The ever‐growing field of microfluidics requires precise and flexible control over fluid flows at reduced scales. Current constraints demand a variety of controllable components to carry out several operations inside microchambers and microreactors. In this context, brand‐new nanophotonic approaches can significantly enhance existing capabilities providing unique functionalities via finely tuned light−matter interactions. A concept is proposed, featuring dual on‐chip functionality: boosted optically driven diffusion and nanoparticle sorting. High‐index dielectric nanoantennae is specially designed to ensure strongly enhanced spin−orbit angular momentum transfer from a laser beam to the scattered field. Hence, subwavelength optical nanovortices emerge driving spiral motion of plasmonic nanoparticles via the interplay between curl−spin optical forces and radiation pressure. The nanovortex size is an order of magnitude smaller than that provided by conventional beam‐based approaches. The nanoparticles mediate nanoconfined fluid motion enabling moving‐part‐free nanomixing inside a microchamber. Moreover, exploiting the nontrivial size dependence of the curled optical forces makes it possible to achieve precise nanoscale sorting of gold nanoparticles, demanded for on‐chip separation and filtering. Altogether, a versatile platform is introduced for further miniaturization of moving‐part‐free, optically driven microfluidic chips for fast chemical analysis, emulsion preparation, or chemical gradient generation with light‐controlled navigation of nanoparticles, viruses or biomolecules. The power of the spin−orbit coupling effect in all‐dielectric nanophotonics is harnessed to propose a novel, all‐optical nanomixing and sorting device potentially integrable in lab‐on‐a‐chip platforms. Specifically, under simple plane wave illumination, a dielectric structure with carefully tailored optical near fields is shown to induce nanofluid vortices, effectively boosting diffusion of admixtures. For this purpose, fast mixing is highly required to avoid the reactive process being delayed by this critical step, and to reduce potential side products.The multidisciplinary nature of microfluidics has brought together seemingly unrelated fields, such as electrical and mechanical engineering, biology, chemistry, and optics. For example, in the context of chemical engineering, the utilization of distributed microreactors working in parallel can enhance production significantly and facilitates the design of new products.14 How In the most conventional situation where only passive mixing happens, the main driving mechanism corresponds to diffusion (Brownian motion), implying mixing to take place at a very low rate. Consequently, the effective distance that the molecules of a fluid need to travel in a mixer before interacting with another fluid  becomes restrictively long. Passive mixers depend solely on decreasing the mixing length by optimizing the flow channel geometry in order to facilitate diffusion. In contrast, active schemes rely on external sources injecting energy into the flow in order to accelerate mixing and diffusion processes and drastically decrease the mixing lengths.Given the low Reynolds numbers at which fluid flow occurs in microreactors, fluid mixing represents a significant challenge.18 In  Because of the power and size constraints involved in microfluidics, research efforts have been focused on the utilization of mixing principles not involving moving mechanical parts such as surface tension‐driven flows, ultrasound and acoustically induced vibrations, and electro‐ and magnetohydrodynamic action.Most early studies related to micromixers have been focused on the passive type. Conversely, despite their higher cost and complex fabrication methods, the enhanced efficiency of active micromixers with respect to passive ones has drawn the attention of the scientific community in the recent years.17 Bec sort objects according to their size or optical properties, or self‐arrange colloidal particles into optically bound structures. Nowadays the additional degrees of freedom offered by complex shaping of laser beams have made possible the manipulation and trapping of large amounts of microparticles. In particular, they allow to create optical vortices with helical phase front  carrying both linear and angular momentum. When such an optical microvortex is scattered by particles, it induces an optical torque on them leading to their orbital motion around the focus of the laser beam. Due to the angular momentum conservation, elastic scattering of a circularly polarized beam possessing spin−angular momentum (SAM), by optically anisotropic or nonspherical objects leads to their spinning around the direction of propagation of the incident illumination. Combining both types of optical angular momentum leads to complex spin−orbital interaction and novel interesting phenomenon, e.g. detection of spin forces.Given the small operation scales of microfluidics, micron‐scale focusing of laser beams, as well as different types of light−matter interactions make possible to provide sufficiently strong optical forces to propel particles,27 sor On the other hand, the recently growing field of all‐dielectric nanophotonics presents itself as a promising alternative for the integration of optomechanical concepts in microfluidic devices. Properly designed dielectric nanostructures with finely tuned Mie resonant response provide the means for tailoring electric and magnetic components of the scattered light. They allow to obtain strong near fields, which induce substantial optical forces acting upon other subwavelength scatterers dispersed in the medium surrounding the nanostructure.At the nanoscale, metal‐based plasmonics dominates and provides exciting means for trapping and manipulating nano objects.55 On  of the scattered field mediated by a specially designed nanostructure constituted of a realistic high refractive index material (silicon). In contrast to the above‐mentioned methods, the optical vortex field created in this way is very localized, only reaching a few hundreds of nanometers in diameter. Moreover, the induced optical forces are strong enough to propel gold (Au) nanoparticles of particular sizes along spiral trajectories around the nanostructure. Based on the latter effect, we propose a novel method for mixing fluid in nanovolumes mediated by chemically inert Au nanoparticles 65 of 2 allowing for lateral‐scattering only. On the other hand, azimuthal forces arising due to helicity inhomogeneities in the scattered near field (curl−spin forces) may also enable rotational motion. Hereinafter, we optimize both effects taking into account that we, actually, do not require the total suppression of forward and backward scattering as in, and, therefore, we can tune the parameters in order to obtain an enhanced optical subwavelength vortex.The spiral motion of nano‐objects in an optical nanovortex driven by an out‐of‐plane light source Figure  requires68 alln ≈ 4  and edge 158 nm is illuminated by a circularly polarized plane wave propagating along the negative z‐axis :I0 is the incident light intensity. Since the nanostructure has negligible losses, the total angular momentum of the incident and scattered light is conserved. This conservation law for the total angular momentum implies that part of the incident SAM, given by Equation . A careful analysis reveals the most pronounced vortex‐like energy flux arises at the magnetic quadrupole (MQ) resonance  from a circular plane wave propagating against the z‐axisijM is ij‐th component of the MQ tensor. The center of the nanocube is placed at the origin of the coordinate system, with the x,y and z‐axis oriented perpendicular to its sides. Taking into account symmetry, we obtain the following nonzero tangential component Sϕs of the scattered Poynting vector:r = |r|. In the x−y plane θ = π/2 and Sϕs=0.While the numerical results shown in Figure 75Pex‐ and y‐axis, consequently, the components of the excited MQ tensor oscillate accordingly. In analogy with a rotating electric dipole, Equation . Substituting the scattered Poynting vector in Equation (S2), Supporting Information, the time‐averaged scattered angular momentum density component in the z‐axis zJ can be determined asThe intuitive physical picture is as follows: during an oscillation period, the incident circularly polarized electric field gradually changes its polarization between the c dipole,77 EquEquation  shows thzJ depends on the choice of origin of the coordinate system it can be directly correlated with the extrinsic OAM of the scattered field. Further inspection of Equations (rn− (where n is a positive integer) in the near field, the vorticity of the Poynting vector is very high close to the particle, but decreases very fast going away from it, as confirmed in Figure Comparing Equation  with Equte system78 it quations  and 4)  Jz depenIn this section, we have described the excitation of the MQ mode and proposed an intuitive physical picture explaining the multipolar origin of the tangential component of the Poynting vector giving rise to an optical vortex in the near field of the nanocube.3Fo〉 acting upon such a nanoparticle in the optical nanovortex can be written asmn is the refractive index of the host medium, E is the sum of the incident and scattered (by the nanocube) electric fields, 〈Ls〉 is the average SAM flux density (see the Supporting Information), and α ′and α ″ are the real and imaginary parts of the particle dipole polarizability, respectively. The first term on the right‐hand side of Equation  multipole. At the resonance, pure electric or magnetic multipoles strongly break electromagnetic duality, and, consequently, do not present a well‐defined helicity. This effect manifests itself strongly in the near field, and implies that the SAM flux density, which is linked to the helicity density, features a nonuniform spatial distribution. Therefore, the second term in 〈Fsc〉 acknowledged as the curl−spin force is not only nonnegligible but also plays an essential role in the dynamics of nanoparticles.We can now proceed to study the effect of the scattered field on small (dipolar) particles. The time‐averaged optical force 〈en as]Fo=α′4∇. The latter depends on the azimuthal components of the time‐averaged Poynting vector and the near‐field curl−spin forces, as well as on the optical response of the particles themselves (α ″).Importantly, due to spin−orbit coupling, the particles will experience an orbital torque oriented along the Interestingly, in the case of the MQ, it is possible to show that the contribution of the scattered field to the curl−spin force only has an azimuthal component, i.e., it only induces orbital motion. This result is general to any magnetic (TE) multipole field. The interference with the incident illumination leads, however, to important radial and polar components . Remarkably, particles whose centers of mass are located at different heights experience different contributions from the curl−spin (ΓzSpin) and radiation pressure (ΓzP) torques, as can be visually appreciated in the force field plots shown in Figure ΓzP is nonzero at z = 0, contrarily to what one might initially expect from Equation .Here, we have introduced analytical expressions for the optical forces and torques induced on dipolar absorbing nanoparticles, which allowed us to unambiguously distinguish the contributions of the radiation pressure and the spin forces. The numerical calculations presented in Figure 4We now turn our attention toward the potential applicability of the considered effect as a mixing method for microfluidic reactors. In order to illustrate the concept, we consider the water around the nanocube contains a dilute solution of chemically inert, biologically compatible nanoparticles. The dynamics of the latter will be affected by the optical forces arising due to the interaction with the cube's scattered field together with the Brownian and viscous drag forces induced in the fluid. The obvious and most convenient candidates to act as mixing mediators are Au nanoparticles, because they would not interact with the chemical and/or biological compounds dissolved in the solutions and are utilized in a broad range of microfluidics applications.83Fsc〉/〈Fo〉 should be maximized. For high enough ratios, scattering forces govern the nanoparticle dynamics, causing them to undergo spiral paths around the nanocube and act as stirrers enhancing convective fluid motion and thus diffusive mixing of any admixtures present in the water solution.In order to increase the mechanical orbital torque transferred to the Au nanoparticles and to prevent them from sticking to the walls of the nanocube due to attractive gradient forces, the ratio 〈dk is the wavenumber in water. a1 denotes the first electric Mie coefficient, which depends on the refractive index contrast between the particle and the medium m=εAu(ω)/nm and the dimensionless parameter dRpk, where pR is the nanoparticle radius. Details on the model for the permittivity of the nanoparticles εAu with appropriate size‐dependent corrections are given in the Supporting Information. Combining Equations ().The scattering force can be a leading force acting upon the nanoparticle only if the real part of the nanoparticle polarizability is negligible in contrast to the imaginary one (see Equation . For sim86(6)quations  and (6) FigurepR ≥ 35 nm can fulfill the condition α ′ = 0 with enhanced values of α ′′. For example, for particles with pR = 40 nm, the full suppression of the gradient force occurs at 500 and 530 nm .pR ≥ 35 nm could be considered to break the limits of the electric dipole approximation assumed in Equation  forces FB acting on the nanoparticle of mass pm, the Langevin equation of motion can be written in the following form:r¨p is the particle instantaneous acceleration vector. Once the scattering force distribution is determined, Equation . We assume the system to be at ambient temperature.To accurately reproduce the motion of the nanoparticles while restricting ourselves to a two‐dimensional analysis, the term The parameters for the simulations are given in Tables S1 and S2, Supporting Information.Figure−2 , mechanical orbital torque is transferred to the Au nanoparticles and drives them along spiral trajectories 2〉=DRefft+ωavg2t2, where DReff is an effective rotational diffusion coefficient and ωavg is the average angular speed. This analysis leads, as expected, to ωavg = 0 for the case of passive (Brownian) diffusion, and ωavg=0.37 deg μs−1, 0.08  deg μs−1 for particles placed, respectively, at 210 and 300 nm from the center of the nanocube. The results confirm that, in the near field of the nanocube, strong rotational motion can be achieved, and the nanoparticles enter a “superdiffusive” regime. Based on the previous information, we introduce the effective radius mr which specifies the area of influence of the optical nanovortex 2〉 = 4D0t, where D0 is the diffusion coefficient calculated for spherical particles as D0 = BTk/6πμxxpR,  further verifying the correctness of our calculations. Therefore, the proposed light‐driven setup strongly boosts diffusion.Due to the persistent orbital torque inside the vortex, the nanoparticles are actively rotating, as shown by the remarkable increase in the azimuthal angle as a function of time. The MSAD curves can be fitted with equations of the form mr reaches about half of the incident wavelength in water and thus the mechanical effect of optical vortices upon a nanoparticle takes place in the subwavelength region. Such a reduced scale cannot be reached using any focused far field, e.g., radial and Bessel beams. Up to our knowledge, this is the first proposal providing optical nanovortices created in a simple, realizable setup avoiding the need of lossy plasmonic nanoantennas, short wavelength guided modes, or complex chiral structures. Such optical nanovortices represent a promising component for on‐a‐chip OAM exchange driving light−matter interactions .The radius el beams.94 Up 5 We consider simplified forms of the last two equations assuming laminar, incompressible flow, in accordance with the previous results for the particle trajectories. Furthermore, we impose open boundary conditions at the edges and simulate a large fluid domain around the nanocube .To study in detail the liquid flow driven by the proposed nanomixing design, we once again utilize direct time‐domain simulation in COMSOL Multiphysics. At each time step, the particle position and velocity, as well as the fluid pressure and velocity fields are obtained by solving Equation , the Nav101 WeFigureThe velocity streamlines are more inhomogeneous at shorter times, when the nanoparticles start moving. Already at 150 µs, only small fluid distortions take place very close to the nanoparticles and the nanocube. Therefore, a possible way to further enhance the fluid nanomixing would be to realize periodic switching between left‐ and right‐hand circularly polarized incident light, which would reverse the direction of particle motion maintaining a high level of inhomogeneity in the fluid stress field. Nanomixing in the UV region could be advantageously combined with photochemically active processes of the involved chemical compounds.Noteworthy that, while all the previous calculations were performed for Au nanoparticles in the visible range, similar dynamics can also be obtained for Ag nanoparticles in the UV range of the spectrum, where α ′ → 0.102 Na6Hereinafter, we demonstrate the important capability of the proposed configuration to realize optical force‐mediated particle on‐chip sorting. In this section, we illustrate a novel, dynamical, contact‐less size sorting method for Au nanoparticles in liquid solutions addressing one of the most challenging targets of conventional microfluidics with the help of dielectric nanophotonics.FigureThe proposed method is based on the sign switch displayed by α ′ close to the plasmon resonance as we demonstrated in Figure However, in region I, there is a competition between Brownian, gradient, and scattering forces, where the first introduces an unbiased random displacement, and the other two drag the nanoparticles in opposite radial directions. A careful analysis considering the contributions of each force is therefore required to determine the viability of the sorting method.Figure Nanoparticles smaller than 15 nm have very low polarizabilities, resulting in negligible optical forces in comparison with Brownian forces Figure . However toxicity, and Raman signal intensity.The results in this section demonstrate that our novel platform can operate as a sorting device for Au nanoparticles by exploiting their inward or outward motion toward the nanocube as a function of their dimension. A precise, in situ size control of Au nanoparticles is a crucial step in many applications, e.g., biological cell uptake rates,104 to7We present conditions for maximal conversion of SAM of the incident light to OAM of the scattered light via the specially designed transversely scattering silicon nanocube. The azimuthal component of the Poynting vector of the scattered field originates from the strong MQ resonance. A Au nanoparticle of appropriate size, illuminated by such optical field and dispersed in the fluid surrounding the nanocube, experiences a combination of spin and radiation pressure forces with non‐zero azimuthal component. They are significant only up to a distance of about half of the illuminating wavelength from the silicon nanoantenna. The exceptionally compact optical nanovortex drives the dynamics of the nanoparticles, inducing a convection fluid flow at the nanoscale. The direction of particle motion can be reversed simply by flipping the helicity of the incident circular polarization. Therefore, the proposed mechanism can serve as a nanoscale fluid mixer and diffusion booster driven by light in a contact‐less and flexible way. Arrays of the studied dielectric nanoantennae can be easily imprinted on the surface of a microfluidic chip and controllably illuminated in an independent fashion. Hence, we shed light on very exciting perspectives such as light‐controlled mixing or even on‐chip directional fluid navigation. Employing the dependence of the optical properties of Au nanoparticles on their size, we demonstrate feasibility to drag nanoparticles affected by the optical vortex either toward or outwards the nanocube. Thus, smaller nanoparticles (15−30 nm in radius) can be aggregated at the silicon nanoantenna surface, while larger nanoparticles move away from it and drive the fluid flow. This behavior can be utilized to perform in situ size separation directly inside the microfluidic chip.The proposed, rather simple concept can be extended to nanostructures of different shapes, to an array of such nanostructures and to different types of dispersed nanoparticles, e.g., silver nanoparticles offer an exciting option to combine optical nanovortex with photochemistry at the nanoscale. Our approach opens a new room of opportunities for the integration of simple, optically driven nanosorting or filtering modules in on‐chip platforms paving the way toward more efficient functionalities in micro‐ and nanofluidic systems.The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


The rapid spread of severe acute respiratory syndrome coronavirus 2 led to the declaration of a global pandemic within 3 months of its emergence.COVID‐19) experience a mild illness that can usually be managed in the community. Patients require careful monitoring and early referral to hospital if any signs of clinical deterioration occur.The majority of patients presenting with coronavirus disease 2019 . Investigational therapies for COVID‐19, with thousands of cases likely to present over the coming years.Australian clinicians need to be able to recognise, diagnose, manage and appropriately refer patients affected by  In December 2019, a novel coronavirus emerged in Wuhan, Hubei Province, China, leading to a global pandemic. The virus, named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), causes a clinical syndrome termed coronavirus disease 2019 (COVID‐19).The first reports of an undiagnosed pneumonia in Wuhan on 8 December 2019 were followed by an alert from China to the World Health Organization (WHO) about a cluster of pneumonia cases on 30 December. Isolation of a novel coronavirus occurred on 3 January 2020. On 30 January, the WHO declared a public health emergency of international concern, and a pandemic was declared on 12 March 2020.Similar to other coronaviruses, SARS‐CoV‐2 is predominantly spread by respiratory droplets, although spread by contact with contaminated fomites also occurs, as does transmission by aerosols in certain circumstances.Based on the experience in China, the typical incubation period of COVID‐19 infection has been estimated to be a median of 5.1 days , with 97.5% of those who develop symptoms doing so within 11 days of exposure . This has informed the use of a 14‐day time period for quarantining potentially exposed individuals in an effort to limit onward spread.The recognition of asymptomatic infection has been an area of intense interest in understanding the epidemiology of COVID‐19. The ratio of asymptomatic to symptomatic infection is currently uncertain. Cross‐sectional studies have reported asymptomatic infection in women attending a maternity service in New York Symptomatic COVID‐19 infection usually presents as a respiratory syndrome, most commonly with fever and cough.Fever has been reported in up to 99% of people at some time during the course of their illness, but importantly in one cohort, it was reported to be present at the time of hospital presentation in only 44% of patients, and at some time during the hospital admission in 89%.Around 80% of COVID‐19 infections present as a mild respiratory illness in a patient who is ambulatory and can generally be managed outside the hospital. Around 15% typically need hospital care , and another 5% have critical illness requiring more intensive supports.Of those who require hospitalisation, the median time from first symptoms to onset of dyspnoea is 5 days , the median time to hospital admission is 7 days , and in those who develop more severe manifestations, the median time to acute respiratory distress syndrome is 8 days IQR, 6–12 days).–12 days.At presentation to hospital, the most common laboratory feature of COVID‐19 infection is lymphopenia (reported in 70.3% of cases).Nasopharyngeal specimens, deep nasal swabs, throat swabs or lower respiratory samples  sent for molecular detection of SARS‐CoV‐2 by polymerase chain reaction (PCR) are currently the best means of specific diagnosis of COVID‐19 in Australia. Faecal samples may also be PCR positive for COVID‐19 but the role of the oral–faecal route for transmission remains unclear.Patients with suspected or confirmed COVID‐19 should be assessed for features of severe disease and risk factors for progression to severe disease. This assists in determining whether a patient can safely be managed in the community or requires referral and admission to a health care facility able to provide acute inpatient care. Current data suggest that older patients and those with comorbidities have increased risk of progression to severe disease and mortality. In a large surveillance report from China including over 44 000 confirmed cases of COVID‐19, the case fatality rate was < 0.5% for patients aged < 50 years, but rose to 8.0% for those in their 70s, and 14.8% in those aged > 80 years.v 24.7%; P < 0.001); lower initial oxygen saturation ; and higher total white blood cell count but lower lymphocyte count at presentation accompanied by a lower lymphocyte count, expressed as a lower lymphocyte percentage .9/L, and elevated lactate dehydrogenase levels.Clinical features that have been identified more often in COVID‐19 infected patients who have had a fatal outcome compared with those who survive are: dyspnoea at presentation 2] < 94% on room air), hypotensive (systolic blood pressure < 100 mmHg), have an acutely altered mental state, or who have extensive pulmonary infiltrates evident on chest imaging.Patients with moderate or severe illness will generally require admission to hospital. This includes those who are dyspnoeic on minor exertion, tachypnoeic at rest (respiratory rate > 22 breaths/min), hypoxaemic .Supplemental oxygen should be administered for patients with SpOManoeuvres to improve gas exchange should be implemented, such as positioning patients appropriately in bed (on either side with regular turning), elevating the bed head to 30 degrees, encouraging deep breathing every hour while awake, sitting patients out of bed every day when possible, and mobilising when able. For mechanically ventilated patients with persistent hypoxaemia, prone positioning may be effective.In the setting of progressive hypoxaemia despite low or moderate flow oxygen , high flow oxygen can be considered. Whether high flow oxygen devices > 10 mL/min) are potentially aerosol‐generating is being studied, but current guidelines0 mL/min There are emerging views that the respiratory dysfunction observed in COVID‐19 infections is not uniform.Empirical antibiotic therapy for bacterial pneumonia should be considered in patients whose illness is severe, where there is evidence of sepsis or septic shock, or where the patient is clinically deteriorating.Hypovolaemia may be contributed to by reduced oral intake and increased losses, but management requires cautious administration of intravenous fluids with regular assessments given the risk of exacerbating pulmonary oedema in the setting of acute respiratory distress syndromeA range of possible complications related to SARS‐CoV‐2 infection have been reported and their incidence is being monitored. These include thromboembolic events in the lungsThere is considerable interest in monitoring large patient cohorts and conducting analysis of linked datasets at a population level to establish whether there are any rare or longer term complications or associations of COVID‐19 with other medical conditions. Given the very recent emergence of SARS‐CoV‐2, data are currently limited but it is likely that information will emerge in coming months from populations that have experienced a high attack rate. An example of a rare condition with potential association is paediatric inflammatory multisystem syndrome temporally associated with SARS‐CoV‐2, presenting as hyperinflammatory shock with features similar to atypical Kawasaki disease.A range of pharmacotherapies have been proposed as possible treatments for COVID‐19. Early evidence of clinical benefit for some agents has emerged. The WHO interim guidance on the clinical management of COVID‐19The understandable interest in evaluating potential treatments has led to a large number of clinical trials being registered globally; by late April 2020, over 1100 clinical studies were registered, including over 500 randomised controlled trials.Lopinavir–ritonavir, a combined antiretroviral agent, was proposed as a potential treatment for severe acute respiratory syndrome in 2003, based on apparent reductions in mortality in preliminary research in Hong Kong.On 18 March 2020, a randomised controlled open label trial of lopinavir–ritonavir in 199 hospitalised adults with COVID‐19 in China was published.Chloroquine and hydroxychloroquine are antimalarial agents which also have immunomodulatory properties that led to established indications for use in the treatment of rheumatological conditions. Potential adverse effects include retinal toxicity, QT interval prolongation and other cardiological and dermatological effects.In early February 2020, chloroquine was reported to inhibit SARS‐CoV‐2 replication in vitro.Despite the lack of clinical evidence from randomised clinical trials, several institutional and local guidelines, and notable public figures, have supported the potential use of chloroquine or hydroxychloroquine for the treatment of COVID‐19.However, given the current lack of evidence of clinical benefit and reports of significant limitations of supply of hydroxychloroquine for patients with rheumatological conditions, in March 2020, the Pharmaceutical Society of Australia and the Australasian Society for Infectious Diseases called for immediate cessation of prescribing and dispensing of hydroxychloroquine for indications relating to COVID‐19, outside use in approved clinical trials.On 5 June 2020, the chief investigators on the RECOVERY trial  issued a press release stating that no beneficial effect of hydroxychloroquine had been observed.In January 2020, the first patient diagnosed with COVID‐19 in the US received the investigational nucleotide prodrug remdesivir, supplied on a compassionate basis.P < 0.001); no significant difference in mortality was found. Benefit was reported for the group requiring oxygen but not yet requiring invasive or non‐invasive ventilatory support. This new evidence has led Australian national guidelines to adopt a conditional recommendation for use of remdesivir outside of a trial setting where necessary.On 27 May 2020, the first positive results of a randomised double‐blind controlled trial of a treatment for COVID‐19 were published.n = 24) with a combination of lopinavir–ritonavir, ribavirin and subcutaneous interferon beta‐1b (n = 52).v 13 days; P < 0.0001) and shorter median length of hospital stay  if the combination was commenced in the first 7 days from symptom onset. Importantly, the cohort of patients studied was not particularly unwell, with very few requiring ICU support and no deaths in the group.In May 2020, a randomised trial in Hong Kong reported results of a comparison of lopinavir–ritonavir alone  among ventilated patients, and for those receiving oxygen without mechanical ventilation, mortality was reduced by 20% . No benefit of dexamethasone was observed among hospitalised patients who did not require respiratory support. While peer review and formal publication of this analysis is awaited, it is likely that these findings will be reflected in national and international guidelines.However, on 22 June 2020, a preliminary report regarding interim findings from the UK RECOVERY trial suggested that low dose dexamethasone  may substantially reduce mortality in hospitalised patients with COVID‐19 who received supplemental oxygen or mechanical ventilation.Tocilizumab is a humanised monoclonal antibody which binds to interleukin 6 (IL‐6) receptors, resulting in reduced immune activation and inflammation. It is licensed in Australia for use in autoimmune conditions including rheumatoid arthritis and giant cell arteritis. In addition to complications of immunosuppression including serious infections, adverse effects include hepatotoxicity and gastrointestinal complications. The theory behind use of tocilizumab or other agents that target the IL‐6 pathway  in the context of COVID‐19 is that part of the pathogenesis in some patients may be attributable to an acute inflammatory syndrome or cytokine storm, which is associated with elevated IL‐6 levels. Clinical trials of these agents are currently underway.Numerous immunomodulatory agents have been proposed as potential adjunctive treatments for COVID‐19, with a range of different immunological targets including other inflammatory cytokines. These include anakinra (an IL‐1 receptor antagonist), bevacizumab , and eculizumab .A preliminary, uncontrolled case series of five critically ill Chinese patients with COVID‐19 who received convalescent plasma containing high SARS‐CoV‐2‐specific antibody titres was published on 27 March 2020.A global pandemic causes understandable fear and anxiety for many people in the community. For those at particular risk of worse outcomes of infection — older people and those with significant pre‐existing illness or multiple comorbidities — COVID‐19 represents a particular threat. In addition, the health care workforce is under substantial strain and faces a potentially overwhelming challenge in delivering care to patients. Ensuring emotional care for the most vulnerable and those experiencing high levels of stress will be a fundamental determinant of the resilience of our society during this challenge.For vulnerable and frail patients at particular risk of poor outcomes, it is important to provide personalised care and to develop an understanding of each individual's perspectives and preferences for health management. Involving caregivers and family members in decision making and establishing goals of care is necessary.It is essential to ensure that all patients receive the best standard of care irrespective of the setting in which the care is delivered, or of the existence of any proposed limitations to life‐extending interventions. Under no circumstances should the best possible symptom control and compassionate, individualised care be denied any patient affected by COVID‐19.SARS‐CoV‐2 has caused a global pandemic with a profound public health impact, changing the daily lives of billions of people. It has exposed weaknesses in even strong and well resourced health systems internationally, and the economic impact alone will be staggering.However, never before has the global community had the tools currently available to address a pandemic threat. A strong commitment to social and public health strategies and communicable disease control will ensure our health system retains the capacity to address COVID‐19, including sufficient hospital and intensive care resources to care for those with severe illness.Biomedical innovations such as new and rapid point‐of‐care diagnostics, effective specific treatments and preventive vaccines are very high priorities which are rightly attracting substantial attention and funding. In the interim, high quality, evidence‐based clinical care — scaled up to face the pandemic challenge — together with robust public health interventions will save the lives of thousands in Australia, and millions globally.No relevant disclosures.Commissioned; externally peer reviewed.


Low skeletal muscle mass is highly prevalent in older cancer patients and affects 5% to 89% depending on the type and stage of cancer. Low skeletal muscle mass is associated with poor clinical outcomes such as post‐operative complications, chemotherapy toxicity and mortality in older cancer patients. Little is known about the mediating pathophysiological mechanisms. In this review, we summarize proposed pathophysiological mechanisms underlying the association between low skeletal muscle mass and poor clinical outcomes in older cancer patients including a) systemic inflammation; b) insulin‐dependent glucose handling; c) mitochondrial function; d) protein status and; e) pharmacokinetics of anticancer drugs. The mechanisms of altered myokine balance negatively affecting the innate and adaptive immune system, and altered pharmacokinetics of anticancer drugs leading to a relative overdosage of anticancer drugs are best‐substantiated. The effects of glucose intolerance and circulating mitochondrial DNA as a consequence of low skeletal muscle mass are topics of interest for future research. Restoring myokine balance through physical exercise, exercise mimetics, neuro‐muscular activation and adapting anticancer drug dosing on skeletal muscle mass could be targeted approaches to improve clinical outcomes in older cancer patients with low skeletal muscle mass. We specifically focus on the pathophysiological consequences of low skeletal muscle mass as illustrated in the directed acyclic graph in Figure 2Figure 3Skeletal muscle fibres are able to actively shape the immune system in both a pro‐ and anti‐inflammatory manner, regulating innate and adaptive immune responses.Patients with low skeletal muscle mass at the time of hospital admission have a doubled risk of nosocomial infections during the first weeks of hospitalization3.1Based on the suggestion that skeletal muscle acts as an endocrine organ,IL‐6 represents another myokine which is expressed in high levels in skeletal muscle tissue. IL‐6 exerts pro‐inflammatory effects in response to pathogens, including T‐cell recruitment and promoting antibody production from B‐cells.Research on the effects of prescribing exercise in oncological patients is rapidly expanding,Other myokines worth mentioning are IL‐8 and myostatin. IL‐8 expression is elevated in cancer cachexiaSince exercise is accompanied by an increase in the blood concentration of a large number of myokines,It should be emphasised that other indirect exercise‐induced adaptations may contribute as well to the observed effects. In this review, we highlight the role of skeletal muscle in the pathophysiology of clinical outcome measures, and it is likely that exercise‐induced maintenance or increase in muscle mass and oxidative capacity per se contribute to understanding the underlying mechanisms. Indeed, a 16‐week high‐intensity exercise training intervention in breast cancer patients was found to maintain or increase muscle citrate synthase activity, size and capillarization of both slow‐switch (type I) and fast‐twitch glycolytic (type II) fibres.4Skeletal muscle has a primary role in insulin‐mediated glucose metabolism as it is the main target organ of insulin‐dependent glucose uptake.This whole‐body insulin resistance might simply be because of a lower skeletal muscle mass in cachectic cancer patients,5A high skeletal mitochondrial function is generally associated with a higher endurance capacity and a lower sense of fatigue during submaximal exercise. As a result, an impaired skeletal mitochondrial function can directly explain an increased feeling of fatigue in patients with cancer.More recent evidence hints to an additional role of mitochondria in the pathophysiology of skeletal muscle wasting‐induced cancer progression. When mitochondria are defective and are broken down during mitophagy, fragments of mtDNA can be found in the circulation. A high level of circulating mtDNA is linked to a faster cancer progression and poor survival of patients with ovarian cancer.6An important contributing mechanism to the development of low skeletal muscle mass is protein status alteration. Muscle protein synthesis rate is determined by the overall health status, nutrient availability and physical activity.It is widely accepted that low protein status is a reflection of a poor nutritional status, which is prognostic for poor clinical outcomes in cancer patients.7Pharmacokinetics play an important role in patients with cancer since the majority of patients are treated with systemic therapies such as chemotherapy. Pathophysiological mechanisms caused by an alteration in pharmacokinetics of anticancer drugs because of low skeletal muscle mass that may increase the risk of poor clinical outcomes in cancer patients are highlighted in Figure Next to the decreased distribution of chemotherapeutics, clearance might be altered in cancer patients with low skeletal muscle mass. Patients with low skeletal muscle mass were found to have a higher area under the curve (AUC) and lower plasma clearance of multiple chemotherapeutics compared to patients with normal skeletal muscle mass.Another process of pharmacokinetics is the absorption of anticancer drugs. Low skeletal muscle mass in cancer patients is accompanied by an increase in permeability of the gut barrier, causing a leakage of endotoxins into the systemic circulation evoking a low‐grade systemic inflammatory response.Other roles of how low skeletal muscle mass affects pharmacokinetics are via inflammation and overall protein status. The low‐grade inflammatory state that accompanies low skeletal muscle mass leads to a decrease in liver cytochrome activity.Skeletal muscle mass was predominantly measured using bio‐impedance analysis derived lean body mass in the aforementioned pharmacokinetics studies. Bio‐impedance analysis is considered a valid tool to for the assessment of total body and segmental body composition.8The majority of this review is based on associations only, as longitudinal studies assessing the association between low skeletal muscle mass, pathophysiological mechanisms and poor clinical outcomes in cancer patients are scarce. Thus, mediating roles of pathophysiological mechanisms cannot be substantiated firmly, as they can also reversely affect skeletal muscle mass.9This review focussed on low skeletal muscle mass only. Other aspects of sarcopenia and cachexia or the components of muscle failure,The work presented in this review summarized how low skeletal muscle mass might lead to poor clinical outcomes in older cancer patients. The first step in reducing the risk of poor clinical outcomes in older cancer patients would be to prevent the loss of skeletal muscle mass. Inducing myokine production through physical exercise may act as a therapeutic target to prevent or counteract skeletal muscle mass decline10In the underpinning of the association of low skeletal muscle mass with poor clinical outcomes in older cancer patients, pathophysiology‐based mechanisms of altered myokine balance affecting the innate and adaptive immune system and altered pharmacokinetics of anticancer drugs leading to a relative overdosage are best‐substantiated. The effects of insulin resistance and circulating mitochondrial DNA as a consequence of low skeletal muscle mass require further exploration. It remains elusive whether these mechanisms are caused by low skeletal muscle mass, and reverse causation should be considered carefully. Developing targeted interventions to restore myokine balance through physical exercise, neuro‐muscular electrical stimulation or exercise mimetics and adapting anticancer drug dosing based on skeletal muscle mass, might be targeted approaches to improve clinical outcomes in older cancer patients with low muscle mass.The authors declare that they have no conflict of interest.Supplementary MaterialClick here for additional data file.


Female social empowerment has the potential to enhance women’s cognitive abilities. Our previous work investigating the role of gender equity in education and improved living conditions during early adulthood suggest that European women gain more from societal improvements over time than their male counterparts. This study extends this work by investigating the association between women’s social empowerment during childhood and gender differences in adults’ cognition for more than 30 OECD countries. We analyze established cognitive competence measures in literacy and numeracy with mixed effect models using the national survey data PIAAC collected within three rounds in 2011, 2014, and 2017. Our preliminary findings suggest that gender equity factors associated with women’s empowerment, are more beneficial for women’s cognitive key competences than men’s. High cognitive competences are particularly relevant at advanced age to enable an independent life and long economic activity.


Congenital absence of the portal vein (CAPV) is a rare malformation in which intestinal and splenic venous blood bypasses the liver and drains into systemic veins. CAPV is classified into two types based on the absence (type I) or presence (type II) of portal venous flow into the hepatic parenchyma and is associated with multiple other anomalies such as usually benign hepatic tumors. There have been only two case reports describing hepatocellular carcinoma (HCC) in patients with CAPV type II to date. We report the third such patient. A 50‐year‐old woman was referred to our hospital for management of a giant hepatic tumor. Contrast‐enhanced computed tomography (CECT) indicated a huge mass occupying the right lobe of the liver; the radiological diagnosis was HCC. CECT also demonstrated that the superior mesenteric vein (SMV) and the splenic vein (SpV) joined to form a shunt draining into the left renal vein and that a hypoplastic portal vein branched from the confluence of the SMV and SpV and drained into the liver, indicating that the CAPV was type II. Liver resection was successfully performed to treat the HCC, and the pathological diagnosis was well‐differentiated HCC. Seven months after the operation, a recurrent small HCC was detected and treated with radiofrequency ablation without complications. The patient has been carefully followed for 6 months to date without any evidence of further recurrence. Patients with CAPV are predisposed to developing HCC and require close surveillance. A 50‐year‐old woman was diagnosed with a giant hepatocellular carcinoma (HCC) that was associated with congenital absence of the portal vein (CAPV) type II. Patients with CAPV type II are predisposed to developing HCC and require close surveillance. Congenital absence of the portal vein (CAPV), which was first reported by John Abernethy in 1793 and is also known as an “Abernethy malformation,” is a rare anomaly of the splanchnic venous system where intestinal and splenic venous blood bypasses the liver and drains into systemic veins, such as the renal veins, hepatic veins, or inferior vena cava.Here, we describe a rare CAPV type II in a 50‐year‐old woman with a giant well‐differentiated hepatocellular carcinoma (HCC) that was successfully treated with liver resection. To our knowledge, this is the third reported incidence of CAPV type II that is associated with HCC development.A 50‐year‐old woman was referred to our hospital for management of a giant hepatic tumor. She had been well until 1 month prior, at which time she experienced a sensation of abdominal distension and noticed a loss in appetite. She underwent abdominal ultrasonography at another hospital, whereupon a giant hepatic mass was discovered in the right lobe. The patient was then referred to our hospital for further investigation and treatment of the hepatic tumor. Physical examination demonstrated hepatomegaly; her laboratory test results at the initial visit were as follows: liver function tests showed evidence of nonicteric cholestasis with mild transaminase enzyme level elevation. Screening for viral hepatitis yielded negative results. Levels of the liver‐specific tumor marker “protein induced by vitamin K absence‐II” were highly elevated. No hyperammonemia was detected, and no episodes or signs of encephalopathy were noted. Abdominal ultrasonography showed a giant hypoechoic mass measuring 139 × 120 mm in the right lobe of the liver. Contrast‐enhanced computed tomography (CECT) demonstrated a huge mass that occupied the right lobe of the liver and showed inhomogeneous hyperenhancement in the arterial phase, as well as uniform isoenhancement in the portal venous phase  ‐enhanced magnetic resonance imaging (MRI); this lesion was successfully treated with radiofrequency ablation. She has been carefully followed for 6 months to date without any evidence of further recurrences.CAPV is a rare condition in which the intestinal and splenic venous drainage routes bypass the liver and deposit directly into systemic veins through various venous shunts.CAPV is classified into two types based on whether the portal vein is present.CAPV can have various clinical presentations ranging from no symptoms to systemic manifestations such as encephalopathy, hepatopulmonary syndrome, or symptoms related to hepatic masses. CAPV is often associated with metabolic disorders such as hypergalactosemia and hyperammonemia,et al. reported that patients with CAPV type I have a significantly higher prevalence of hepatic tumors and other anomalies than do those with type II.et al. reported a 5‐year‐old girl who had multiple liver tumors associated with CAPV type II and had experienced learning disabilities. The liver tumors were not treated, and after she died at the age of 19 years, postmortem examination indicated that the tumors were multifocal HCC and multiple adenomas.et al. reported an HCC within an adenoma in a 42‐year‐old woman with CAPV type II.CAPV often causes hepatic tumors such as focal nodular hyperplasia, nodular regenerative hyperplasia, hemangioma, and HCC. In most cases, hepatic tumors in patients with CAPV are benign.et al. reported that 20% of HCCs arise in noncirrhotic livers, where their risk factors are non‐alcoholic fatty liver disease, chronic viral hepatitis, inherited diseases such as alpha‐1 antitrypsin deficiency, and intake of genotoxic substances such as aflatoxin B1.It remains unclear how CAPV causes HCC. Previous investigators have hypothesized that the absence of portal venous flow compensatively increases the hepatic arterial flow, which might provide a permissive environment for tumor development,et al. suggested that the risk of HCC among patients with CAPV may be similar to that among alcoholics or patients with hepatitis C‐induced cirrhosis.The lifetime risk for HCC development in patients with CAPV is yet to be determined owing to the rarity of the disease and lack of longitudinal studies. Konstas In conclusion, ours is the third reported patient with CAPV type II to develop HCC, for which she underwent a radical resection. A postoperative recurrent lesion in the remnant liver was successfully treated with radiofrequency ablation. Taken together, the data suggested that patients with CAPV type II are predisposed to HCC and therefore require close surveillance.


Salvage surgery after failed organ preservation treatment offers challenges for both the patient and the surgeon. The outcome is often uncertain and even today, 5‐year overall survival does not exceed 50 per cent. The chemoradiotherapy induced toxicity asks for meticulous discussion and planning in a multidisciplinary manner in a changing environment of increasing incidence of human papillomavirus induced oropharyngeal tumours, evolving surgical techniques and patient participation. Herein, we discuss the latest literature on salvage surgery and the need for identifying the proper prognosticators to ensure for an optimal treatment plan in potentially salvageable patients. Patients eligible for SS have previously been through the process of HNC treatment with accompanying anxiety and uncertainties. Therefore, they should be guided accordingly and informed in a truthful and concise manner meaning that salvage surgery is a last resort treatment with an often uncertain outcome both considering cure and function impacting quality of life. Salvage surgery should never be considered a fall back option in case patients elect organ preservation treatment over an advised primary surgical treatment. Performing surgery in previously irradiated tissue, especially when combined with systemic treatment enhancing toxicity, is a very difficult and comes with many both short‐ and long‐term complications.Although surgical and radiation techniques have improved, salvage surgery remains a journey not easily embarked on with current success rates often not exceeding 30%.This paper sets out to give an overview of current literature with regard to prognosticators in salvage surgery in light of developments such as increasing incidence of human papillomavirus in oropharyngeal squamous cell carcinoma, the use of transoral robotic surgery, necessity of multidisciplinary management and the increasing awareness for value‐based health care.2Although salvage surgery has always played a role in HNC, its prospects have changed over the last decades with the introduction of combined modality treatment for advanced stage disease. The use of mainly cisplatin and later cetuximab in platinum unfit patients has added toxicity causing bigger challenges for uneventful outcome in salvage surgery  is different in that respect since surgery (with or without radiotherapy) is the primary treatment option. Reported recurrence rates are 25%–45% and even 50% for advanced stage disease. Locoregional recurrence after salvage surgery is around 60%  and with primary (chemo)radiation. Due to the increasing incidence of HPV‐positive OPSCC, this particular subsite has been highlighted since HPV‐positive OPSCC is a biologically different disease . Therefore, he concluded that recurrent stage was a highly significant predictor of recurrence‐free survival where he could not confirm this for specific sites. The fact that stage means more than site has been supported by the majority of authors, with the important note that that data on non‐laryngeal advanced stage disease are sparse , may be used to assess chemosensitivity and/or to reduce the radiation field. It is known that the addition of platinum‐based therapy to radiation gives a survival benefit of 4%–8%. Besides this positive effect, chemotherapy also increases toxicity making SS more challenging. It has been reported that previous chemotherapy in salvage candidates for HNC is negative prognosticator. The primary choice for chemoradiation portends an aggressive course of the disease‐advanced stage disease or high grade features—which could be predictive of a recurrence  and in HPV + patients who underwent salvage surgery (p = .004) ‐positive OPSCCs is increasing. A new staging system for p16‐positive OPSCC has been introduced in the eight edition of the UICC/AJCC , surveillance is sufficient. In this group of relatively young patients, toxicity reduction is key to prevent xerostomia, dysphagia, carotid artery atherosclerosis and risk reduction for a radiotherapy‐induced tumour. The introduction of TORS has improved the accessibility for oropharyngeal resection and has also taken its role in the unknown primary setting by means of tongue base mucosectomy increasing the identification rate from 40% to 80%  is impacting outcome of salvage surgery. The majority of recurrent HNCs are diagnosed within 18 months after initial treatment  have been established to provide optimal care, including the framework of salvage surgery. Each HNC patient is discussed for a tailor made treatment plan. To objectify the added value of MDT meetings, several studies have analysed its role. Results show that MDT discussed cases, mainly stage IV patients, have superior outcome with regard to 5‐year OS. MDT discussed patients were more likely to receive multi‐modality treatment than non‐MDT discussed patients (Friedland et al., 4In addition to tumour characteristics, adequate patient selection and optimization in the pre‐, per and postoperative period is paramount. Patients should have a realistic perspective of cure and preservation of vital functions such as swallowing and speech. Patients with poor functional status after primary treatment are likely to experience further deterioration. These patients need to be able to undergo extensive surgery with often the use of free flaps necessitating the need for proper perfusion. Patients with a medical history of poorly controlled diabetes or cardiovascular disease are therefore at risk for a complicated postoperative course. Comorbidities have proven to be an important factor to consider (Kim et al., In the present time of increasing numbers of HPV‐positive OPSCC patients, there is a distinct group of young and relatively healthy patients eligible for salvage surgery even by means of TORS in select cases, thus avoiding open surgical approaches. White et al.  describeThe “ideal candidate” for salvage surgery could be defined as a young patient having an early‐stage local laryngeal recurrence without any comorbidities. In reality, this category of patients makes up for a very modest percentage of salvage candidates. Patient selection should be done after extensive and realistic consultation with the patient and his family and to ensure for modern‐day shared decision‐making. MDT discussion of salvage candidates contributes to proper decision‐making, specifically in case of a realistic chance of adjuvant treatment.5To optimize the chances of uneventful recovery, introduction of well‐vascularized tissue in a toxicity exposed area is vital. Initially, pedicled flaps were used for this purpose such as the pectoralis major flap and the latissimus dorsi flap Ariyan, . These v6Since salvage is performed in previously treated tissue, complication rates are relatively high. Previously induced fibrosis and toxicity deteriorate healing tendency. Goodwin (Bonner et al., 7Improvements have been made over the last decades in HNC treatment as for salvage. Introduction of designated head and neck centres, increasing use of MDTs, evolution in reconstructive surgery and improved patients optimization have all contributed. The increasing number of HPV‐positive OPSCC patients may play a role in improved outcome in SS. Jayaram et al.  describeNone to declare.Stijn van Weert: Conceptualization; Data curation; Formal analysis; Methodology; Writing‐review & editing. C. René Leemans: Conceptualization; Formal analysis; Writing‐original draft; Writing‐review & editing.https://publons.com/publon/10.1111/odi.13582.The peer review history for this article is available at


The COVID‐19 pandemic has reduced well‐being and economic security on a number of dimensions, likely worsening mental health. In this paper, we assess how mental health in the US population has changed during the pandemic. We use three large, nationally representative survey sources to provide a picture of mental health prior to and during the pandemic. We find dramatic but broad‐based declines in the level of mental health from pre‐pandemic baseline measures across both people and places. Rates of poor mental health have jumped roughly 25 percentage points, from a base of roughly one‐third. We document substantial disparities in mental health but show that the pandemic has generally preserved, rather than widened, these. Significant worsening in relative mental health among Hispanics and respondents aged 30 and older are exceptions. Consistent with an important role for pandemic‐specific shocks, We find that income loss, food insecurity, COVID‐19 infection or death in one's close circle, and personal health symptoms are all associated with substantially worse mental health. If anything, the decline in mental health is worsening as the pandemic wears on and is becoming less related to local COVID‐19 case rates. IAlmost from the beginning of the COVID‐19 pandemic in the United States, observers have expressed concern about the mental health consequences of the pandemic. There are good reasons for this concern. The overall strain of facing a serious disease that is readily transmissible through everyday activities is likely to be significant. Exposure to other rare but unpredictable risks that one can incur in everyday life, such as crime, are known to depress mental health.These effects also have the potential to fall unequally on different groups. Service occupations employ many young, less‐educated and minority workers and have been heavily affected by layoffs. At the same time, lower‐income, minority and older individuals are at greater risk from COVID‐19 complications because of their disproportionate rates of suspected risk factors. This may cause greater strain for these groups as they weigh the additional risk in daily life alongside the challenges of keeping themselves safe. Geographic disparities are also likely to emerge. Cities and states differ in many ways that can contribute to COVID‐19 risk as well as the economic and social costs of mitigation, such as for example, segregation, pre‐pandemic inequality, and connectedness between neighbourhoods and cities.To investigate pandemic‐era changes in mental health in the United States, We draw on evidence from two pandemic‐era survey sources: the Data Foundation's COVID Impact Survey (CIS) and the Census Bureau's Household Pulse Survey (HPS). We measure mental health using an indicator for recent poor mental health experiences that we show is comparable across sources. Both surveys launched in late April 2020 with similar mental health modules, and both ask respondents about the economic and financial changes they have experienced during the pandemic. Beyond that, the surveys offer different advantages and disadvantages for this analysis. The CIS asks detailed questions about current physical symptoms, exposure to COVID‐19 and behavioural changes; however, it is a smaller survey with less regular administration than the HPS. The HPS is much larger and has coverage for 12 consecutive weeks following its introduction, but a number of factors – potentially important for mental health – are only asked in the CIS. We combine our analysis of pandemic‐era sources with a major pre‐pandemic benchmark survey source, the Behavioral Risk Factor Surveillance System (BRFSS).We first construct a data set that allows us to analyse aggregate local mental health outcomes at the place level, i.e. for state and metropolitan area populations. We explore whether pre‐pandemic place characteristics and local COVID‐19 caseloads are associated with changes in local mental health from the BRFSS baseline. We then turn to regressions using individual‐level data to document disparities across demographic groups in mental health, as well as to assess whether these disparities have changed during the pandemic. Finally, we use the same microdata analysis to explore the relationship between pandemic‐era shocks to financial security, health or behaviour patterns and mental health.We report several findings. We find dramatic declines in mental health from pre‐pandemic baseline measures across both people and places in both sources. Rates of poor mental health have jumped roughly 25 percentage points, from a base of roughly one‐third. Place‐level variation in poor mental health has increased but is not well explained by local characteristics that precede the pandemic. Local mental health is only modestly related to local COVID‐19 cases and, if anything, this relationship is weakening further as the pandemic progresses.Analysis by demographic groups also shows large declines in mental health in the COVID‐19 era. Individual‐level analysis identifies several groups with both significantly worse and better reported mental health states than average. However, we show that the pandemic has generally preserved, rather than widened, these mental health disparities. Significant worsening in relative mental health among Hispanics and respondents aged over 30 are exceptions. We also find that several pandemic‐era specific experiences – including income loss, food insecurity, COVID‐19 infection or death in one's close circle, and personal health symptoms – are associated with substantially worse mental health. These experiences are associated with a decline in mental health that is large in magnitude. The impacts of these factors are in many cases roughly comparable to the average 20 percentage point increase in poor mental health. We conclude that economic shocks, health concerns, and personal loss and risk also compound the general decline in mental health for those who experience them, but these are not confined to particular demographic groups.This paper aligns with papers studying the disparate effects of COVID‐19 on mental health and other outcomes. Several studies document features of mental health in the United States during the pandemic.A number of other papers explore disparities in other pandemic era outcomes. Montenovo et al.  use CPS IIThe HPS and the CIS were both launched in the first month of the pandemic with similar goals. Both are designed to assess a broad spectrum of well‐being measures at high frequency in order to deliver timely data on the pandemic's effects. The two surveys are similar in length, taking about 15–20 minutes to complete, and both make extensive use of questions from other data sources in order to allow comparisons with pre‐pandemic benchmarks.Despite these many similarities, the two sources differ in their particular scope and scale. The CISIIIThe two surveys administer similar mental health modules to respondents. This allows us to construct comparable measures of mental health in both sources. To understand the measurement of mental health across surveys, Table Table Although there is considerable overlap in question wording and response options, there are limits to comparability across these surveys. The differences in the reference windows might lead to rates of mental health issues that are lower in the pandemic‐era surveys than the BRFSS. If so, the true 14‐day incidence of mental health issues in the pandemic‐era data might be higher than that reported in the table. Hence, the table may understate pre‐pandemic and pandemic‐era differences in aggregate mental health. It is also unclear whether differences in the low incidence categories across the CIS and HPS/BRFSS contribute to these differences. On the one hand, more respondents are eligible to report positive days of mental health issues when the lowest category is strictly zero, which would lead to lower rates of reporting in the CIS than in the other two sources. On the other hand, respondents with very low incidence may be reluctant to report ‘several’ days of an issue and hence round down to the zero category, leading to lower rates of reporting in the HPS/BRFSS relative to the CIS. Ultimately, we conclude that these sources are sufficiently comparable as to be informative, despite these limitations.Another limit to comparability is that the specific mental health items in Table For ease of comparison, this indicator for any recent poor mental health is the preferred outcome measure that we will use for analysis going forward.IVWe begin by examining which places in the CIS sample of states and cities have experienced the biggest changes in mental health from the pre‐pandemic environment. This analysis allows us to assess whether recent mental health changes have been more severe in certain types of places.y‐axis than the equivalently scaled x‐axis. Place‐level dispersion in poor mental health rates has roughly doubled in the COVID‐19 era. Finally, the scatters by week have considerable overlap, indicating little temporal pattern in mental health.We first compare pre‐pandemic and pandemic‐era place‐level measures of average mental health. Pre‐pandemic means are constructed using the 2018 and 2017 BRFSS.x‐ and y‐axis values for a place from Figure The figures show widespread declines in the level of local mental health, but have certain types of places experienced more substantial changes in these measures than others? To assess this, we run place‐level regressions of the measured changes from baseline  places in the HPS (CIS) data, place‐level analysis can only accommodate a limited number of covariates.8 places The results are reported in the two panels of Table The analysis so far shows that pre‐existing place characteristics are not associated with changes in local mental health. Thus, while declines in mental health have been substantial across the United States, and while there is more heterogeneity in mental health across places in the pandemic‐era data than the pre‐pandemic data, it does not appear that certain types of places faced systematically larger declines. However, the geographic spread of COVID‐19 has been uneven, and differences in the incidence of COVID‐19 across places may account for varying levels of local mental health.New York Times GitHub repository of county‐level confirmed cases. In Figure We assess this possibility by combining the place aggregates at the weekly level with data on per capita COVID‐19 cases from the VGiven concerns about inequitable effects of COVID‐19 on health and economic security for lower‐earning workers and workers of colour, it is important to analyse people in addition to places. Another way to study the effects of COVID‐19 on mental health is to look at the same changes from baseline by demographic group as we examined in the place‐level analysis. Thus, we turn to individual‐level data to assess the role that individual experiences during the pandemic play in determining mental health status.For this analysis, we use the national sample component of the CIS and all microdata from the HPS.The group‐level changes in mental health appear very broad, with many groups experiencing large declines from baseline. However, which of these pandemic‐era disparities in mental health persist after controlling for respondent characteristics simultaneously? Also, are any of these disparities more substantial than in normal times?We begin by assessing disparities in mental health using microdata that allow us to control for multiple respondent characteristics simultaneously. We regress an indicator for experiencing any of the four poor mental health states on a range of demographic and socio‐economic characteristics. The results are reported in Table The estimates in the first two columns of Table Some of these results are surprising at first. Results indicating lower rates of poor mental health among black respondents are particularly striking, as the disease has disproportionately affected this community. This is possibly due to a level effect in symptom reporting, and is consistent with findings across pre‐pandemic surveys in the epidemiology of mental health.These patterns are robust across sources in the COVID‐19 era, but do they represent a departure from pre‐pandemic mental health disparities? A partial answer to this is provided in the final column of Table Figure Consistent with its larger sample size, the HPS coefficients have smaller standard errors and are more often significantly different from their pre‐pandemic values. While the results across the two surveys are similar, the results for age groups are substantively different. HPS data show that mental health has worsened significantly for older respondents relative to the youngest group, though Table Table The first two columns of Table The final two columns of Table This specification also includes measures of personal behavioural changes during the pandemic, measured as total protective steps taken out of 19 possible steps, as well as personal restrictions experienced, again of our total of 19 possible restrictions. Protective steps are significantly associated with worsened mental health, but the magnitude is modest compared with other items. Experienced restrictions seem to have little relationship to mental health.The last column in Table VIWe use two survey sources, the CIS and the HPS, to study the incidence of poor mental health in the United States during the COVID‐19 era and to compare it to pre‐pandemic baselines.We report several findings. First, mental health has worsened substantially in the United States since the onset of the pandemic. The rate of poor mental health days has nearly doubled for the US population, rising by 25 percentage points from a base level of roughly one‐third. The decline in mental health is apparent across a broad set of places and individuals. All states have experienced declines in mental health in their populations of roughly this magnitude. We find that place‐level dispersion in mental health has doubled in the pandemic era compared with pre‐pandemic data, but place‐specific factors pre‐dating the pandemic do little to explain this dispersion. We also find that local COVID‐19 infection rates are only modestly related to local mental health levels and, if anything, this relationship has weakened recently.Analysis of individual‐level data reveals that mental health has worsened for individuals across the board. All identifiable demographic groups report worse mental health in the pandemic era than in a comparable pre‐pandemic source. Moreover, although disparities in mental health were significant in the pre‐pandemic era, the pandemic has generally preserved these rather than widened them. Two substantive exceptions to this are Hispanic respondents and those over 30. Both groups have seen their mental health worsen relative to other groups, compared with their pre‐pandemic levels. Notably, in both cases, this relative decline reflects a narrowing disparity in which mental health worsened in one group to reduce the gap with others. The fact that relative mental health has not worsened for some groups known to experience disproportionate changes to employment and daily life – notably black respondents and women – is something of a surprise. However, further analysis reveals that income loss and food insecurity are associated with large declines in mental health, as is exposure to a COVID‐19 infection, death, or personal COVID‐19 symptoms. Taken together, these results suggest that pandemic‐era shocks to financial security and health meaningfully worsen mental health, but the large, population‐wide declines in mental health swamp most relative changes in mental health across groups.• Online AppendixClick here for additional data file.


Pelviperineal wound complications frequently occur after salvage surgery for chronic pelvic sepsis despite using an omentoplasty. Sufficient perfusion of the omentoplasty following mobilization is essential for proper healing. This study investigated the impact on short‐term clinical outcomes of fluorescence angiography (FA) using indocyanine green for assessment of omental perfusion in patients undergoing salvage surgery.This was a comparative cohort study including consecutive patients who underwent combined abdominal and transanal minimally invasive salvage surgery with omentoplasty at a national referral centre for chronic pelvic sepsis between December 2014 and August 2019. The historical and interventional cohorts were defined based on the date of introduction of FA in April 2018. The primary outcome was pelviperineal non‐healing, defined by the presence of any degree of pelviperineal infection at the final postoperative evaluation.n = 50) or rectal cancer (n = 38), with even distribution among the cohorts (P = 0.811). FA led to a change in management in 28/36 (78%) patients. After a median of 89 days, pelviperineal non‐healing was observed in 22/52 (42%) patients in the cohort without FA and in 8/36 (22%) patients in the cohort with FA (P = 0.051). Omental necrosis was found during reoperation in 3/52 and 0/36 patients, respectively (P = 0.266).Eighty‐eight patients underwent salvage surgery with omentoplasty for chronic pelvic sepsis, of whom 52 did not have FA and 36 did have FA. The underlying primary disease was Crohn's disease (After introduction of FA to assess perfusion of the omentoplasty, halving of the pelviperineal non‐healing rate was observed in patients undergoing salvage surgery for chronic pelvic sepsis. The study aim was to evaluate short‐term clinical outcomes in patients undergoing salvage surgery for chronic pelvic sepsis with and without the use of fluorescence angiography (FA) of the omentoplasty. In the cohort with FA, a clinically relevant halving of the pelviperineal non‐healing rate was observed.Therapy‐refractory pelvic Crohn’s disease and complications after rectal cancer surgery can lead to chronic pelvic sepsis. Salvage surgery without restoration of continuity can offer source control, but persistent pelvic sepsis and pelviperineal wound healing problems might occur, with reported rates up to 60% , 2, 3, 4In a pilot study, the use of intra‐operative fluorescence angiography (FA) using indocyanine green was found to potentially contribute to the diagnosis of omental ischaemia in patients who were treated by salvage surgery and a pedicled omentoplasty , 9. HoweTherefore, the aim of this study was to examine the short‐term clinical outcomes after salvage surgery with omentoplasty for chronic pelvic sepsis with the use of FA, and to compare the results to a historical control cohort of patients who underwent a similar procedure without the use of FA. We hypothesized that a well‐vascularized omentoplasty would lower pelviperineal non‐healing after salvage surgery for pelvic sepsis.This study was performed at a national referral centre for chronic pelvic sepsis . All consecutive patients who underwent salvage surgery with omentoplasty for chronic pelvic sepsis by a combined abdominal and transanal minimally invasive (TAMIS) approach between December 2014 and August 2019 were included. FA was introduced as standard clinical practice for assessment of omental perfusion in April 2018. Eligible patients were divided into a historical control cohort before the introduction of FA and an interventional cohort in which FA was routinely used.Chronic pelvic sepsis originated either from therapy‐refractory pelvic Crohn’s disease or complications after rectal cancer surgery. Therapy‐resistant pelvic Crohn’s disease (referred to as pelvic Crohn’s disease) included poorly controlled proctitis or pouchitis, with or without fistula tracts or anal stenosis. Complications after rectal cancer surgery  included chronic sepsis or a chronic presacral sinus. Prior rectal cancer surgery included transanal endoscopic microsurgery, low anterior resection with primary anastomosis, or a Hartmann’s procedure. Patients who underwent salvage surgery and omentoplasty for a different indication other than chronic pelvic sepsis, a non‐TAMIS procedure, and patients who objected to participation were excluded from the study.Patient data were retrospectively collected using the electronic patient files. The study was approved by the Institutional Review Board of the Amsterdam UMC, location AMC, and the need for written informed consent was waived due to the retrospective nature of the study with no burden for the patient. All patients were sent information concerning the study including an opt‐out letter. When there was no reply within 4 weeks, approval for the use of the data was assumed.in situ or resection of the colonic conduit/pouch with debridement of the sinus and/or fistula tracts. When not already present, a permanent stoma, either ileostomy or colostomy, was created. The omentoplasty was constructed depending on local anatomy, bulk, length of the omentum and the surgeon's preference. The omentum was mostly pedicled on indication, using either the right or left gastroepiploic artery. The route to the pelvis could be on the right or left side of the middle colic artery, with or without the need for a mesocolic window. After conventional white light assessment of omental perfusion, the decision was made whether or not there was a need for partial omental resection due to ischaemia. From April 2018 onwards, FA was subsequently performed as previously described . All the 30 patients with pelviperineal non‐healing had persisting deep infections, and 16 (53%) patients were treated for pelvic Crohn’s disease.Postoperative outcomes are demonstrated in Table P = 0.168). Of these, one superficial and six deep pelviperineal infections healed by secondary intention.Overall, pelviperineal infections at any time during the postoperative course occurred in 25 (48%) out of 52 patients in the cohort without FA and in 12 (33%) out of 36 patients in the cohort with FA (P = 0.266). All cases of omental necrosis occurred in the group after rectal cancer surgery. The proportion of complications with a CD score above 2 was eight (32%) out of 25 in the cohort without FA compared to seven (58%) out of 12 in the cohort with FA (P = 0.164). All reoperations in the cohort without FA were performed for omental necrosis. In the cohort with FA, reoperations were performed for persistent pelvic sepsis but with a viable omentoplasty .Omental necrosis confirmed during reoperation occurred in three out of 52 patients in the cohort without FA, and none of the patients in the cohort with FA had omental necrosis  are demonstrated in Tables post hoc univariate regression analysis on the effect of a left vs right pedicled omentoplasty on deep pelviperineal infection showed an OR of 9.800  when no FA was used. After the use of FA, this risk had an OR of 2.187 .Results separated for pelvic Crohn’s disease and rectal cancer surgery patients and for the technique of omentoplasty  out of 52 patients in the cohort without FA and 0 out of 36 patients in the cohort with FA.This study evaluated the potential clinical value of FA of the omentoplasty for pelvic filling in patients with chronic pelvic sepsis who underwent salvage surgery. Patients in the cohort with FA demonstrated a trend towards less deep pelviperineal infections, and importantly no omental necrosis. This resulted in less pelviperineal non‐healing at the last postoperative evaluation with a non‐ statistical significance, but potential clinical relevance. These results support to some extent the hypothesis that FA and subsequent resection of poorly perfused omentum may prevent postoperative omental necrosis with risk of secondary infection.Postoperative omental necrosis has been reported in the literature in merely 2%–4% of cases , 13, 14,However, there is a clear discrepancy between the change in management rate in the cohort with FA and reduction of postoperative omental necrosis, even when adding the reduction of deep infections that may have been secondary to occult omental necrosis. In the current study, omental perfusion was judged to be partially compromised in most patients 89%) after use of both conventional white light and FA assessment. The percentage of intra‐operative detection of partial omental ischaemia by conventional assessment  corresponds to reported rates in the literature . In the 9% after Several explanations can be considered for the observed discrepancy. First, the interpretation of FA remains subjective. There are no thresholds to guide whether the perfusion as assessed by FA is sufficient or not. This means that what has subjectively been interpreted as ‘poor perfusion’ may actually be sufficient and not lead to omental necrosis. Another explanation may be related to the fact that probably not all cases of omental necrosis will give rise to secondary infection or healing problems. Partial necrosis of fatty tissue has been described to be associated with non‐specific complaints such as low grade fever or abdominal pain, and is often self‐limiting . In a feAn interesting finding of this study was that FA had less impact when a right pedicled omentoplasty was performed. When comparing the results between left and right pedicled omentoplasties, the differences in outcomes were larger in patients in the cohort without FA. This might be explained by the fact that the possible hampered perfusion after a left pedicled omentoplasty in patients who received FA was corrected by the partial omentectomy due to the FA assessment. The hypothesis that the right gastroepiploic artery is the stronger one as the diameter is bigger is not novel , but thiThere are some limitations to this study. First, it was implicated that non‐healing was mostly due to  omental necrosis. Although omentum necrosis is expected to be a major cause of non‐healing problems, other major causes include inadequate debridement, infected haematoma, any necrotic tissue, undrained fluid, and patient risk factors including duration and extent of pre‐existing infection and diabetes mellitus. In the historic cohort a higher rate of cardiovascular comorbidity was observed. Although this patient factor could have led to bias in the results, cardiovascular comorbidity is expected to play a minor role according to our own experience. Secondly, the sample size was still relatively small and the study may have been subject to confounding factors due to the retrospective design with a historical comparison. The results could be confounded by change in surgical technique of omentoplasty and change in approach regarding management of complications over time. Comparing the interventional with the historical cohort, a laparoscopic approach was used more often and more pedicled omentoplasties were performed. Patients in the cohort with FA could potentially have received better quality omentoplasties with sufficient length and bulk in the pelvic cavity. However, the added value of FA could be larger for pedicled omentoplasties, particularly left omentoplasties. In this study, the effect of FA was also noticed for non‐pedicled omentoplasties. An explanation might be the change in anatomy after prior procedures leading to ligation of omental arterial branches. In the FA cohort, less pelviperineal infections and no omental necrosis were observed; however, more reoperations were performed. This could be explained by more active surgical management of persistent sepsis over time. Reoperations could also have contributed to the primary outcome of less pelviperineal non‐healing in both cohorts. Furthermore, follow‐up included only short‐term complications, and a proportion of patients were lost to follow‐up before 90 days postoperatively. Reasons for loss to follow‐up usually concerned patient’s return to the referring hospital when there was an uncomplicated postoperative course, and usually the referring hospital reported when new complications occurred. Also, pelviperineal infections are difficult to distinguish retrospectively into pelvic and perineal infections, which is the reason for combining the two in one denominator. Finally, we included a heterogeneous patient population with chronic pelvic sepsis originating from both therapy‐refractory pelvic Crohn’s disease and after rectal cancer surgery. However, the effect of FA was similar for both subgroups.Nevertheless, this comparative study adds to the literature as there is no available data yet on the effect of FA on an omentoplasty in patients undergoing salvage surgery for chronic pelvic sepsis, and the results strongly support future research. Future studies should be carried out prospectively in a larger cohort to confirm our results. Also research on FA of omentoplasty should focus on the determination of fluorescent thresholds to point out adequate perfused tissue.RH: unrestricted grant and materials Stryker European Operations B.V.The protocol of the study was approved by the Institutional Review Board of the Amsterdam UMC, location AMC (W19_065), and confirmed that the Medical Research lnvolving Human Subjects Act (WMO) did not apply.The need for written informed consent was waived due to the retrospective nature of the study with no burden for the patient. All patients were sent information concerning the study including an opt‐out letter. When not replied to within 4 weeks, approval for the use of the data was assumed.Table S1. Prior therapy.Table S2. Subgroup analysis.Click here for additional data file.