in delta and alpha variant and were relate to transmissibility or immunity evasion.3Vaccination against COVID‐19 has become a critical public health solution as global pandemic of COVID‐19 continues to worsen throughout the world. There were more than 400 randomized controlled trials (RCTs) and 200 nonrandomized studies of vaccines for COVID‐19.Many studies showed effectiveness of vaccines in COVID‐19. Vaccines reduced the risk of symptomatic and asymptomatic disease and might therefore reduce the spread of SARS‐CoV‐2.Some vaccines could still provide fine protection for SARS‐CoV‐2 variants. In the aspect of vaccine efficacy, AstraZeneca vaccine was effective against alpha variant with an effectiveness of up to 90% after a second regimen.Emergency use of a single booster shot of the Pfizer‐BioNTech vaccine has been authorized in the United States. Certain populations were eligible to receive a booster shot at least 6 months after receiving their second shot, including people aged ≥65 years, people aged ≥18 years who have underlying medical conditions, and people aged ≥18 years who live or work in high‐risk settings.4Herd immunity is an important concept for epidemic control. A proportion of population needs to be immuned by natural infection or vaccination to stop generating large outbreaks.However, the impacts of the pandemic are felt unequally across the world, with varying public health strategies leading to different epidemic trajectories. Due to the challenges of vaccine supply and promotion, coupled with the potential emergence of highly infectious SARS‐CoV‐2 variants, it was controversial whether current vaccination strategies would generate herd immunity. A study from Korea showed that even with the SARS‐CoV‐2 variants, vaccination program may significantly reduce the disease burden associated with COVID‐19, such as symptomatic infection, hospitalization, and death.The issues in dealing with COVID‐19 pandemic were how and when herd immunity would be achieved and at what we should cost, especially as more transmissible SARS‐CoV‐2 variants continue to emerge.5In transmission of SARS‐CoV‐2 variants, public health and social measures (PHSM) including infection prevention and control (IPC) measures have been proved effective in reducing COVID‐19 cases, hospitalization, and death. COVID‐19 vaccination can also reduce the spread of SARS‐CoV‐2 and help to protect both oneself and people around. Many countries struggling with continuous waves of COVID‐19 are encouraged to strengthen existing PHSM and IPC measures and monitor the spread of SARS‐CoV‐2 variants by detecting unusual epidemiological events. Reducing transmission and avoiding introductions of animal populations through established and proven disease control measures are essence of the global strategies to reduce occurrence of mutations.6The prioritization population has been recommended for vaccination based on underlying physiological differences and epidemiological features of COVID‐19 deaths during the first wave.7The incidence and mortality of COVID‐19 were lower in children than adults in the early waves of infection. And children infected with SARS‐CoV‐2 present mild symptoms or were asymptomatic. However, the mortality of COVID‐19 was higher in children (aged 0–18 years) during recent delta variant outbreak in Malaysia.A number of population‐based SARS‐CoV‐2 seroprevalence and viral shedding studies investigated whether the infection rate in children was the same as that in adults. Children infected with SARS‐CoV‐2 spread the virus in their respiratory tract and possible in their feces.8Immunocompromised patients including those with solid tumors or hematologic malignancies, solid organ transplant recipients, hematopoietic cell transplant recipients and patients with human immunodeficiency virus (HIV), and primary immunodeficiency were at higher risk of developing COVID‐19‐related severe outcomes.9To obtain safe and effective outcomes, applying risk–benefit assessments and shared decision models to the massive COVID‐19 vaccination is needed. The potential life‐saving benefit of vaccination in the setting of global pandemic makes it important to assess every patient who may have an allergic reaction to prevent unnecessarily refusal of vaccination. For highly allergic individuals, professional guidance recommended appropriate information and support to receive the COVID‐19 vaccines. The patients with potential allergic reaction to the first dose of SARS‐CoV‐2 vaccine should be carefully evaluated to determine whether there is a real allergic reaction occurred and decide whether and how to receive the second dose.10Lessons learned from other outbreaks, for example, Ebola, suggested that there are individual differences in vaccine confidence gap.Vaccination decisions are influenced by people's social interactions, such as family members, friends, health professionals, and others who interact with them. The encouragement and social pressure from people whom they respect and trust increased vaccine uptake. The willingness or unwillingness to vaccinate can be transmitted through the social cascade when one group affects another group, and then the two influence the third, and so on. Targeting health professionals who have more opportunities to influence vaccination behavior would have a greater impact on behavior changes.Trust in COVID‐19 vaccine would be crucial to its success. Further trials to investigate efficacy in older adults are now needed. Efficacy is considered including the longevity effects, reduction in severe infections, and safety in high‐risk groups. The approaches to enhance vaccine acceptance among people were important for the mass vaccination: (1) highlighting norms in favor of vaccination, (2) leveraging the role of health professionals, (3) supporting health professionals to promote vaccination, and (4) amplifying endorsements from trusted community members.11A novelty of COVID‐19 oral antiviral candidate PF‐07321332 (Paxlovid).PF‐07321332 was designed to block the activity of the SARS‐CoV‐2‐3 CL protease, an enzyme that is required in replication. PF‐07321332 inhibited viral replication at a stage known as proteolysis, which occurs before viral RNA replication, while it did not demonstrate evidence of mutagenic DNA interactions in preclinical studies.12Similar to influenza virus, vaccines might be formulated every year to match the SARS‐CoV‐2 variants, as they evolve antigenically owing to antigenic drift.13As living together with COVID‐19, millions of people have multiple episodes of a mild sore throat and lost productivity in few days with the highly transmissible and unstable virus. Post‐COVID‐19 syndrome is one of the challenges, having become increasingly common as the pandemic evolves. The latest estimates suggest that 10% to 20% of the COVID‐19 patients who undergo an acute symptomatic phase are experiencing effects of the disease beyond 12 weeks after diagnosis.Last but not the least, efforts are needed to increase vaccination coverage, especially as prioritization population such as the elder, multicomorbidities, immunocompromised person, and children under the age of 5 years have not yet been vaccinated. To maintain nonspecific prevention strategies is necessary. The use of PHSM including physical distancing, cleaning hands, coughing to bent elbow or paper, and adequate ventilation in indoor environment and masks should be consistently and appropriately implemented.The authors report no conflicts of interest.None.Hou DN contributed in concept and design, manuscript preparation, and editing. Chen CC and Bi J did literature search and manuscript editing. She J designed the study and did manuscript preparation and editing. Song YL contributed in concept and design and reviewed this manuscript. The manuscript has been read and approved by all the authors. The requirements for authorship have been met. Each author believes that the manuscript represents honest work.


Optical nanoantennas provide control of light at the nanoscale, which makes them important for diverse areas ranging from photocatalysis and flat metaoptics to sensors and biomolecular tweezing. They have traditionally been limited to metallic and dielectric nanostructures that sustain plasmonic and Mie resonances, respectively. More recently, nanostructures of organic J‐aggregate excitonic materials have been proposed capable of also supporting nanooptical resonances, although their advance has been hampered from difficulty in nanostructuring. Here, the authors present the realization of organic J‐aggregate excitonic nanostructures, using nanocylinder arrays as model system. Extinction spectra show that they can sustain both plasmon‐like resonances and dielectric resonances, owing to the material providing negative and large positive permittivity regions at the different sides of its exciton resonance. Furthermore, it is found that the material is highly anisotropic, leading to hyperbolic and elliptic permittivity regions. Nearfield analysis using optical simulation reveals that the nanostructures therefore support hyperbolic localized surface exciton resonances and elliptic Mie resonances, neither of which has been previously demonstrated for this type of material. The anisotropic nanostructures form a new type of optical nanoantennas, which combined with the presented fabrication process opens up for applications such as fully organic excitonic metasurfaces. Optical nanoantennas based on organic anisotropic J‐aggregate materials with strong exciton absorption provide dual functionality in the same nanostructure. They can support hyperbolic localized surface‐exciton polariton resonances on one spectral side of the exciton resonance while they support elliptic Mie resonances on the other side. The first type is metallic nanostructures, strongly interacting with light via excitation of their localized surface plasmon resonance (LSPR). The origin of the plasmonic response is the negative real part of the permittivity of metallic materials, where the restoring forces on free charge carriers lead to resonant collective oscillations. The resulting electric field enhancement is confined in the surrounding area outside the nanostructures. While plasmonics research has primarily been restricted to inorganic metals like gold and silver, we recently introduced organic conducing polymers for a new type of dynamic plasmonics based on redox tuning. The other main type of nanooptics is based on dielectric nanostructures made of high refractive index materials. They can also strongly interact with light, but via Mie resonances instead of plasmons. The origin of Mie resonances is the optical geometry of the nanostructures. For example, the magnetic dipole resonance, which is the lowest order Mie resonance, occurs when the wavelength of light confined inside the nanostructures becomes comparable to their optical dimension . Materials with high refractive index, and thus large positive permittivity, are required for nanostructures to support Mie resonances in the visible spectral range. For high resonance quality factors it is also essential to have a large contrast in refractive index between the nanostructure and the surrounding media, which lowers radiation leakage and improves field confinement.Nanostructured materials are essential building blocks in nanooptics. Their unique ability to manipulate light at the nanoscale, which cannot be found in their non‐structured counterparts, facilitates a multitude of applications including biosensing, flat optics, holography, subwavelength super‐resolution imaging, etc.4, 5 The relative permittivity of such materials with a single Lorentz type exciton resonance can be described asω0 is the resonant angular frequency, f is the reduced oscillator strength of the excitonic transition, γ is the damping rate and εb is the nonresonant background permittivity of the material. The imaginary part of the permittivity forms a peak responsible for the dissipative absorption of the material, whereas the real part of the permittivity shows a peak‐dip feature in consequence of the Kramers–Kronig relations. Interestingly, if the oscillator strength is large and the damping rate is small, the dip in the real permittivity can reach below zero, meaning that the material behaves optically like a metal in this region. This opens up for excitation of surface exciton polariton (SEP) resonances that resemble plasmons yet originate from electron‐hole pairs instead of free charge carriers as for plasmonic materials. Low temperature measurements were required for the observation of SEPs in inorganic materials, because of the binding energy of Wannier–Mott excitons being lower than room temperature thermal energy. By contrast, the high binding energy of Frenkel excitons in organic materials has enabled observation of propagating SEPs even at room temperature.Organic excitonic materials with strong and narrow absorption, such as J‐aggregated molecules, have recently been proposed as alternatives to achieve metal‐like negative permittivity in certain spectral ranges, even though they do not have free charge carriers.12 The nanodisks and nanodisk dimers, and core‐shell structures. Even surface lattice resonances in periodic arrays have been suggested, based on the assumption of existence of LSEPs. However, the realization of these systems and the associated observation of LSEPs have been hampered not least because of fabrication challenges. For instance, conventional photo‐/electron‐beam‐lithography techniques cannot be directly applied to these relatively vulnerable organic solids. Up to date, the most successful attempts at nanostructuring excitonic material is local bleaching of thin films via electron beam or femtosecond laser exposure.Nanostructured organic excitonic materials are of particular interest because they are expected to support localized surface exciton polaritons (LSEPs) with subwavelength light confinement, resembling LSPRs of metallic nanostructures. A series of optical calculation studies have predicted LSEPs in various organic excitonic nanostructures, including nanospheres,16 nan assisted by reactive ion etching (RIE). Atomic force microscopy (AFM) images confirm that this method is suitable for nanostructuring sensitive organic materials with sub‐hundred‐nm lateral resolution. The resulting nanostructures support not only plasmon‐like resonances, but also Mie‐like resonances, providing dual functionality. This intriguing result is attributed to the excitonic material having both a negative permittivity region where it behaves optically as a metal and a closely spaced spectral region with large positive permittivity where the material instead behaves as a high index dielectric. Furthermore, we show that the permittivity of the organic excitonic thin films is highly anisotropic, as attributed to an anisotropic nature of the J‐aggregate structures. As a result, the material provides hyperbolic (elliptic) isofrequency surface in the negative (positive) permittivity regions, respectively. The nanostructures thereby support hyperbolic LSEPs and elliptic Mie resonances, with spectra showing good agreement with simulated results using the finite‐difference time‐domain (FDTD) method. The simulations further reveal the characteristic nearfield distribution of the resonance modes in the anisotropic excitonic nanostructures.In this study, we experimentally realize well‐defined nanostructured J‐aggregate materials using solvent‐assisted nanoscale embossing (SANE)22 ass2Figure As organic J‐aggregate excitonic material, our study employed the J‐aggregated cyanine dye TDBC benzimidazol‐2‐ylidene]propenyl]‐1‐ethyl‐3‐(4‐sulfobutyl)benzimidazolium hydroxide, inner salt, sodium salt). TDBC doped polyvinyl alcohol (PVA) films have been widely utilized especially when strong oscillator strength is necessary, such as in strong light‐matter coupling, because PVA increases the wettability and stability of TDBC, while maintaining the J‐aggregate structure of the TDBC. However, increasing PVA concentration inevitably leads to a decrease in the number of TDBC molecules per volume, which weakens the intensity of the J‐band absorption. To maintain maximum J‐band absorption, we therefore used pure TDBC throughout this study.Figure 2 plasma reactive ion etching (RIE) to form cylindrical TDBC nanostructure arrays with different diameters. AFM imaging after the final fabrication step confirmed that our method was able to successfully produce TDBC nanocylinders of the desired dimensions down to 50 nm in diameter  are in accordance with a typical Lorentzian type exciton resonance (Equation (εz) showed almost no resonant features and positive values in the whole measured spectral range , which show distinct differences from the experiments  measurements to provide further details on the anisotropic nature of the TDBC films from which the nanocylinders are made Figure 4. ResulFigure xz‐plane  of the TDBC nanocylinders for the wavelengths where the absorption cross‐section exhibits resonant peaks, as designated with colored inverted‐triangle markers in Figures d = 100 and 150 nm) seem to support LSEP resonances in the negative permittivity regions, showing dipolar nearfield profiles resembling LSPRs. However, in contrast to LSPRs of traditional (isotropic) metals, the electric field penetrates into the anisotropic nanostructure and induces a magnetic field near the center , where the hyperbolic polariton propagation is directionally restricted at a fixed angle. Similar nearfield profiles have been reported in previous studies of hexagonal boron nitride  nanocones. The resonances in the negative permittivity region for the anisotropic TDBC nanostructures should therefore be referred to as hyperbolic LSEPs. On the contrary, the fictitious isotropic TDBC acts like a normal metal in the negative permittivity region and prohibits electric field penetration due to evanescent decay of the electromagnetic field into the nanostructure  in contrast to the anisotropic nanocylinders, as attributed to different geometry‐dependence of LSEPs and hyperbolic LSEPs.To further investigate the characteristics of the nanooptical resonances in our system, we analyzed simulated electric and magnetic nearfields for each resonance. y‐direction at the center of the nanocylinder  where the permittivity changes sign . Thereby, this finding should rather be understood as the disappearance of one type of resonance and the appearance of another when crossing the exciton resonance position. In this respect, the nearfield cross‐hatch pattern forms a signature of hyperbolic polaritons and becomes a key feature to identify the type of resonances. We note that the nearfield profiles for both resonances in the negative permittivity region (marked in red) show these cross‐hatch patterns whereas those in the positive permittivity region  do not  negative permittivity and elliptic properties in the positive permittivity region. The organic excitonic nanostructures could therefore support hyperbolic LSEP resonances and elliptic Mie resonances in these two different spectral regions, respectively. Neither of these types of resonances were previously reported for this excitonic material, which has typically been treated as isotropic. Optical simulations based on measured anisotropic TDBC permittivity successfully reproduced the experimental results, and gave further insight on the optical nearfields. Our study highlights organic excitonic materials as promising building blocks in nanooptics and adds anisotropic TDBC to the palette of hyperbolic organic materials.35 ComThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Periprosthetic bone loss is an important factor in tibial implant failure mechanisms in total knee arthroplasty (TKA). The purpose of this study was to validate computational postoperative bone response using longitudinal clinical DEXA densities. Computational remodeling outcome over a population was obtained by incorporating the strain‐adaptive remodeling theory in finite element (FE) simulations of 26 different tibiae. Physiological loading conditions were applied, and bone mineral density (BMD) in three different regions of interest (ROIs) was considered over a postoperative time of 15 years. BMD outcome was compared directly to previously reported clinical BMD data of a comparable TKA cohort. Similar trends between computational and clinical bone remodeling over time were observed in the two proximal ROIs, with most rapid bone loss taking place in the initial months after TKA and BMD starting to level in the following years. The extent of absolute proximal BMD change was underestimated in the FE population compared with the clinical subject group, which might be the result of significantly higher initial clinical baseline BMD values. Large differences in remodeling response were found in the distal ROI, in which resorption was measured clinically, but a large BMD increase was predicted by the FE models. Multiple computational limitations, related to the FE mesh, loading conditions, and strain‐adaptive algorithm, likely contributed to the extensive local bone formation. Further research incorporating subject‐specific comparisons using follow‐up CT scans and more extensive physiological knee loading is recommended to optimize bone remodeling more distal to the tibial baseplate. An alternative way to gain more understanding about the relative effects of these parameters is through computational modeling. Previous finite element (FE) models have assessed periprosthetic tibial bone loss using strain differences,2FE models were created using a custom‐made workflow,In the initial processing step, knee alignment angles were measured and tibiae were segmented from the available CT scans, taken in supine position. The hip–knee–ankle (HKA) and tibial varus–valgus (VV) angles of each knee were measured in the anteroposterior (AP) view using CT scan annotations in Slicer 3DThe tibiae were automatically segmented based on boundary enhancement filtering and graph cut optimizationTibial alignment, resection planning, and tray size determination were performed relative to the mechanical reference frame. For each tibia, a size‐matched cemented cruciate‐retaining, rotating platform (RP), cobalt–chromium‐alloy (CoCr) implant  was placed following mechanical implant alignment. This alignment was achieved by placing the implant according to the mechanical axes, resulting in 0° of postoperative HKA and tibial VV angles, regardless of constitutional deformity and anatomical joint line orientations. The applied loading conditions accounted for 3° external rotation of the femoral component relative to the posterior condyles, which was adopted to compensate for flexion and extension gaps.The tibial resection level was defined 8 mm distally from the lowest point of the highest condyle, and the internal/external rotation of the RP tray was optimized to maximize the coverage of the resected bone surface. The correct implant size was set to be the largest tray size which could be placed on the resection surface with a maximum overhang below 2 mm, in line with a reported tibial coverage study.A cement layer was generated based on a 0.75 mm offset over the entire bone contact surface of the tibial component, and used as outline for resection of the tibia by applying a Boolean operation . The tibiae were distally resected 150 mm beneath proximal resection level. The proximal tibia was fixed distally in order to reduce computational cost in the final FE simulations. All parts in the assembly were (re)meshed using first order tetrahedral elements with a size of 2 mm and were connected using fixed contact definition.Consistent preoperative and postoperative tibial bone meshes were used by reconstructing the intact preoperative models out of the two resected proximal bone parts, to allow for element‐wise evaluation of TKA‐related strain differences. The difference in alignment between preoperative and postoperative models, in case of native varus and valgus knees, was accommodated for by rotating the resected bone meshes toward their respective VV angles, consistent with the definitions used in the applied loading conditions, as depicted in Figure Bone material properties of the tibial meshes were assigned per element using corresponding CT intensities.Implant‐specific and alignment‐specific knee loading during physiological activity cycles was computed at the University of Denver using inverse dynamics,In the preoperative models, the COPs of the forces, according to the subject's native deformity, were connected to the closest nodes on the proximal tibial surface using springs; the number of connected nodes was determined as function of the total related contact area, and spring constants were individually assigned based on distance and a compressive modulus of 9 MPa representing the intermediate articular cartilage.Sref and S, respectively, considered as stimulus for density change in time dρ/dt.lazy zone and no net remodeling was assumed. Outside of this range, the rate of local bone apposition or resorption was dependent on its available free bone surface a, representing the porosity and specific surface and determined based on the corresponding bone density ρ.a was assumed to be more responsive to changes in SED, since remodeling activity takes place at these free surfaces.The averaged strain energy density (SED) after application of the three activity peak loads was considered as measure for bone strains during daily living. Subsequent iterative bone density changes were simulated using strain adaptive remodeling, with the difference between local preoperative and postoperative SED per unit bone mass, dρ/dt following the strain adaptive theory,Definition of the local bone remodeling rate Simulations were time‐scaled using computer time units (CTU) defined relative to the maximum stimulus per iteration; each postoperative year was considered to correspond to 30 CTU. Used lazy zone and time conversion values were established in a study by Tarala et al.,3 in a three‐dimensional matrix,2, defined relative to the position of the tray and according to the definition of Minoda et al.,Two‐dimensional AP projections were made by mapping the element numbers of the FE models using a cubic voxel size of 0.2 mm3A comparison between available preoperative parameters in the different Japanese TKA populations used in computational and clinical remodeling is shown in Table Computational bone remodeling outcome over time was compared with reported clinical postoperative BMD outcome at different follow‐up time points in Figure p < .05). Despite slightly more initial medial bone loss in native varus knees, the mean BMD and associated variance of the two alignment groups became constant and almost equal again after the first 5 years. No considerable difference was found in the distal bone formation. The single native valgus case did not show a deviating trend from either of the other two alignment groups. No statistically significant difference was found between remodeling in male and female knees.The effect of alignment on periprosthetic bone changes was mainly observed in the lateral ROI, where a difference was seen between varus and neutral groups, with native neutral alignment cases displaying more bone loss at all time points Figure . HoweverOther FE subject characteristics were tested against initial BMD, and against relative and absolute 15‐year ROI BMD difference  loading conditions and strain‐adaptive theory. To improve computational remodeling, it is recommended to perform further research using intrasubject comparisons, based on longitudinal clinical CT data and physiological load cases including soft tissue representations. Being able to reliably predict tibial periprosthetic remodeling is helpful to guide clinical practice, by identifying risk factors in implant design, surgical technique and tibial features for potential long‐term failure due to excessive regional bone loss.


There is limited knowledge on the association between lifestyle behaviour in adolescence and musculoskeletal pain in young adulthood. This study aimed to investigate whether an accumulation of adverse lifestyle behaviours in adolescents with and without musculoskeletal pain at baseline, was associated with persistent musculoskeletal pain (pain duration ≥3 consecutive months the last year) 11 years later.Longitudinal data from the Trøndelag Health Study in Norway including 1824 adolescents (13–19 years old) was analysed. The outcome was persistent musculoskeletal pain (≥3 months). The number of adverse lifestyle behaviours  were summed up to comprise an ordinal variable and analysed with 0 or 1 adverse behaviours as the reference. Multiple logistic regression analyses, stratified by individuals with and without baseline musculoskeletal pain, were conducted. The results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs).In adolescents with musculoskeletal pain at baseline, reporting ≥ four adverse lifestyle behaviours increased the odds of persistent musculoskeletal pain  11 years later. Two and three adverse behaviours were not associated with future persistent musculoskeletal pain. In adolescents without musculoskeletal pain at baseline, an accumulation of adverse lifestyle behaviours was not associated with future persistent musculoskeletal pain.An accumulation of adverse lifestyle behaviours in adolescents with musculoskeletal pain at baseline was associated with persistent musculoskeletal pain 11 years later, but not in adolescents without musculoskeletal pain at baseline.An accumulation of four or more adverse lifestyle behaviours in adolescents with musculoskeletal pain was associated with persistent musculoskeletal pain in young adulthood. In future health care of adolescents with musculoskeletal pain, lifestyle behaviours should be assessed, with emphasis on accumulation of multiple adverse lifestyle behaviours. Focusing on an accumulation of multiple adverse lifestyle behaviours, rather than each individual behaviour, might provide a potential area for future research and interventions targeting musculoskeletal pain in youth. Of these, 277 participants were excluded in our study due to age ≥ 20 years, juvenile arthritis, or incomplete pain data at baseline, resulting in 7922 adolescents who met the inclusion criteria . The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines have been followed  in Norway, and the Norwegian Centre for Research Data (543422). All participants, and the parents or guardians of adolescents under the age of 16 years, signed a written informed consent form. The study protocol was published at 2.2persistent musculoskeletal pain at follow‐up, was defined as musculoskeletal pain lasting for at least three consecutive months  and illicit drug use, as described below. The variable was arranged as an ordinal variable and expressed as 0–1 (reference), 2, 3 and ≥4 adverse lifestyle behaviours in the model of individuals with musculoskeletal pain at baseline, and 0–1 (reference), 2 and ≥3 adverse lifestyle behaviours in the model of individuals without musculoskeletal pain at baseline, due to a low number of individuals with 4 or more adverse behaviours in the latter group.The physical activity level was assessed with a question asking how many days a week the adolescents on average played sports or exercised outside school hours, to the point where they breathed heavily and/or got sweat. The question was adopted from the World Health Organization (WHO), Health Behaviour in School‐aged Children (HBSC) study  used in the WHO HBSC study  was measured by the questions “have you ever tried drinking alcohol?” and “have you ever been drinking so much alcohol that you felt intoxicated (drunk)?” The questions are adopted from the WHO HBSC study    and age were measured. BMI (kg/m2) was calculated based on objective measurements of weight and height.2.6SD) if continuous and normally distributed, and with median and range if skewed. To assess possible selection bias, characteristics  of respondents in the follow‐up survey were compared to characteristics of non‐respondents and respondents with incomplete outcome data, using independent T‐test for normally distributed continuous data, Mann–Whitney U test for skewed data and Chi‐square tests for categorical data.Variables were presented as counts and percentages if categorical, with mean and standard deviation .Logistic regression analyses were used to estimate the association between the number of adverse lifestyle behaviours in adolescence and persistent musculoskeletal pain 11 years later. Individuals with musculoskeletal pain at baseline and individuals without musculoskeletal pain at baseline were analysed separately. In all models, persistent musculoskeletal pain was considered a binary outcome . The associations were investigated in crude and adjusted analyses and reported as odds ratios (ORs) with 95% confidence intervals (CIs). Adjustments were conducted in two blocks; firstly for sociodemographic factors only , secondly for sociodemographic factors Sensitivity analyses were performed with lower threshold of alcohol intoxications (intoxicated 2–3 times) for the younger age group (13–15 years old), as lifetime alcohol intoxication is higher in the older adolescent age groups. To get an estimate of the individual contribution of each lifestyle behaviour, we conducted additional logistic regression analyses examining the association between individual lifestyle behaviours in adolescence and persistent musculoskeletal pain 11 years later, adjusted for sociodemographic and health factors.For the regression analyses, missing data on exposure and confounders were replaced using a chained equation multiple imputation method, aiming to reduce potential selection bias due to missing data. All variables used in the regression analyses were used in the imputation model   and ≥3 adverse lifestyle behaviours  at baseline, were not statistically significantly associated with persistent musculoskeletal pain at the 11‐year follow‐up, adjusted for sociodemographic and health factors , and for adolescents without baseline musculoskeletal pain and ≥3 adverse lifestyle behaviours compared to the reference group (0/1) .Contrasted with analyses of the imputed data, the results from the complete case analyses Tables  and S5 i4The aim of this study was to investigate whether an accumulation of adverse lifestyle behaviours in adolescence was associated with persistent musculoskeletal pain (pain duration ≥3 consecutive months the last year) 11 years later. The results showed, after adjustment for sociodemographic and health factors, that an accumulation of four or more adverse lifestyle behaviours in adolescents with musculoskeletal pain at baseline, including any combination of low physical activity level, sleep problems, insufficient fruit/vegetables consumption, smoking, frequent alcohol intoxication (drunkenness) and illicit drug use, was associated with persistent musculoskeletal pain 11 years later. An accumulation of adverse lifestyle behaviours in adolescents without musculoskeletal pain at baseline was in this study not associated with persistent musculoskeletal pain 11 years later.To the best of our knowledge, this is the first study to investigate an accumulation of lifestyle behaviours in adolescence in relation to persistent musculoskeletal pain in adulthood, in a large population‐based study.Our findings of an association between an accumulation of lifestyle behaviours and future persistent musculoskeletal pain in individuals with baseline pain, show similarities with findings from two previous studies on pain prognosis in adults. The studies reported that a combination of healthy lifestyle behaviours reduced the risk of long‐duration troublesome low back pain in women with occasional low back pain . The non‐respondents were more likely to be males, younger, to have an additional chronic disease, to have less psychological distress, to have a lower number of pain sites and to smoke compared to those with complete data at follow‐up. These differences are a potential source to selection bias. The non‐respondents also had slightly more adverse lifestyle behaviours compared to the respondents, but the difference was not statistically significant (P=0.052). It is unknown whether the non‐respondents had a different occurrence of the outcome at follow‐up. Another limitation was low statistical power in the analyses of adolescents without musculoskeletal pain due to few exposed cases. The time interval between baseline and follow‐up was 11 years. During this period lifestyle behaviour might have changed, which encourages us to be careful with the interpretation of the associations. More frequent follow‐ups could have given a better insight into trajectories of pain and lifestyle behaviours during the period.All the lifestyle behaviours were self‐reported, which may have caused misclassifications. Misclassifications and loss of in‐depth information may also have occurred through dichotomisation of the variables. For example, both high and low physical activity levels have been associated with low back pain in previous research . The funder organization played no role in designing the study, in the collection, analysing or interpretation of the data, or in writing the manuscript.We declare no conflicts of interest.Tables S1‐S5Click here for additional data file.


Vt), the maximum falling speed of a seed in still air. Accurate estimates of Vt are crucial for predicting intra‐ and interspecific variation in seed dispersal ability. However, existing methods produce biased estimates of Vt for slow‐ or fast‐falling seeds, fragile seeds, and seeds with complex falling trajectories. We present a new video‐based method that estimates the falling trajectory and Vt of wind‐dispersed seeds. The design involves a mirror that enables a camera to simultaneously record a falling seed from two perspectives. Automated image analysis then determines three‐dimensional seed trajectories at high temporal resolution. To these trajectories, we fit a physical model of free fall with air resistance to estimate Vt. We validated this method by comparing the estimated Vt of spheres of different diameters and materials to theoretical expectations and by comparing the estimated Vt of seeds to measurements in a vertical wind tunnel. Vt estimates closely match theoretical expectations for spheres and vertical wind tunnel measurements for seeds. However, our Vt estimates for fast‐falling seeds are markedly higher than those in an existing trait database. This discrepancy seems to arise because previous estimates inadequately accounted for seed acceleration. The presented method yields accurate, efficient, and affordable estimates of the three‐dimensional falling trajectory and terminal velocity for a wide range of seed types. The method should thus advance the understanding and prediction of wind‐driven seed dispersal.Seed dispersal by wind is one of the most important dispersal mechanisms in plants. The key seed trait affecting seed dispersal by wind is the effective terminal velocity (hereafter “terminal velocity”,  Accurate estimates of seed terminal velocity, the key seed trait affecting seed dispersal by wind, are crucial for predicting intra‐ and interspecific variation in seed dispersal ability. However, existing methods produce biased estimates of terminal velocity for slow‐ or fast‐falling seeds, fragile seeds, and seeds with complex falling trajectories. We present a new video‐based method that yields accurate, efficient and affordable estimates of the three‐dimensional falling trajectory and terminal velocity for a wide range of seed types, and should thus advance the understanding and prediction of wind‐driven seed dispersal. Vt is the most important seed trait determining wind‐driven seed dispersal  accurately measure Vt of single seeds, (2) work for various seed types, (3) estimate Vt of seeds that still accelerate, and (4) be nondestructive so that seeds can be used for further measurements. To our knowledge, no existing method fulfills all these criteria.Seed dispersal by wind is one of the most important and best understood dispersal mechanisms  takes about 10 s.The apparatus consists of a seed release device and a box Figure . The see33.1xd and zd) and in the mirror part of the image (with image coordinates ym and zm) , we fitted a linear model that predicts the respective coordinate from the main effects and interactions of the two horizontal image coordinates (xd and ym). For the vertical coordinate z, we fitted a linear model containing the main effects and interactions of the two vertical image coordinates zd and zm. Each of these three linear conversion models explained >99% of the variance in x, y, and z, respectively. The conversion functions and all other R code are contained in R package “velocimeter” (https://github.com/jinleizhu/velocimeter) developed under R 4.0.3  Figure . To recon Figure . The pren Figure  and imagVideos of falling seeds are analyzed automatically with ImageJ  then cleans the ImageJ output in four steps. First, it removes objects at the very edges of the falling corridor. Secondly, the largest object in both the direct and the mirror parts of the image is selected. Thirdly, the function considers the resulting pair of objects in the direct and mirror parts as representing a putative seed if their vertical coordinates (zd and zm) are sufficiently close. Fourthly, the function selects the longest sequence of consecutive images containing a putative seed as depicting the seed trajectory. After data cleaning, the function uses the abovementioned conversion functions to derive a time series of three‐dimensional seed coordinates.R function calculate.terminal.velocity.phys . We note, however, that alternative models can be used to estimate Vt. The model predicts the vertical distance traveled over time t as z0 is position at t=0, and g is the gravitational acceleration (9.81 m/s2). We estimated Vt and z0 by fitting this simple physical model to the time series of vertical positions using nonlinear least squares (R function nls).Estimation of Observed seed falling trajectories may deviate from the simple physical model because of uncertainty in the determination of seed positions via image analysis or because seeds violate model assumptions. In particular, the simple model ignores effects of low Reynolds numbers, small‐scale turbulence at the seed surface, and vertical forces that may result from seed rotation or horizontal seed movement  for each seed trajectory (function rmse.veloc). When RMSE is high, the function absdiff.veloc can be used to plot these velocity differences against time, indicating which phases of the seed trajectory are poorly approximated by the model. These functions are provided in the R package n = 40 seeds per species). The physical model fitted individual falling trajectories very well . The slight underestimation of Vt for spheres made of Styrofoam (30 mm) and Polyoxymethylene might be due to their somewhat rough surface and/or limited applicability of the empirical approximation for the drag coefficient  in a vertical wind tunnel at the Institute of Agricultural Engineering in the Tropics and Subtropics, University of Hohenheim, Germany. The vertical wind tunnel accurately measures the distribution of Vt for seed batches when seed falling trajectories are simple and Vt is relatively high    of the variance in log‐transformed terminal velocity, with the remaining proportion arising from the variance between repeated measures of the same seed Table . The ICCs Figure .4.2Vt estimates for five plant species that cover a variety of seed sizes and shapes to the mean Vt in the TRY database, which predominantly contains measurements of average velocity after seeds had fallen a certain distance and thus does not account for seed acceleration  only reach 99% of Vt after a falling distance of 8.2 m , which have a very high Vt (7.84 m/s), over several hundred meters . Seeds with high τ take longer to accelerate in response to gravity or changes in vertical and horizontal wind speed , the video‐based method can be used to quantify to what extent within‐seed variability arises from measurement error versus intrinsic variability in the flight behavior of a given seed , the presented method should enable the efficient dispersal phenotyping of seeds from multiple plant genotypes grown in multiple environments. This would be a crucial step toward unraveling the genetic architecture of how dispersal responds to environmental variation and quantifying how rapidly dispersal can evolve in changing environments ; data curation (lead); formal analysis (lead); methodology (lead); software (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). Carsten M. Buchmann: Conceptualization (lead); data curation (supporting); formal analysis (supporting); methodology (lead); software (lead); validation (lead); visualization (supporting); writing – original draft (supporting); writing – review and editing (supporting). Frank M. Schurr: Conceptualization (lead); funding acquisition (lead); methodology (supporting); project administration ; software (supporting); supervision (lead); visualization (supporting); writing – original draft (supporting); writing – review and editing (supporting).The authors have no conflict of interest.Supporting InformationClick here for additional data file.


In this report, we correlated the incidence of rosacea with coffee (regular and decaffeinated) and tea consumption in a large cohort of middle‐aged men and women living within the United Kingdom. Caffeinated coffee drinkers had lower odds for rosacea diagnosis compared to non‐coffee drinkers. We hypothesize that the vasoconstrictive effects of caffeine in regular coffee overpower the vasodilatory effects associated with hot beverages and support it to be protective against rosacea. The UK Biobank was approved by the National Health Service (NHS) National Research Ethics Service. To the Editoret al.et al.Rosacea is a chronic inflammatory disease that is often associated with symmetrical facial erythema. Current data regarding the effects of coffee intake on rosacea are conflicting. WilkinWe analysed data from the UK Biobankp = 0.018). The difference in rosacea between decaffeinated and non‐coffee drinkers was not significant . No significant difference in rosacea diagnoses was seen when tea drinkers were compared to non‐tea drinkers  (data not shown).As shown in Figure et al.The effect of caffeine intake on rosacea, whilst observing tea consumption, has been previously evaluated by Li Our study suggests that caffeinated coffee consumption has an inverse association with rosacea. The strengths of this study include the large sample size and the comparison of rosacea with both coffee and tea intake habits. However, participation in the UK Biobank was voluntary so these self‐selected subjects may differ from the general population. Moreover, the self‐reported dietary habits, at the time of touchscreen questionnaire, may be different from those at the time of rosacea diagnosis. Future studies are needed to address the effects of caffeine on both the inflammatory and vascular symptoms of rosacea.The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.Ahmet Miguel Yildirim: Conceptualisation (Lead); Data curation (Lead); Investigation (Lead); Methodology (Lead); Writing – original draft (Lead). Wei Fang: Formal analysis (Lead). Michael S. Kolodney: Project administration (Lead); Supervision (Lead); Writing – original draft (Supporting); Writing – review & editing (Lead).William Weldon Endowment Fund.


Athene noctua) within a gradient of habitat quality. We supplemented food to nestlings, thereby relieving the parents’ effort for brood provisioning. We used radio‐tracking and Bayesian multistate modeling based on marked recapture and dead recovery to estimate survival rates of adult little owls across the year as a function of food supplementation and habitat characteristics. Food supplementation to nestlings during the breeding season increased parental survival not only during the breeding season but also during the rest of the year. Thus, the low survival of parents of unfed broods likely represents both, strong ecological and strong intrinsic costs of reproduction. However, while immediate ecological costs occurred also in high‐quality habitats, intrinsic costs carrying over to the post‐breeding period occurred only in low‐quality habitats. Our results suggest that immediate costs resulting from ecological mechanisms such as predation, are high also in territories of high habitat quality. Long‐term costs resulting from intrinsic trade‐offs, however, are only paid in low‐quality habitats. Consequently, differential effects of habitat quality on immediate ecological and delayed intrinsic mechanisms can mask the increase of costs of reproduction in low‐quality breeding habitats. Intrinsic costs may represent an underrated mechanism of habitat quality affecting adult survival rate thereby considerably accelerating population decline in degrading habitats. This study therefore highlights the need for a long‐term perspective to fully assess the costs of reproduction and the role of habitat quality in modifying these costs.Although the costs of reproduction are predicted to vary with the quality of the breeding habitat thereby affecting population dynamics and life‐history trade‐offs, empirical evidence for this pattern remains sparse and equivocal. Costs of reproduction can operate through immediate ecological mechanisms or through delayed intrinsic mechanisms. Ignoring these separate pathways might hinder the identification of costs and the understanding of their consequences. We experimentally investigated the survival costs of reproduction for adult little owls  over the rest of the year. Intrinsic costs may therefore represent an underrated mechanism of habitat quality affecting adult survival rate thereby considerably accelerating population decline in degrading habitats. A central paradigm of life‐history theory is that parental investment into the current reproduction should reduce future reproduction, often through a reduction in parental survival Stearns, . While tDistinguishing between different mechanisms resulting in reproductive costs might be important for understanding the costs’ variation and the trade‐off's plasticity and thus the consequences for life‐history evolution in different environments. On the one hand, the importance of a distinction between intrinsic and ecological mechanisms is increasingly recognized , a short‐lived nocturnal raptor species. We experimentally supplied food to nestlings being raised in a gradient of habitat quality. Food supplementation in this species has shown to increase the nutritional state and survival of nestlings . Little owl breeding pairs occupy areas of varying quality  were caught during the early breeding season with mist nets or by removing them from nest boxes. Of those, 77 individuals  had already been ringed as nestlings, providing us with information of their exact age. As in the long‐term ringing project in our nest box population a high rate of adult birds were already ringed, we assumed an age of one year for captures of non‐ringed birds. Each captured individual was weighed and equipped with a very high frequency (VHF) transmitter of own construction  and control broods (n = 66) every second day. Experimental broods received dead laboratory mice (deposited in the nestbox) with a total weight of 20 g per nestling during the first six visits and mice with a weight of 30 g per nestling during the subsequent 12 visits, summing to a total of 480 g additional food per nestling . To test whether the effects of the focus variables differed between the two time periods, we calculated the effects for each focus variable as well as the interaction between food‐rich habitat and food supplementation for the two periods separately. In addition, we included year as a fixed effect with 2010 (the first non‐pilot year) as reference year.f‐values < 0.9 and 95% credible intervals non‐overlapping zero).The amount of food‐rich habitat and clutch size were scaled to a mean of zero and a standard deviation of one prior to the analyses. Body mass was scaled to the deviation of the overall sex mean based on our data, with a value of 1 corresponding to a 10 g higher body mass than the sex‐specific mean . Clutch size  and the amount of food‐rich habitat  did not differ between experimental broods and control broods  and control individuals across a gradient of habitat quality during the breeding season and the rest of the year. We found (1) that the biweekly survival rate of parents of un‐supplemented broods was significantly lower during the breeding season compared to the rest of the year and that this effect was particularly pronounced for females, (2) that experimental food supplementation of nestlings increased parental survival not only during the breeding season but notably also over the whole rest of the year, and (3) that the experimental effect during the breeding season was large also in high‐quality habitats, while after reproduction it was mainly present in adults breeding in low‐quality habitats. These results clearly show that environmental conditions affect the costs of reproduction. Moreover, they suggest that, irrespective of the habitat quality, the costs of reproduction are mostly paid during the time of reproduction, but that in low‐quality habitats costs also carry over to post‐reproductive phases. Our study therefore provides fundamental insights into how direct and indirect mechanisms shape survival costs of reproduction in habitats of different quality and highlights the need for a long‐term perspective to fully assess the costs of reproduction and the role of habitat quality in modifying these costs.During the breeding season, animals are expected to mainly face direct or short‐term indirect costs mediated by ecological mechanisms ; Data curation (lead); Formal analysis (lead); Investigation ; Methodology ; Project administration ; Resources ; Validation ; Visualization ; Writing – original draft ; Writing – review & editing . Matthias Tschumi: Conceptualization (supporting); Data curation (supporting); Formal analysis (supporting); Investigation ; Methodology ; Validation ; Visualization ; Writing – original draft ; Writing – review & editing (lead). Beat Naef‐Daenzer: Conceptualization ; Data curation (supporting); Formal analysis (supporting); Funding acquisition (supporting); Investigation ; Methodology ; Project administration ; Resources ; Supervision (supporting); Validation (supporting); Writing – original draft (supporting). Herbert Keil: Data curation (supporting); Investigation ; Project administration (supporting); Resources . Martin U. Grüebler: Conceptualization ; Data curation ; Formal analysis ; Funding acquisition (lead); Investigation ; Methodology ; Project administration ; Resources (lead); Supervision (lead); Validation ; Visualization ; Writing – original draft ; Writing – review & editing (supporting).Supplementary MaterialClick here for additional data file.


The treatment landscape of chronic lymphocytic leukemia (CLL) has witnessed immense changes in the past decade. Several newer target therapies and their combinations with anti‐CD 20 therapies have got approval for management of CLL in the treatment‐naïve and relapsed/refractory setting. Also, the availability of newer diagnostic techniques has helped differentiate the disease into high‐ and low‐risk CLL which acts not just as a prognostic marker but also helps decide the best drug management that can be administered to the patients. Targeted therapy has largely overtaken chemoimmunotherapy in the management of CLL, except for a small subset of the population (young and fit with IGHV mutation). However, with targeted therapy, there is also an issue of previously uncommon treatment‐emergent adverse events, the duration of therapy, and financial toxicity. The aim of this review article is to gather results from all landmark CLL trials and discuss the feasibility of incorporating Acalabrutinib in the CLL landscape from an Indian perspective. Treatment of newly diagnosed CLL has shifted from chemotherapy‐based regimens a decade ago to targeted therapies in the current era. Most treatment naïve CLL patients will receive either a Bruton tyrosine kinase (BTK) inhibitor or a B‐cell lymphoma 2 (BCL 2) inhibitor at some point in their treatment cycle. The treatment of CLL in resource‐constrained settings, where the majority of treatment cost comes from “out‐of‐pocket” expenditure, adds another dimension to the choice of treatment in a particular patient. This review focuses on the unique challenges posed by such cost constraints and looks at the evidence for the newly introduced Acalabrutinib to the mix of therapies. It also looks at the evidence for use of this drug both in frontline and relapse settings.9/L B‐lymphocytes in the peripheral blood, sustained for at least 3 months. The clonality of these B‐lymphocytes should be demonstrated by immunoglobulin light chain restriction using flow cytometry , a deletion of part of the long arm of chromosome 11, harboring the gene ATM, have shorter survival than patients with normal karyotypes. The absence of ATM gene makes the disease less susceptible to chemotherapy ..23].50 kinase inhibition study [50 concentrations for ITK (tyrosine‐protein kinase) and EGFR  were more than 200‐fold higher (less inhibition) than for BTK. Concentrations for ERBB4 (Erb‐B2 Receptor Tyrosine Kinase 4) and BMX (bone marrow tyrosine kinase gene in chromosome X) were three‐ and ninefold higher (less inhibition) than for BTK.Acalabrutinib and its active metabolite, ACP‐ 5862, inhibit BTK enzymatic activity irreversibly by covalently binding a cysteine residue in the BT active site. This inhibits BTK‐mediated activation of downstream signaling proteins CD86 and CD 69 as well as malignant B‐cell proliferation and survival. Acalabrutinib has been shown to be more selective than ibrutinib and is hence considered a safer option for patients requiring treatment in CLL . In an ion study , the affP < .0001). Acalabrutinib monotherapy (secondary endpoint) was also associated with statistically improved PFS over obinutuzumab‐chlorambucil . There was consistent PFS benefit with acalabrutinib dual therapy and monotherapy in the prespecified (including high‐risk) subgroups over obinutuzumab‐chlorambucil. The frequency of discontinuations due to adverse events was not higher in the acalabrutinib‐containing groups despite the longer treatment durations . In the ASCEND trial for relapsed/refractory CLL, acalabrutinib monotherapy showed improved efficacy over investigator's choice of therapy in combination with rituximab; idelalisib (I‐R) or bendamustine (B‐R) [P < .0001). Investigator assessed PFS in prespecified subgroups (including high‐risk) was improved with acalabrutinib monotherapy. Even though the median duration of exposure was longest in the acalabrutinib arm, adverse events  . mPFS waA retrospective analysis (January 2013 to October 2015) of 447 adult patients on CLL on ibrutinib revealed high rates of drug discontinuation . At a meIn a phase II study, 60 ibrutinib‐intolerant patients were administered acalabrutinib till disease progression or unacceptable toxicity . The med6IGHV mutation) both in terms of efficacy and toxicity. It is not unusual to experience considerable delays in the release of several of the new drugs to the developing world after it is licensed and widely available in the western world. There are several reasons for this delay; such as poor market performance due to the price, fear of being duplicated during the patency period, and fear of arbitrage if there is any cost reduction. One of the aims of this manuscript is to throw some light on the question of how acalabrutinib would fit into an LMIC (lower and middle income countries) context taking India as an example. Most LMIC healthcare systems are driven predominantly by out of pocket payments by patients, although insurance and various government schemes are increasingly playing significant roles. Newer drugs with their huge cost put additional pressure on most health systems particularly on the patient's pocket in the context of LMIC, but this cost has to be understood in the larger scheme. Chemotherapy agents, although cheaper on the drug cost, are associated with additional supportive care burden . For example, in India, the average cost of chemoimmunotherapy, such as FCR  and BR (bendamustine and rituximab) is around US$ 900 per cycle and US$ 9000 for six cycles. For delivering a chemotherapy regimen like FCR, supportive care cost is high as the average cost of one febrile neutropenia admission is around US$ 2000. Since these costs are significant they may also tilt the cost‐benefit ratio toward the targeted agents especially if generic versions are available. Apart from the issue of cost, there is also a familiarity associated with chemoimmunotherapy agents as many hematologists have been using these combinations for several years. Some physicians claim that even though they are aware of the high risks associated with it, they are trained to manage the adverse events accordingly. These practicing habits are surely changing with time. At present, India is facing the second surge of COVID cases with 350 000‐500 000 cases being reported daily. In such challenging times, for a country like India where the healthcare sector is facing acute shortage of beds and ICU, it is important that the patients suffering from CLL maintain social distancing while staying safe and continue their fight against CLL via oral and safer targeted therapies. Second‐generation BTK inhibitors have a specific role in patients where Ibrutinib is not tolerated or has relative contraindication beyond the conventional indication for BTK inhibitors. BTK inhibitors are the preferred treatment in 17p deleted and or TP53 mutated CLL and possibly in IGHV unmutated CLL. Cardiac toxicity is a major problem with first‐generation BTK inhibitor. In LMIC, there is an increasing trend of developing life‐style diseases and in fact cardiovascular diseases are even now more numerous in India and China than in all the economically developed countries in the world put together. Therefore, second‐generation BTK inhibitors may have a bigger role to play in these countries.From the above data, it is evident that the majority of CLL patients benefit more from targeted treatment than chemoimmunotherapy  where FCR regimen has shown remissions of 10 years or more. Newer and more selective agents have drastically improved the quality of life in patients with CLL, especially those with high‐risk CLL. Even though the BTK inhibitors  generally do not induce a deep remission early on, significant survival advantage especially in terms of progression‐free has been noted when compared to the standard of treatment when they are continued till disease progression or development of treatment‐related adverse events. Although there have been no head‐to‐head trials, acalabrutinib, being a more selective inhibitor of BTK is considered safer and might lead to lesser adverse events and fewer discontinuations over the long term. In the two landmark trials of Acalabrutinib in the first‐line and relapsed/refractory setting (ELEVATE‐TN and ASCEND), it was observed to be more efficacious and safer than comparators as a monotherapy or in combination with an anti‐CD 20 inhibitor. Finite therapy has been established by the addition of venetoclax in combination with anti‐CD 20 antibody. However, more mature data is needed to know whether finite treatment with BCL‐2 inhibitor or indefinite treatment with BTK inhibitors is advantageous in terms of long‐term survival. Finally, we discussed how to implement acalabrutinib in an Indian setting.In this review article, we have discussed in detail the pathophysiology of CLL, the clinical staging systems, the key studies that have helped shape the treatment paradigm of CLL in the treatment‐naïve and relapsed/refractory setting. For more than half a century, chemotherapy was the treatment of choice for all CLL patients with an active disease. With the introduction of newer agents, the use of chemotherapy has declined significantly, except in the small proportion of young and fit patients with low‐risk CLL (Pranav Sopory is an employee of AstraZeneca Pharma India Ltd.