This work was undertaken in an attempt to ascertain the generic characteristics of fatigue behavior of friction-stir welded aluminum alloys. To this end, different alloy grades belonging to both the heat-treatable and non-heat-treatable types in both the cast and wrought conditions were studied. The analysis was based on the premise that the fatigue endurance of sound welds  is governed by residual stress and microstructure. Considering the relatively low magnitude of the residual stresses but drastic grain refinement attributable to friction-stir welding, the fatigue performance at relatively low cyclic stress was deduced to be dictated by the microstructural factor. Accordingly, the fatigue crack typically nucleated in relatively coarse-grained base material zone; thus, the fatigue strength of the welded joints was comparable to that of the parent metal. At relatively high fatigue stress, the summary  stress may exceed the material yield strength; thus, the fatigue cracking should result from the preceding macro-scale plastic deformation. Accordingly, the fatigue failure should occur in the softest microstructural region; thus; the fatigue strength of the welded joint may be inferior to that of the original material.  Due to the high stress concentrations and intrinsic defects, welded structures usually exhibit poor fatigue performance. This is particularly the case for aluminum welds, whose exceptionally low characteristics are widely known and even necessitate using a riveting approach for manufacturing of joint assemblies. However, a recent invention of an advanced friction-stir welding (FSW) technique may principally change this situation. Because of the solid-state nature of this welding process, the produced joints contain no solidification defects and are characterized by relatively low residual stress, as well as the fine-grained recrystallized microstructure ,2. Given significant potential of FSW for transportation industry, considerable research effects have been undertaken to explore fatigue behavior of aluminum friction-stir joints ,14,15,16It is widely known that the volumetric defects associated with improper FSW conditions could essentially degrade fatigue strength. In addition to those, however, the so-called “kissing bond” defect  is also In the light of the well-known initiation of the fatigue failure at the material surface, the characteristic tool marks, which are normally produced during FSW at the upper weld surface, may also represent a considerable problem. Due to the relative sharp profile, these marks may give rise to the stress concentrations during fatigue tests and thus promote the crack nucleation ,10. Similar to the conventional fusion welding, FSW results in local material heating. The concomitant thermal expansion of the hot material gives rise to the tensile residual stress in the weld zone; those are normally equilibrated by the compressive stresses generated in the base material section. It is well accepted that the tensile stress promotes the fatigue failure whereas the compression stress suppresses the fatigues cracks. Despite the magnitude of the FSW-induced residual stress is typically much lower than that generated during the conventional fusion welding, they, nevertheless, may also exert a considerable influence on fatigue endurance ,14,15,16Even accounting for all above factors, the fatigue tests of FSWed aluminum alloys are often characterized by significant experimental scattering and often show even contradictory results . This efThe present work was undertaken in an attempt to elucidate the common trends in fatigue behavior of FSWed aluminum alloys. To this end, several different alloy grades belonging to both the heat-treatable and non-heat-treatable types in both the cast and wrought temper conditions were employed as program materials. To provide a broad view on fatigue behavior aluminum alloy grades, both non-heat treatable Al-Mg-Sc alloy and the heat-treatable commercial 6061 alloy were examined in the present study. The chemical composition of the materials measured by optical emission spectrometry is listed in The homogenized ingots were then either rolled  or extruded  to 75% of area reduction at the homogenization temperature. In the Al-Mg-Sc alloy, the produced material condition was referred as hot-rolled material. To obtain the peak-hardened condition in the 6061 alloy, the extruded material was subjected to T6 tempering treatment, i.e., solutionized at 550 °C for 1 h, water quenched, and then artificially aged at 160 °C for 8 h. The produced material was denoted throughout as 6061 alloy. Further details of the material manufacturing  have been described elsewhere ,19. The In all cases, FSW was conducted using an AccuStir 1004 FSW machine . To avoid a formation of the “kissing bond defect”, a double-side FSW was employed. To this end, two sequent FSW passes in mutually opposite directions were applied on the upper and bottom sheet surfaces. In each case, particular welding conditions were selected based on prior experiments ,21. The In Al-Mg-Sc alloy, the thickness of the welding sheets was 10 mm, and FSW was performed at the spindle (rotation-) rate of 500 rpm and the feed rate of 150 mm/min. The welding tool consisted of a shoulder having a diameter of 16 mm and a threaded probe of 6 mm in length and tapered from 6 mm at the tool shoulder to 4.8 mm at the probe tip. In 6061 alloy, 3-mm-thickness welding sheets were used. FSW was conducted at the spindle rate of 1100 rpm and the feed rate of 760 mm/min. The welding tool consisted of a shoulder of 12.5 mm in diameter and an M5 cylindrical probe of 1.9 in length. To recover mechanical properties of the produced weldments, these were artificially aged at 160 °C for 8 h prior to microstructural observations and mechanical tests. static loading conditions.In all cases, the particular welding variables for each material condition were selected on the basis of the authors’ previous experience in tailoring of mechanical properties of the welded joints for In all cases, microstructural examinations were conducted by using optical microscopy, electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM). For optical microscopy, the samples were prepared by mechanical polishing in conventional fashion, followed by the final etching in Keller’s reagent. A final surface finish for EBSD and TEM was obtained by electro-polishing in a solution of 25% nitric acid in ethanol. TM EBSD system . TEM observations were conducted with a JEM-2100EX TEM .EBSD analysis was performed using a FEI Quanta 600 field-emission-gun scanning electron microscope (FEG-SEM)  equipped with a TSL OIMTo evaluate fatigue performance of the welded joints, dog-bone-shaped specimens were cut perpendicular to the WD by electrical-discharge machining (EDM). In Al-Mg-Sc alloy, the samples were machined from the weld mid-thickness and had a gauge section of 14 mm in length, 7 mm in width, and 3 mm in thickness. In 6061 alloy, the gauge section of the specimens was of 30 mm in length, 8 mm in width, and 3 mm in thickness. In greater detail, the design of the fatigue specimens is given in To achieve a uniform thickness and prevent a potential influence of surface defects on fatigue properties, the specimens were mechanically polished to a final 2400 grit size SiC emery paper. Importantly, the lateral surfaces of the specimens remained unpolished and thus retained the EDM-induced recast layer with relatively high roughness. The fatigue tests were conducted using an Instron 8801 servo-hydraulic testing system under load control mode and at ambient temperature. A sinusoidal load-time function with a frequency of 25 Hz  or 50 Hz  and a maximum-to-minimum load ratio R = 0.1 was used. The total statistics of the fatigue tests is given in Fracture surface of the failed specimens was studied with FEI Quanta 600 field-emission-gun scanning electron microscope (FEG-SEM).−3 s−1. At least two tensile specimens were tested for each material condition.For the aid of comparison, microhardness measurements and static transverse tensile tests were conducted. Vickers microhardness measurements were carried out by applying a load of 200 g. The tensile tests to failure were performed at an ambient temperature and a nominal strain rate of ~10Low-magnification optical images of the weld cross-sections are presented in Typical microstructures evolved in the stir zone are summarized in A considerable fraction of relatively coarse second-phase particles was also worthy of remark . This perhaps implies a relatively low resistance to a propagation of the fatigue crack. Striation patterns in As mentioned above, the fatigue performance of friction-stir welded joints is believed to be governed by four primary factors including (i) welding defects, (ii) surface quality, (iii) residual stress, and (iv) microstructure . Since tThe residual stresses generated in the weld zone are normally tensile in nature and thus they should promote fatigue cracking. On the other hand, the considerable grain refinement in the stir zone, induced during FSW , is beneGiven the revealed dependence of the failure location from the magnitude of cyclic stress , a diffeAs shown in 2ψ approach. A cobalt target and accelerated voltage of 25 kV were used. The stress were calculated from the strains of the {311} Bragg reflection at 148.9. To examine a distribution of the residual stress on the weld cross-section, the measurements were conducted on a rectangular grid with a step size of 1 mm. For each point, 10 measurements with 1-s exposure time were performed. Further experimental details are given in Ref. [Hence, it seems that the nucleation of the fatigue crack at low cyclic stresses was governed by the microstructure rather than the residual stresses. Attempting to comprehend this result, a magnitude of the residual stresses was measured in the welded 6061 alloy by x-ray diffraction (XRD) technique using a PROTO-LXRD diffractometer  and the sin in Ref. . The obtThus, considering the relatively low residual stress but drastic grain refinement, both attributable to FSW, it is expected that the fatigue crack at low cyclic stresses should typically nucleate in the coarse-grained base material region. Accordingly, the welded joints should exhibit the fatigue strength comparable to that of the parent material, as indeed observed in the present study .The welds fatigued at relatively high cyclic stress (with the peak magnitude ≥0.74 fraction of the static yield strength) often failed either in stir zone  or the hTo examine this suggestion, appropriate microhardness profiles were measured across the welded specimen before- and after the fatigue tests, and the typical result is shown in In the present work, the welding conditions were carefully tailored in order to minimize the softening effect in the wrought Al-Mg-Sc alloy and the heat-treatable 6061 alloy . AccordiDespite a vast volume of experimental data on fatigue behavior of FSWed aluminum alloys existing in the scientific literature, the generic characteristics of this phenomenon are still unclear. The present study was undertaken to shed some light on this issue. To this end, (i) defect-free welds were obtained in various alloy grades and initial temper conditions, (ii) the fatigue specimens were carefully machined to remove the characteristic tool marks and the “kissing bond” defects, and (iii) the data analysis was based on the presumption of the dominant role of the FSW-induced residual stress and microstructure in fatigue cracking. Since FSW typically results in tensile residual stresses in the weld zone (which are harmful for the fatigue life) and considerable grain refinement , it was suggested that the fatigue behavior of the FSW joints was governed by the competitive influence of these two factors. It was shown that the residual stress constituted only ~25% of the static yield strength, thus being relatively low. On the other hand, the mean grain size in the stir zone was found to vary from 1 to 5 μm, thus indicating a pronounced character of the grain refinement effect. In a view of the above circumstances, the fatigue performance at relatively low cyclic stress was deduced to be dictated by the microstructural factor. Accordingly, the fatigue crack typically nucleated in relatively coarse-grained base material zone; thus, the fatigue strength of the welded joints was comparable to that of the parent metal. At relatively high fatigue stress, however, the summary  stress may exceed the material yield strength and thus the fatigue cracking should result from the preceding macro-scale plastic deformation. Accordingly, the fatigue failure should occur in the softest microstructural region; thus, the fatigue strength of the welded joint should be inferior to that of the original material.


To guide LTCFs in preventing the entrance and spread of SARS-CoV-2.The guidance is based upon the literature available on August 17, 2020. It lists (1) measures that can be implemented to keep COVID-19 out of LTCFs, and (2) COVID-19 symptoms that require RT-PCR testing in residents, staff members and visitors. It also (3) indicates the strategy to be used when a first LCTF resident or staff member is infected, and (4) proposes measures to limit adverse effects of the quarantine of residents tested positive for COVID-19.The EuGMS guidance enables LTCFs to adapt and suitably implement infection prevention and control measures, considering that the priorities are (1) early detection of symptomatic and asymptomatic COVID-19 residents, staff members and visitors who contribute to the entrance and dissemination of COVID-19 infection in LTCFs and (2) to limit the negative effects of isolation in infected residents. The European Geriatric Medicine Society (EuGMS) is launching a second interim guidance whose aim is to prevent the entrance and spread of COVID-19 into long-term care facilities (LTCFs).The EuGMS gathered experts to propose a guide of measures to prevent COVID-19 outbreaks in LTCFs. It is based on the specific features of SARS-CoV-2 transmission in LTCFs, residents’ needs, and on experiences conducted in the field.Asymptomatic COVID-19 residents and staff members contribute substantially to the dissemination of COVID-19 infection in LTCFs. An infection prevention and control focal point should be set up in every LTCF for (1) supervising infection prevention and control measures aimed at keeping COVID-19 out of LTCFs, (2) RT-PCR testing of residents, staff members, and visitors with COVID-19 symptoms, even atypical, and (3) isolating subjects either infected or in contact with infected subjects. When a first LCTF resident or staff member is infected, a facility-wide RT-PCR test–retest strategy should be implemented for detecting all SARS-CoV-2 carriers. Testing should continue until no new COVID-19 cases are identified. The isolation of residents should be limited as much as possible and associated with measures aiming at limiting its negative effects on their mental and somatic health status.An early recognition of symptoms compatible with COVID-19 may help to diagnose COVID-19 residents and staff more promptly. Subsequently, an earlier testing for SARS-CoV-2 symptomatic and asymptomatic LTCF staff and residents will enable the implementation of appropriate infection prevention and control. The negative effects of social isolation in residents should be limited as much as possible. Long-term care facilities (LTCFs) across Europe encompass a broad range of institution types from home-like facilities to those providing specialised medical care. These facilities include nursing homes, skilled nursing facilities, retirement homes, assisted-living facilities, residential care homes, and palliative care or rehabilitation centres. All these services take care of older people who are no longer able to live independently in the community due to a combination of physical, mental, intellectual or sensory impairments. The European Centre for Disease Prevention and Control estimates that in 2016–2017, there were 64,471 nursing homes, rehabilitation centres and mixed LTCFs in EU/EEA countries, representing a total of 3,440,071 beds [As with the common cold, influenza and other commonly circulating human coronaviruses, LTCFs are high risk environments when it comes to severe outbreaks of SARS-CoV-2 or coronavirus disease (COVID-19). Not only are LTCFs enclosed environments in which the virus can spread rapidly but, more importantly, LTCF residents are extremely vulnerable to complications from the virus, with a mortality rate of > 25% .Traditional infection-control and public health strategies are not adapted and implemented suitably for the specific features of COVID-19 transmission in LTCFs;The diagnostic strategy in residents and staff members is not adapted to the strengths and limitations of the SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing;No measures are implemented to reduce the mental and physical adverse effects of quarantine in residents when it is necessary.Coronavirus outbreaks in LTCFs will probably continue to occur in Europe with the likelihood of tens of thousands of additional deaths if:https://www.jnursinghomeresearch.com/current-issue.html), the specific features of COVID-19 transmission in LTCFs   and will be regularly modified according to newly published data and new experiences. The present guidance, that should not take precedence over local, regional, or national recommendations, should be considered as an aid document for LTCFs to define, depending on local possibilities, the best protection strategy for residents and caregivers and possibly to help write local, regional, or national recommendations when they do not exist. Considering that certain proposed measures  may have potential adverse effects, the document provides a list of measures that each require an assessment of the risk–benefit ratio on a case-by-case basis. This article also prepares LTCFs for future waves of the pandemic, as the number of COVID-19 cases rises sharply in many countries at the time of manuscript transmission.This suggests that infection prevention and control (IPC) measures aimed at keeping COVID-19 out of LTCFs and early detection of SARS-CoV-2 carriers, including those who are asymptomatic and with atypical symptoms, are essential for limiting transmission in LTCFs .Family, visiting health care professionals, and LTCF staff initially contributed to the transmission of SARS-CoV-2 within LTCFs, leading to a “lockdown” within the facilities. LTCF staff—including interim temporary or agency staff (hired from private organisations to compensate for gaps in LTCF rotas due to COVID) who moved between LTCFs—were then vectors for virus transmission within the facility and spread among the community [This suggests that, as part of the reopening process, and for as long as the virus circulates outside the LTCFs, any SARS-CoV-2 introduction and transmission within LTCFs will be due to staff members, visitors, or residents who may have had contact with COVID-19 subjects outside the LTCF, especially during medical examination, hospitalisation or when residents go home or go to their family’s home for visits .SARS-CoV-2 is highly contagious, due to elevated viral loads in the upper respiratory tract. The long incubation period for COVID-19 (up to 14 days)  associatThe reverse transcription polymerase chain reaction (RT-PCR) test, performed using nasopharyngeal swab  is currently the most commonly used and reliable test for diagnosing COVID-19 . The UniTesting (when possible) residents, staff members, and visitors with COVID-19 symptoms may be an appropriate strategy for the early diagnosis of the first COVID-19 cases in LTCFs .When a new case of COVID-19 is confirmed in a LTCF resident, staff member, or visitor having entered the LTCF over the past 14 days, LTCF-wide testing (when possible) of all residents and staff members (even asymptomatic) and repeating this testing strategy once a week in all previously negative subjects until the testing identifies no new COVID-19 cases for at least 14 days may be an appropriate strategy for diagnosing asymptomatic SARS-Cov-2 carriers and for preventing SARS-Cov-2 dissemination .Because RT-PCR testing sensitivity is lower in staff members than in residents (partly because they are less immunocompromised and therefore less often symptomatic than residents when infected) , generalThe sensitivity of the RT-PCR test seems acceptable in LTCF residents, probably higher than 90% (i.e. less than 10% of residents who develop SARS-CoV-2 antibodies in the following days have a negative RT-PCR) . ConversThe duration of the positive SARS-CoV-2 test result may be higher in immunocompromised than in non-immunocompromised subjects (positive RT-PCR testing lasts longer in residents than in staff members), and in subjects with severe disease . Thus, aThis suggests the need to adapt the duration of isolation and the precautions implemented in subjects tested positive for COVID-19 to their health status  and to their symptoms (longer in the case of severe disease or of remaining symptoms) , 12, 19.However, detection of viral RNA 10 days after positive testing in non-immunocompromised asymptomatic subjects and 20 days after positive testing in immunocompromised asymptomatic subjects does not indicate the presence of a viable virus , 17. AftThis suggests that testing may be warranted in subjects who remain or become symptomatic after the above isolation period (10 or 20 days), and in whom an evaluation fails to identify a diagnosis other than SARS-CoV-2 infection , 12, 19.A few cases have also been reported positive after an initially negative RT-PCR test result. It is unclear as to whether this represents testing error, reinfection, or reactivation .This sugThis suggests that social isolation has to be restricted to infected subjects and to those in close contact with infected subjects. When necessary, isolation has to be associated as much as possible with measures to prevent negative effects on residents’ mental and health status –24.Many older adults in LTCFs undergoing strict social isolation have developed depression, anxiety, worsening dementia, sarcopenia, functional impairment, and failure to thrive.The EuGMS guidance supports the IPC World Health Organization guidance  and recoLimitation of the number of visitors, with due consideration that the isolation of residents may have a negative effect on their mental and somatic health status . Indeed, the need to protect residents from the spread of COVID-19 should be balanced with the critical need of support provided by families and other persons , 26–29. General measures in accordance with national rules for residents, staff members, and visitors, especially those relating to hygiene and social distancing, for all activities conducted outside the LTCF Boxes , 5 19, –32.Screening for COVID-19 symptoms  before allowing staff members, visitors, or residents to enter the facility , especially when the virus is circulating substantially in the visited area .Consider regular testing  of staff members, visitors, and residents who are at a high risk of encountering COVID-19 outside the LTCF  .Checking that residents, LTCF staff, and visitors previously tested positive for COVID-19 meet the LTCF entrance criteria according to national guidance. For example, in the US, the UK, and France, return-to-work criteria for staff members with mild to moderate illness who are not severely immunocompromised are: (1) at least 10 days have passed since symptoms first appeared and (2) at least 24 h have passed since last fever without the use of fever-reducing medications and (3) symptoms  have improved. In subjects who were asymptomatic throughout their infection: at least 10 days have passed since the date of their first positive viral diagnostic test. In immunocompromised subjects or in subjects with severe illness , isolation should last for at least 14 to 20 days and for as long as the subject has symptoms compatible with COVID-19 infection. In subjects who become symptomatic during the 90 days following positive testing and whose evaluation fails to identify a diagnosis other than SARS-CoV-2 infection , evaluation for SARS-CoV-2 reinfection is warranted .Limit short-stay admissions to LTCFs , unless these residents—who represent a higher infection risk to residents—are in a building or unit with separate entrance, staff and services .Box 3TasBox Healthcare professionals and family members visiting the LTCF and allowed to enter the facilities should sign a form agreeing to adhere to standard and transmission-based precautions to prevent a COVID-19 spread within the LTCF Boxes , 6. TheyThe US CDC has published specific guidance for standard and transmission-based precautions to prevent COVID-19 spread in the memory care units of LTCFs .Every new resident should be admitted to a single occupant room and isolated for 14 days, in the same way as residents leaving the LTCF . If COVID-19 symptoms occur  Box  should bAdministrative records should be updated daily on the basis of COVID-19 symptoms, to record whether a resident has received a COVID-19 test, has been isolated due to COVID-compatible symptoms, and/or has required any other non-standard IPC measures.The infection prevention and control focal point (IPCFP) should also organize the following tasks:Provide information to the residents and their family/health care providers and organize advance care planning to support them in understanding and sharing their personal values, life goals, and preferences regarding medical care, including appropriate advance directives (ADs) and decisions about escalation to hospital in the event of any future COVID-19 outbreak in the LTCF. An explanation of the limited success of mechanical ventilation in older adults with COVID-19 should be given as well as a description of care that can be provided in the LTCF in the event of non-hospitalization . AdvancePrepare a file with all data necessary for the laboratory to organize testing and test result reporting  in the event of a COVID-19 outbreak in the LTCF. There should also be a list of those responsible for performing specimen collection, including the facility’s trained staff members. These people need to be trained to collect specimens correctly, using the appropriate personal protective equipment (PPE) .The IPCFP should also:In a cohort study of French LTCFs, mortality rates related to COVID-19 were lower among nursing homes that implemented staff confinement with residents compared with those in a national survey, suggesting that self-confinement of staff members with residents in areas with substantial community transmission may help protect LTCF residents from mortality related to COVID-19 and residents and staff from COVID-19 infection .In some countries, COVID-19 geriatric support platforms have been set up in local hospitals, often in conjunction with public health, with a hotline for LTCFs . These sMeasures that need to be taken as quickly as possible when a new case of COVID-19 is confirmed in a resident, staff member, or visitor include the following:Staff should be made aware of the existence of the advance care planning, including advance preferences or directives for all residents who provide consent .Residents should be restricted to their room and visits reduced to essential health care professionals only  , 20, 26 If it is not possible to exclude staff members for organizational reasons, the US CDC has published Strategies to Mitigate Healthcare Personnel Staffing Shortages .If a resident tests positive for COVID-19, admission to a COVID-19 setting specialized in geriatric care  should be considered or set up via the application of zoning in the nursing home itself. This will separate the infected resident from the others, and optimize care for the COVID-19 residents , 34, 41.Within the first 12 h:The establishment of COVID-positive “red” areas also enables residents, with and without dementia, to mobilise safely outside their rooms, minimising the risk of deconditioning associated with prolonged isolation in a private room , 42.Therefore, if possible, such a COVID-19 LTCF unit should have a separate entrance/exit or try to install temporary walls or doorways at the entrance. If it is not possible to segregate COVID-19-positive patients in a separate unit, such patients should be cohorted in one area of the affected unit and dedicated staff should be assigned to care for them. This is particularly important for residents with dementia .The estaAny staff member entering the room of a resident with known or suspected COVID-19  should adhere to standard precautions , apply cFacility-wide testing of all LTCF residents, staff members, and visitors having entered the LTCF over the past 14 days, including those without symptoms. This can be challenging for some of the residents, especially with cognitive impairment, for staff members, and for visitors who may refuse testing. All subjects who cannot be tested have to be managed in the same way as COVID-19 positive subjects  .Repeat this testing strategy once a week in all previously negative subjects until the testing identifies no new COVID-19 cases for at least 14 days since the most recent positive result. The US CDC has published guidance for preparing LTCFs to perform facility-wide testing . The LTCReport positive SARS-CoV-2 results to local authorities and maintain records of staff members and residents who have positive tests to facilitate the reporting of aggregate data to national databases .Assess IPC practices with help from the proximity COVID-19 support platform for LTCFs or a hygiene platform in the proximity hospital while conducting facility-wide testing .Isolation and COVID-19 precautions in residents tested positive for COVID-19 should last until they meet the end of isolation criteria, in accordance with national guidance. As indicated previously, isolation and COVID-19 related precautions in residents/staff members previously tested positive for COVID-19 should probably end safely :Within the first 24–48 h:In non-immunocompromised persons: 10 days after symptom onset (or 10 days after the positive testing in subjects who are not symptomatic) and when subjects are asymptomatic for at least 24 h.In immunocompromised persons (the case for most of the LTCF residents) or those with a severe illness: 20 days after symptom onset or after positive testing and when subjects are asymptomatic for at least 24 h. Some experts recommend to end isolation 14 days after positive testing and when subjects have been asymptomatic for at least 24 h .Entries are only possible at least 14 days after the end of the isolation of the last resident tested positive when no new residents and staff members have any signs of COVID-19 .Because immobility may lead to sarcopenia and functional impairment , measureIf control testing is implemented in patients with a Ct of above 33  monitor residents for COVID-19, (2) follow protocols to keep residents physically distant and (3) implement public health measures to reduce the transmission of the virus. This is particularly the case when isolating COVID-19 residents with dementia who may not understand or follow the procedure exacerbates their behaviour .The workload of LTCF staff members is has been increased by the pandemic because of: the ban of family members and other volunteers who provide supportive care; and the increase of staff absenteeism due to COVID-19 symptom and/or fear of contracting the virus or transmitting it to their loved ones. In addition, due to the COVID-19 pandemic, the actions of health authorities have generated a feeling of abandonment in LTCF staff members and of degrading . CoupledPolicies and waivers implemented by the American Centers for Medicare and Medicaid Services (CMS) to give long-term care providers and professionals flexibility to meet the demands of resident and patient care needs in response to the COVID-19 pandemic can be very useful for the European countries . These pCMS have also enabled the opening or use of non-LTCF buildings for unmet COVID-19 isolation and treatment as well as the temporary use of rooms in the facilities  for resident care, to expand surge capacity and for purposes of cohorting and infection control.As described in Box CMS also allow for physician delegation of tasks or required visits to a physician assistant, nurse practitioner, or clinical nurse specialist. CMS recommend that a LTCF may not employ a nurse assistant for longer than four months unless he/she meets certain training/certification requirements. The CMS allow for the redeployment of employed physicians, utilization of available trainee staff, and recruitment of community and retired physicians in LTCFs.It must however be strongly reminded that all new HCPs must adhere to standard and transmission-based precautions to prevent a COVID-19 spread within the LTCF Box .To enable clinicians to better focus on the care needs of residents, CMS have temporarily given LTCF providers relief from paperwork, reporting and audit requirements .nfluenza, Norovirus, Clostridium difficile), is higher for larger facilities in urban locations [The probability of having a COVID-19 case in LTCFs, such as other infections (iocations . The COVocations , 59.This second EuGMS Interim guidance to prepare European Long-term care facilities for COVID-19 takes into account studies, guidance, documents, and experience available up to August 25, 2020.Any changes to the current guidance will be published according to new knowledge on this topic, especially once data are available on the follow-up of symptoms, interventions, course of the disease in COVID-19-positive residents, vaccination schedules, point of care testing, interactions between COVID-19 and flu, and on serology in residents, visitors, and staff members.


We report a cluster of surprisingly high spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with a single nursery in Poland. Our findings contrast with the presumed negligible role of children in driving the SARS-CoV-2 pandemic. Children 1–2 years of age might be effective SARS-CoV-2 spreaders. Despite robust research, knowledge about coronavirus disease (COVID-19) spread and effective control measures is still limited. Until recently, research has indicated that children rarely spread the infection to adults and are not the primary drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission  was confirmed on June 4. Subsequent PCR testing of nursery staff, children attending the facility, and family members   revealedThe overall positivity rate in our cluster was 27%. COVID-19 prevalence in Poland is low. The number of tests conducted in the country was 124,194 in June, whereas the number of positive cases was 1,374, which corresponded to a positivity rate of 1% . However, such estimations are open to bias, given that most published data were obtained at the time of lockdown, when children’s social contacts were limited to family members. Another limitation of those publications is that they applied mostly to school-age children.Several reports concerning clusters of COVID-19 in childcare settings imply little to no SARS-CoV-2 transmission among children and from children to adults (The high infection attack rate among children in our cluster could be explained by prolonged close contact between very young children, who are less able to adjust to control measures. Similarly, specific intimate contact between toddlers and their family members could have led to effective spread within families. This observation might be particularly important in light of novel findings that nasopharyngeal SARS-CoV-2 levels are the highest in the youngest children (Our study has some potential limitations. We could not determine whether the infection in the nursery worker was the real index case because one of the children’s parents had tested positive within the previous 2 weeks and that child could also have been the primary case. Moreover, we could not verify the information we obtained from the nursery about the facility’s prevention methods.Our report questions the role of young children in driving the COVID-19 pandemic. Of note, most children in our study were asymptomatic, and this cluster would likely not have been detected without subsequent testing of persons who had direct contact with the index case-patient. We believe further studies are needed to clarify young children’s role in the transmission of SARS-CoV-2.Additional information about SARS-CoV-2 cluster in nursery, Poland.


Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy . COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional ‘surges’ in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI. COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and is an independent risk factor for all-cause in-hospital death in patients with COVID-19. This Consensus Statement from the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI and for areas of future research, with the aim of improving understanding of the underlying processes and outcomes for patients with COVID-19 AKI. The primary pulmonary pathology seemed to show not only diffuse alveolar damage but also evidence of direct viral cytopathy, implying a direct causative role of virus-induced damage in the development of ARDS rather than it resulting from a generalized inflammatory response.A third novel coronavirus leading to severe respiratory infection  was first identified in Wuhan, China in December 2019; as of August 2020, there have been 23 million confirmed cases with 800,000 deaths worldwide. The clinical spectrum resulting from infection with the responsible virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is broad, ranging from an asymptomatic response or development of a mild upper respiratory tract infection to critical illness. Initial reports of hospitalized patients in Wuhan described a high proportion of individuals with atypical pneumonia requiring critical care admission with features of acute respiratory distress syndrome (ARDS)7. However, growing evidence has demonstrated that AKI is in fact prevalent among patients with COVID-19, particularly among patients in the intensive care unit (ICU)19. The reported rates of AKI are extremely variable; however, available evidence suggests that it likely affects >20% of hospitalized patients and >50% of patients in the ICU19. Similar to the association of AKI with other forms of community-acquired pneumonia20, AKI is now recognized as a common complication of COVID-19. As with AKI from other causes, COVID-19-associated AKI (COVID-19 AKI) is associated with adverse outcomes, including the development or worsening of comorbid disease as well as greater use of health-care resources. However, despite considerable advances in our understanding and management of other forms of AKI, relatively little is known about the pathogenesis or optimal management of COVID-19 AKI.Initial reports also indicated that rates of acute kidney injury (AKI) were negligibleGiven the paucity of knowledge with regard to optimal prevention and treatment strategies for COVID-19 AKI, the 25th Consensus Conference of the Acute Disease Quality Initiative (ADQI) focused on this new disease entity. The process was aimed at reviewing the current literature relating to COVID-19 AKI, including its epidemiology and pathophysiology, and compare our current understanding with that of other forms of AKI, with the aim of providing recommendations for the diagnosis, prevention and treatment of COVID-19 AKI. In addition to recommendations for the provision and delivery of renal replacement therapy , we also explored the role of other extracorporeal techniques.21.The Conference Chairs of the 25th ADQI consensus committee  convened a diverse panel of clinicians and researchers representing nephrology and critical care from the Americas, Europe and Asia to discuss the issues relating to AKI associated with COVID-19. The conference was held virtually, over 4 weeks, with weekly virtual consensus meetings from 23 May to 13 June 2020. This consensus meeting followed the established ADQI process, and used a modified Delphi method to achieve consensus, as previously describedNational Institutes of Health (NIH) COVID-19 portfolio and PubMed. Where possible, delegates were asked to note the level of evidence for consensus statements using the Oxford Centre for Evidence-based Medicine Levels of Evidence22. All of the individual workgroups presented their output to conference participants during the four videoconference plenary sessions for debate, discussion, suggested revisions, and the final product was then assessed and aggregated in a videoconference session attended by all attendees, who approved the consensus recommendations.Conference participants were divided into five workgroups  and development of AKI33. Finally, whether pathological data will emerge to support a major role for thrombosis and microangiopathy in the kidney in patients with COVID-19 (as has been documented in the lung) remains to be seen35.Histopathological data relating to COVID-19 AKI are limited, but available evidence suggests that numerous causes of AKI exist in the setting of COVID-19  and Middle East respiratory syndrome  — high levels of pro-inflammatory cytokines were associated with more severe respiratory disease45. However, circulating levels of IL-6 reported for patients with COVID-19 are considerably lower than those observed in patients treated with chimeric antigen receptor T cell therapy; nearly 10,000-fold lower than those in patients with cytokine release syndrome, and >20,000-fold lower than those in patients with sepsis47. These comparisons indicate that cytokines are only moderately elevated in COVID-19 and are therefore unlikely to be directly pathogenic in most patients. An alternative explanation may be that these moderately elevated cytokines reflect the underlying critical illness, rather than representing a ‘storm’ of inflammatory processes per se. However, it is important to note that cytokine assays are not well standardized, and comparisons between studies using different assays are often not reliable. Cytokine levels, therefore, should be evaluated in larger cohorts of patients with COVID-19, as should concomitant analysis of immune cell count and activity. Understanding the role of innate and adaptive immune dysfunction in AKI patients should be a research priority.Infection with SARS-CoV-2 is associated with activation of an inflammatory response that has been termed a ‘What are the indirect pathogenic mechanisms implicated in COVID-19 AKI?Systemic effects of COVID-19 and critical care interventions may contribute to AKI.Organ crosstalk is likely an important mechanism for AKI in patients with COVID-19.Baseline patient characteristics contribute to AKI, acting as modifiers of direct pathogenic mechanisms.49. Moreover, individuals who develop secondary infections  are at increased risk of secondary sepsis-associated AKI50. Patients with severe COVID-19-associated pneumonia and/or ARDS are also at a high risk of AKI as a complication of mechanical ventilation. Specifically, COVID-19-associated ARDS is often treated by increasing 51. In addition, all forms of positive pressure ventilation can increase sympathetic tone, leading to secondary activation of the renin–angiotensin system53. In the setting of ARDS after shock resolution, patients are often managed with a restrictive fluid strategy. However, in the setting of COVID-19, patients may initially present with relative volume depletion due to fever and gastrointestinal losses, and therefore careful attention to volume status is needed to avoid hypovolaemia.In addition to direct pathophysiological mechanisms, renal dysfunction in the context of COVID-19 might also arise through the systemic effects of SARS-CoV-2 infection and critical illness , and the presence of other comorbidities  are associated with worse outcomes and also represent risk factors for the development of AKI in patients with COVID-19. These clinical features are characterized by low-grade inflammation and increased immune senescence, although how these impact the kidney in the setting of COVID-19 is unknownWhat are the potential mechanisms for recovery from COVID-19 AKI?Whether recovery from COVID-19 AKI differs from other forms of AKI is unknown. More research is needed to better understand the direct impact of the SARS CoV-2 virus on long-term renal fibrosis and recovery.58. Although we do not yet know whether kidney fibrosis occurs in patients who recover from COVID-19 AKI, the development of fibrosis and progression to CKD among patients who recover from other forms of AKI suggest that this scenario is likely. Moreover, the loss of functioning nephrons following injury might enhance the development of renal fibrosis. We recommend that patients with COVID-19 AKI be followed over a period of 2–3 months post-discharge, depending on the severity and acute needs of the patient, to evaluate kidney recovery59.Pulmonary fibrosis in patients following recovery from COVID-19 has been reportedWhat are the rates of COVID-19 AKI, and how should it be diagnosed?Timing of AKI with symptom onset, hospitalization, confirmation of infection, disease severity and level of care should be characterized for appropriate clinical management (not graded).We recommend use of the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition for AKI, including serum creatinine (SCr) level and urine output, in clinical practice (evidence level: 1A).We suggest using kidney-specific tests along with measures of kidney function to characterize clinical presentations, course and outcomes of AKI (evidence level: 2B).60  with significant haematuria demonstrated in 11.3%5. Examination of urinary sediment can be an effective tool in clinical scenarios in which more than one possible cause of AKI may exist that could affect medical management, for example, to distinguish acute tubular necrosis from pre-renal AKI, although special precautions may be needed when handling biospecimens from patients with COVID-19 (ref.63). The role of urinary markers for injury or stress in the diagnosis of COVID-19 AKI remains unclear. Patients with COVID-19 AKI and high levels of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein-7 [TIMP-2] × [IGFBP-7] were more likely to progress to RRT than patients with AKI but with low [TIMP-2] × [IGFBP-7]64. Elevated urinary alpha1-microglobulin in hospitalized patients was associated with the subsequent development of AKI64. Patients with COVID-19 AKI have also been reported to have higher levels of systemic markers of inflammation, particularly ferritin, C-reactive protein, procalcitonin and lactate dehydrogenase, than patients with COVID-19 and normal kidney function17.Although urine volume is reported infrequently, two-thirds of patients have low urinary sodium concentrations at the time of AKI, and the majority are oliguric at RRT initiationWhat are the risk factors for AKI with COVID-19 infection?We suggest that patients be stratified for risk of AKI based on their comorbidities and demographics. Information about baseline CKD, comorbidities, and demographics should be obtained to define risk profiles of COVID-19 AKI (Box (evidence level: 2C).Risk factors for community and hospital-acquired AKI, severity of illness, process of care, along with the threshold for admission to the hospital and the ICU should be considered when evaluating patients with COVID-19 (not graded).Box 1 Potential Risk Factors for COVID-19 AKIDemographic risk factorsOlder ageDiabetes mellitusHypertensionCardiovascular disease or congestive heart failureHigh body mass indexChronic kidney diseaseAPOL1 genotype; ACE2 polymorphisms)Genetic risk factors  inhibitors and/or angiotensin-receptor blockers (ARBs), statins, nonsteroidal anti-inflammatory drugs (NSAIDs)Risk factors for AKI during hospitalizationNephrotoxins VasopressorsVentilation, high positive end-expiratory pressureFluid dynamics (fluid overload or hypovolaemia)17. Among patients with COVID-19, those with AKI are more likely to require vasopressors as well as mechanical ventilation17. No data exist on criteria for ICU admission, or the association between medications and procedures  and COVID-19 AKI.Risk stratification is important to tailor monitoring and initiate prevention and/or early treatment strategies for patients who will benefit the most from intervention. Data from China and the USA suggest that male sex, older age, Black race, diabetes mellitus, CKD, hypertension, cardiovascular disease, congestive heart failure and higher body mass index are associated with COVID-19 AKI66 than among patients in the USA68 and Europe60. This difference may be attributed to differences in the patient population studies; for example, patients in the Chinese studies had fewer comorbidities and were admitted to hospital with less severe respiratory disease or ARDS than patients in other cohorts .When feasible, renal histology, particularly in cases of heavy proteinuria, may help to differentiate potential causes of AKI (not graded).16, another study reported a considerable delay in the manifestation of AKI in patients with COVID-19 (median of 15 days from presentation)10, which potentially differentiates COVID-19 AKI from AKI caused by other systemic infections. A temporal association of COVID-19 AKI with intubation has been observed; however, the extent to which these temporal relationships are related to disease progression, organ crosstalk or associated with interventions such as peri-intubation haemodynamic changes is unclear17.Geographic and regional differences in the course and outcomes of COVID-19 AKI are recognized. However, the influence of resource limitations has not been well described. In general, patients with COVID-19 who develop AKI are more likely to be admitted to the ICU and to require mechanical ventilation and vasopressors than patients who do not develop AKI. Few studies have explored the temporal relationship between the onset or severity of SARS-CoV-2 infection and the development of AKI. Although one study reported that approximately one-third of patients presented either with AKI or developed AKI within 24 h of presentation17. Hyperkalaemia has been noted in 23% of patients with COVID-19 AKI, and is often associated with metabolic acidosis69. As mentioned earlier, a large proportion of patients, particularly those who were critically ill and/or had overt AKI, had evidence of haematuria and proteinuria64. Histological evaluation from autopsy series and biopsy case reports of patients with heavy proteinuria have identified several different patterns of injury — collapsing glomerulopathy, proximal tubule injury and microangiopathy with microthrombi — that have the potential to inform subsequent management70. Of note, various factors specific to COVID-19, including the use of mechanical ventilation, anticoagulation requirements, and logistical complexities given the risk of viral transmission, make renal biopsies difficult to obtain in patients with suspected AKI.Available reports indicate that rhabdomyolysis occurs in 7–20% of patients with evidence of COVID-19 AKI8. The mortality of COVID-19 AKI has been reported to be between 35% and 80% with rates as high as 75–90% among patients requiring RRT, serving as an independent risk factor for all-cause in-hospital death in patients with COVID-19 (refs60).The duration of COVID-19 AKI is poorly understood, and only one study has reported recovery of kidney functionFuture studies should consider the impact of geographical variation, differences in health-care systems, the influence of hospital capacity, the preparedness of health-care systems and social determinants on the epidemiology of COVID-19 AKI, including analysis of how these factors influence risk factors, management of disease and outcomes.Future studies should incorporate information about the proportion of different comorbidities in patients with and without AKI, including potential risk factors for the development of COVID-19 AKI before and after hospital admission.Future studies should determine different phenotypes of COVID-19 AKI based on clinical presentation at diagnosis, patterns of injury, duration and course of AKI, and progression to CKD.The severity of COVID-19 disease at AKI diagnosis and the interventions that have been used for the management of the individual should be reported when describing COVID-19 AKI.The relationship between markers of systemic disease  and the severity of pulmonary disease to the development, course and outcomes of COVID-19 AKI warrants further study. Risk factors for developing severe AKI (stage 3 AKI or requiring RRT initiation) need to be explored to identify approaches to prevent AKI.The mechanism, timing and clinical implications of traditional markers of AKI (proteinuria and haematuria) as well as novel biomarkers for the diagnosis and prognosis of AKI need to be studied and correlated with markers of systemic disease.Kidney recovery and mortality should be assessed at ICU and hospital discharge. Post-hospitalization outcomes and long-term renal recovery data should be evaluated across different countries.What standard-of-care strategies are applicable to the prevention and management of AKI in patients with COVID-19?Strategies based on KDIGO and other relevant guidelines are appropriate for risk- and stage-based prevention and management of COVID-19 AKI (Table (not graded).KI Table  .We recommend using balanced crystalloids as initial management for the expansion of intravascular volume in patients at risk of AKI or with AKI unless a specific indication exists for the use of other fluids (evidence level: 1A).We recommend limiting nephrotoxic drug exposure where possible and with careful monitoring when nephrotoxins are required (evidence level: 1B).71)  Table .Fig. 2St72. A randomized clinical trial (RCT) demonstrated that fluid and vasopressor resuscitation based on dynamic haemodynamic assessment may reduce the risk of AKI and respiratory failure in patients with septic shock73. We suggest that a similar strategy may be valuable in patients with COVID-19 to reduce the risk of COVID-19 AKI.Hypovolaemia is common in early COVID-19 and hence individualized fluid management is critical61), more evidence has emerged regarding the importance of the composition of crystalloids used for volume expansion77. The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) demonstrated that compared with saline, use of balanced crystalloids decreased the composite outcome of death, new RRT, or persistent kidney dysfunction among critically ill adults, with the largest effect observed among patients with sepsis78. This beneficial effect was replicated in non-critically ill patients and in the perioperative setting76. However, three systematic reviews of studies in adults and children did not demonstrate reduced rates of AKI or mortality with balanced crystalloids compared with saline in pooled analyses81. Given the possible harm caused by the use of 0.9% saline we recommend using balanced fluids, unless there is an indication for other types of fluid .Since the publication of the KDIGO guidelines for AKI in 2012 .We suggest that ventilator strategies in patients with COVID-19 be selected to reduce the risk of AKI when possible (evidence level: 2C).88  reported that compared with placebo, treatment with remdesivir shortened recovery time among adult patients hospitalized with COVID-19 and evidence of lower respiratory tract infectionWhat interventions in the management of COVID-19 should be modified in patients with AKI?We recommend that the altered pharmacokinetics and renal effects of COVID-19-specific therapeutics are considered when prescribing and adjusting dosage (evidence level: 1C).COVID-19 is associated with malnutrition; however, whether patients with COVID-19 AKI have specific nutritional requirements is unclear (not graded).92; however, no dedicated studies on nutritional management in patients with COVID-19 AKI exist. Therefore, current consensus recommendations for the nutritional management of critically ill patients should be followed95. Protein intake should be gradually increased to 1.3–1.5 g/kg per day in patients with AKI who are not on RRT; 1.0–1.5 g/kg per day for patients on intermittent RRT and up to 1.7 g/kg per day for patients on continuous RRT (CRRT). Early enteral feeding is preferred over parenteral nutrition, and the prone position is not a contraindication to enteral feeding96.Several drugs or their metabolites that have been proposed for use in patients with COVID-19 are excreted and/or metabolized via the kidneys and require dose adjustment or are contraindicated in patients with impaired kidney function or during RRT. In addition, other conventional therapies, such as antibiotics or anticoagulants, have altered pharmacokinetics in patients with AKI  and with different types of RRT.Explore the nutritional status and energy expenditure of patients with COVID-19 AKI, and determine strategies for their optimal nutritional management according to RRT status.If adequate RRT resources are available, are there patient-specific considerations with respect to vascular access, timing, modality, or dose of acute RRT for patients with COVID-19 AKI?We recommend that the use of ultrasound for insertion of vascular access and RRT dose delivery remain based on KDIGO AKI guidelines (evidence level: 1A).Timing of RRT initiation, vascular access site and modality of acute RRT should be based on patient needs, local expertise and the availability of staff and equipment (Tables (not graded). t Tables ,4 .100. The decision to initiate acute RRT in patients with COVID-19 AKI should therefore be individualized, and clinical context should be considered (e.g. initiation of RRT for volume management in patients with severe hypoxaemia) and not based solely on AKI stage or degree of renal function101. Selection of RRT modality will depend on local availability and resources, as no clear benefit with any specific RRT modality is known. However, continuous therapies may be better tolerated in patients with haemodynamic instability and facilitate improved volume and nutrition management, which are important in the management of patients with COVID-19 (ref.61).A number of clinical trials and meta-analyses of RRT initiation strategies in critically ill patients have demonstrated no difference in mortality or renal recovery associated with initiation of RRT in the absence of emergent indications103. In patients with COVID-19, coagulopathy resulting in circuit clotting can interrupt prolonged RRT sessions and substantially affect the dose delivered. This complication of COVID-19 may require the RRT prescription to be adjusted105. If CRRT is used, a reduction in the filtration fraction may reduce circuit clotting106. Acute peritoneal dialysis (PD) might also be an effective option for patients who are unable to receive anticoagulants110.The dose of RRT should be based on KDIGO recommendations and be adjusted in response to changes in clinical, physiological and/or metabolic status2, internal jugular (IJ) sites have lowest infection rates112. Higher rates of vascular access dysfunction have been observed with the use of the left IJ, compared with the right IJ or femoral sites, but many cases of left IJ access dysfunction probably result from the inadequate depth of the catheter tip at the left IJ site113. The use of ultrasound for the placement of IJ vascular access increases the likelihood of successful catheter placement, with reduced complications and time required for the procedure.The choice between jugular or femoral sites for vascular access in patients with COVID-19 is based on the experience and preference of the clinician. For patients with a body mass index >28 kg/mWhat is the optimal anticoagulation strategy for acute RRT in COVID-19 AKI?We recommend that patients with COVID-19 AKI receive anticoagulation agents during extracorporeal RRT (evidence level: 1C).We suggest RRT that circuit performance be closely monitored to ensure maximal circuit patency as the initial anticoagulation strategy may not be effective in all patients; we also recommend that each centre establish a stepwise escalation and/or alternative plans for RRT anticoagulation (evidence level: 2C).61. COVID-19 induces a hypercoagulable state in many patients, which can result in premature extra-corporeal RRT circuit failure117. Additionally, an anonymized survey of the ADQI faculty involved in this Consensus Statement revealed that 64% of respondents identified a high rate of circuit loss or clotting during RRT in patients with COVID-19 as an issue requiring “major revision of treatment and anticoagulation protocols” and/or “significantly compromising patient care even after optimization of anticoagulation,” compared with only 3 of 25 (12%) who reported no differences in frequency of RRT circuit loss compared with that observed in patients without COVID-19.KDIGO recommends the use of anticoagulation for CRRT unless it is contraindicated or the patient is already receiving systemic anticoagulationOwing to the hypercoagulable state of patients with COVID-19, therapeutic, titratable, pharmacological anticoagulation has been used more often during RRT to reduce the risk of filter clotting. However, no studies are available to guide the selection of an anticoagulation strategy. Several anticoagulation strategies can be used with a broad array of extra-corporeal RRT therapies in patients with COVID-19, including regional citrate anticoagulation in CRRT, therapeutic, titratable anticoagulation with unfractionated or low-molecular-weight heparins, direct thrombin inhibitors and combinations of these approaches. Change in RRT modality to intermittent haemodialysis (IHD), prolonged intermittent RRT (PIRRT), or acute PD should be considered in patients with persistent circuit clotting during CRRT despite anticoagulation.Unplanned interruptions due to circuit failures with CRRT, PIRRT or IHD will increase the consumption rate of disposable supplies, increase the risk of exposure of nursing and other staff to infection, increase the risks of inadequate electrolyte, acid-base, fluid balance control, and influence medication pharmacokinetics. Therefore, it is important to strive to maximize the utility of any RRT circuit in order to conserve supplies, as supply chains can become challenged and limited in the context of a pandemic. During an increase in RRT demand, monitoring CRRT circuit lifespan is of paramount importance at both the individual and the organizational level. If poor performance is noted, we suggest prompt implementation of a stepwise approach to anticoagulation to minimize the supply consumption and conserve resources.What are the key considerations when planning for a sudden surge in acute RRT demand?A coordinated response to an increase in RRT demand and/or supply chain failure at an organizational, regional and national level is needed (not graded).Consider adjustments to RRT modality, indications, anticoagulation and dose as part of a local response to an imbalance in supply and/or demand to conserve scarce resources and deliver effective therapy to the greatest number of patients (not graded).118. Additionally, supply chain security may be compromised, further augmenting local shortages120. As part of a local surge response, use of a wider variety of acute RRT modalities  may be needed to maximize the number of patients who can receive RRT. Several institutions reported having to implement acute PD during the initial surge in COVID-19 cases124. In the preparatory and early response phase, hospitals and regional health systems should maintain an ongoing inventory of available RRT devices, disposable RRT equipment, and RRT fluids, and make projections of demand to optimize resource utilization. In addition, workforce planning and response to a surge in COVID-19 cases should project the need for trained RRT nursing support and ensure that the relevant human resources are available125.In any situation with a rapid increase in ICU demand, it is possible that the provision of RRT may be limited. To prepare for such situations, we recommend that health systems create, maintain and periodically update an RRT ‘surge plan’ Fig. . A sudde127. Also, depending on the type of shortages anticipated (machine or disposables), strategies such as lowering blood flows to reduce citrate consumption, moderating the RRT intensity to conserve fluids or running accelerated RRT at higher clearance to treat more patients per machine could form part of a local response128. Finally, earlier transition to IHD with dialysate generated online or acute PD could be valuable options in centres with appropriate resources and expertise110.Excessive consumption of RRT disposables due both to increased demand and poor circuit performance has the potential to cause critical shortages, compromising the ability to deliver RRT to all who might benefit. Aggressive medical management of electrolyte and acid-base disturbances or fluid overload might negate the need for RRT or forestall RRT initiation, thereby enabling improved allocation of finite RRT resourcesA large surge in COVID-19 cases may make delivery of treatment to all who might benefit impossible, despite appropriate planning. Detailed discussion of the ethical and legal considerations in these circumstances is, however, outside the scope of this consensus statement.Develop a registry of patients with severe COVID-19 AKI to research whether variations in clinical practice relating to differences in RRT use and circuit performance affect clinical outcomes.Given the specific issues with circuit loss associated with RRT for COVID-19 AKI, we recommend the planning and initiation of prospective RCTs to examine different anticoagulation strategies for CRRT and PIRRT.We recommend implementation of a programme of operational research, including supply chain management, to examine the local, regional and national responses to the RRT supply–demand imbalance during the COVID-19 pandemic and to develop evidence-based strategies for future emergencies.We recommend that in observational studies, the consequences of a delayed RRT and use of alternative, non-standard modalities in response to the lack of RRT capacity be investigated to determine to what extent the policies developed and implemented during the pandemic were safe and effective.What is the potential biological rationale for using  EBP in critically ill patients with COVID-19?Inflammatory cytokines, DAMPs, pathogen-associated molecular patterns(PAMPs), including endotoxins and SARS-CoV-2 particles, potentially contribute to the development of multiple organ failure and mortality in critically ill patients with COVID-19.EBP techniques have been shown to remove cytokines, DAMPs and PAMPs, including endotoxins and circulating viral particles.130)  Fig. . MultiplWhich EBP techniques can potentially be used to remove circulating molecules implicated in the pathophysiology of COVID-19?Haemoperfusion techniques can remove inflammatory molecules, DAMPs and PAMPs, including SARS-CoV-2 particles.Therapeutic plasma exchange (TPE) can remove inflammatory mediators and proteins associated with hypercoagulability.CRRT with surface-modified AN69 or polymethylmethacrylate membranes can remove target molecules by adsorption, whereas CRRT with medium cut-off or high cut-off membranes can remove target molecules by diffusion or convection.140. In a small RCT of patients with septic shock (EUPHAS), the use of haemoperfusion was associated with improved organ function and a survival benefit141; however, a larger RCT (EUPHRATES) failed to confirm these findings136. A post hoc analysis of the EUPHRATES trial demonstrated possible therapeutic survival effect in a subgroup of patients with endotoxin activity in a specific range140. TPE has been shown in RCTs to improve haemodynamics, induce favourable changes in cytokine profile and improve survival in patients with septic shock143. Removal of inflammatory cytokines with TPE could, in theory, confer some benefit in patients with COVID-19 with hyperinflammation and hypercoagulability144. CRRT with medium cut-off, high cut-off or adsorptive membranes can remove cytokines or myoglobin and potentially prevent myoglobin-induced AKI146.Many health-care agencies have authorized emergency use of various EBP techniques to remove molecules that are potentially causative of the immuno-inflammatory response in critically ill patients with COVID-19. However, these EBP techniques have not yet been formally studied in this patient population .149. However, there are limited data regarding the timing of initiation or duration of use of these therapies, and further studies are needed.If used, EBP therapies should be selected on the basis of the pathophysiology they are designed to target. Numerous clinical criteria, including body temperature, haemodynamic status, need for vasopressor support, respiratory status and oxygenation, multiorgan failure score, cardiac and kidney function, as well as laboratory parameters such as lymphocyte counts, concentration of cytokines, ferritin, lactate dehydrogenase, D-dimers, monocytic expression of HLA, myoglobin, troponin, C-reactive protein, endotoxin activity, procalcitonin and culture results may be useful in evaluating the suitability of a patient for initiation of EBP. However, the precise indication for EBP in patients with COVID-19 remains to be determined. EBP for endotoxin removal has been generally applied for 48 consecutive hours and for 72 h for cytokine removal in studies of septic patients and in ongoing COVID-19 trialsFuture trials should measure the ability of EBP to remove target molecules, including assessment of their kinetics, to confirm the pathophysiological rationale for use of EBP in critically ill patients with COVID-19.Future trials should assess whether use of EBP is associated with improved short-term outcomes, including prevention and mitigation of organ failure.Future trials should assess whether combined or sequential EBP techniques can reach meaningful biological and/or clinical end points.The ability of haemoperfusion to prevent or mitigate organ failure by removal of the SARS-CoV-2 virus in patients with detected viraemia should be investigated.Future studies should validate the biological and clinical parameters that identify individuals who are likely to benefit and respond to EBP, as well as parameters for monitoring and discontinuing treatments.Future studies should evaluate TPE as an alternative for reducing hypercoagulability, hyperviscosity, and hyperinflammation in patients with COVID-19, and also assess the negative consequences of removing potentially beneficial molecules .Future studies should assess the removal of drugs and nutrients during EBP and any resulting potentially negative consequences on patient outcomes.Kidney involvement following SARS-CoV-2 infection is more common than initially thought and is associated with morbidity and mortality. The pathophysiology of COVID-19 AKI is probably multifactorial — in line with the pathophysiology of other forms of AKI. Rates of COVID-19 AKI vary considerably between studies and regions, although available evidence suggests an incidence of over 20% in hospitalized patients. Many features, such as risk factors, likely mechanisms and outcomes, are shared between COVID-19 AKI and AKI arising from non-viral causes encountered in the ICU. Thus, many of the treatment recommendations, as well as preventative measures described in this Consensus Statement, are common to both. Considerations for RRT are also similar with the caveat that more aggressive anticoagulant regimes may be needed and that treatment may need to be adjusted to conserve resources in the context of a surge in COVID-19 cases. Given the potential contribution of systemic inflammation to multiorgan failure in COVID-19, the use of extracorporeal therapies may also be considered. Of note, new data on COVID-19 AKI are continually being published and these recommendations may therefore require modifications as new results become available.Supplementary Information


Pharmacological treatment of mental disorders is currently decided based on "trial and error" strategy. Mitochondrial multifaceted dysfunction is assumed to be a major factor in the pathophysiology and treatment of schizophrenia (SZ) and bipolar disorder (BD). This study aimed to explore the feasibility of using a profile of mitochondrial function parameters as a tool to predict the optimal drug for an individual patient . Healthy controls (n = 40), SZ (n = 48) and BD (n = 27) patients were recruited. Mental and global state of the subjects, six mitochondrial respiration parameters and 14 mitochondrial function-related proteins were assessed in fresh lymphocytes following in-vitro or in-vivo treatment with five antipsychotic drugs and two mood-stabilizers. In healthy controls, hierarchal clustering shows a drug-specific effect profile on the different mitochondrial parameters following in-vitro exposure. Similar changes were observed in untreated SZ and BD patients with psychosis. Following a month of treatment of the latter patients, only responders showed a significant correlation between drug-induced in-vitro effect (prior to in-vivo treatment) and short-term in-vivo treatment effect for 45% of the parameters. Long- but not short-term psychotropic treatment normalized mitochondria-related parameters in patients with psychosis. Taken together, these data substantiate mitochondria as a target for psychotropic drugs and provide a proof of concept for selective mitochondrial function-related parameters as a predictive tool for an optimized psychotropic treatment in a given patient. This, however, needs to be repeated with an expanded sample size and additional mitochondria related parameters. The research domain criteria (RDoC), based on observable behavioral (symptoms) and neurobiological dimensions rather than traditional diagnostic measures4 claims a lack of clear boundaries between SZ and BD. Henceforth, in the present study, we studied SZ and BD as a single entity5.Schizophrenia (SZ) and bipolar-disorder (BD) share emotional and cognitive abnormalities and psychotic symptoms, commonly affecting young adults. Both disorders also share genetic risks and endophenotypes6.More than 40 different antipsychotic and mood stabilizing drugs are currently available. It has long been held that there is little difference in the therapeutic efficacy of antipsychotics other than clozapine and differences in clinical effects were mainly ascribed to variability in sedative and adverse effect profiles. The truth of this assertion has recently been challenged by meta-analyses, which found small but consistent differences between the drugs, corroborating a strong impression among clinicians that inter-individual differences in the efficacy of different antipsychotics do exist. Currently, there is no empirically-supported basis for the decision which psychotropic drug to prescribe to which patient in every day clinical practice. Choice is based on the clinical experience of the psychiatrist, on guidelines and on the individual patient’s clinical state, prior symptom response, and experience of side effects2+ homeostasis, are crucial for neuronal activity. Indeed, multifaceted mitochondrial dysfunction is evident by genetic, molecular, biochemical, structural and imaging studies in SZ and BD9. Changes in mitochondria-related intracellular pathways regulating neuronal transmission, plasticity, oxidative stress, apoptosis and cell survival have been observed in both disorders16. Hence, mitochondrial dysfunction can lead to distorted connectivity of neuronal networks and thereby to abnormal cognitive and emotional behaviors. In line with the latter, we have recently shown that transplantation of healthy mitochondria improved aberrant mitochondrial function, amended neuronal differentiation and synaptic connectivity in SZ-derived neurons and restored behavioral deficit in an animal model of the disorder17. Notably, mitochondria are also a target for psychotropic drugs by virtue of the drugs' modulatory effect on the expression of mitochondrial genes expression and on levels of proteins involved in the tricarboxylic acid cycle, the respiratory chain, apoptosis, autophagy and mitochondrial network dynamics22.Two core mitochondrial functions, energy production and Ca27.It has long been recognized that neuropsychiatric disorders associated with brain mitochondrial malfunction also present aberrant mitochondrial energetics in peripheral cells such as platelets, lymphocytes and leukocytes. In a broader scope, blood cells have been shown to retain a variety of biological abnormalities implicated in mental disorders and have been suggested as a proxy to brain tissueGiven the impairments observed in mitochondria in both disorders, together with the findings that mitochondria are a target for antipsychotics and mood stabilizers (jointly designated psychotropic drugs), we aimed to study the feasibility of using an array of mitochondrial parameters in blood lymphocytes as a tool to predict the optimal drug for an individual patient . To this end the following issues had to be addressed: first, examine whether different drugs exert a specific response profile in-vitro in lymphocytes, which was studied in healthy subjects. Second, study the relevance of these in-vitro drugs profiles to patients. Next, find out whether the in-vitro profile predicts the in-vivo response/non-response to a given drug in a given patient. Finally, further substantiate that mitochondrial function parameters in lymphocytes reflect the long-term response to the drugs. The results we obtained by investigating these four issues justify a larger scale study.Healthy controls (n = 40) were recruited from the staff and faculty of the Beer-Sheva Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva and from Rambam Health Care Campus, Haifa, Israel. Hospitalized and outpatients, recruited from Beer-Sheva Mental Health Center, were evaluated according to Diagnostic and Statistical Manual of Mental Disorders V (DSM-V). Patients were diagnosed with either schizophrenia  or bipolar-disorder  and severity of symptoms was assessed by the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS). All groups (patients and controls) were matched for age and gender as much as possible. The study was approved by institutional review board (IRB). All subjects gave informed consent for participation in the study. Inclusion criteria for the controls were: subjects aged 18–60 years who signed an informed consent form. Exclusion criteria: pregnant women and subjects with a history of neurodegenerative and metabolic diseases that require drug treatment, or any kind of malignancy and substance use. For control subjects—in addition to the above, no psychiatric disorders or family history of psychiatric disorders.28 were tried and optimal concentrations were chosen  for RNA and with PBS containing 10 mM ethylenediaminetetraacetic acid (EDTA) for protein extraction. The dry pellet was frozen at − 80 °C until use.Blood (40–50 ml) was withdrawn and lymphocytes separated on Ficoll-Paque gradient  by centrifugation  (Supplementary Methods 29. Levels of 14 different proteins were measured by indirect Enzyme-Linked Immunosorbent Assay (ELISA) as previously described30 with minor modifications   test if main effect or interactions were significant (P < at least 0.05). Correlations were analyzed by the Pearson correlation test. The STATISTICA software version 12  was used for all analyses. Results exceeding ± 2SDs were excluded.The study was approved by institutional review board (IRB) of Soroka Medical Center Beer-Sheva No. 5223 and of Rambam Health Care Campus No. RMB 0124-17. All subjects gave informed consent for participation in the study.2,73 = 4.273 p = 0.04) among the patient groups. CGI-S and BPRS were significantly different between responding and non-responding patients treated for one month  and  respectively. No significant difference was observed for all other parameters in all groups.Two groups of patients: 1) Chronically (in-vivo) treated (SZ and BD) for at least two years (n = 55) who received the psychotropic drugs that were investigated in the current study. (2) Untreated patients for at least one month (n = 20) 11 of whom could be recruited again after a month of drug treatment and a group of healthy controls (n = 40). Table  ChronicaWe further analyzed all data using age, age of onset of disease and disease duration as continuous predictors in ANOVA and did not find significant influences. Sex, origin, family history of psychotic disease and smoking were used as co-factors in ANOVA and no significant interaction with mitochondrial parameters was observed in any group.38. By comparing mitochondrial parameters with and without drug treatment, a specific profile of the effect of each of the drugs was obtained —complex I subunits , complex II subunit SDHA and complex IV subunit COX2; apoptosis—BAX, Bcl-2, CASP3, mitochondrial fission/fusion—OPA1, MFN1, Drp1, FIS1 and autophagy—Beclin1, p62. Most of the included proteins were reported abnormal in one or both disordersFor mitochondrial respiration parameters we found that olanzapine, haloperidol and risperidone significantly decreased basal- and ATP-linked-OCR, while lithium significantly increased these parameters. Clozapine and risperidone significantly decreased mitochondrial reserve capacity OCR. Olanzapine and risperidone significantly decreased mitochondrial maximal respiration. VPA and perphenazine did not affect any mitochondrial respiration parameter.Proteins significantly decreased by lithium were complex I subunit NDUFV2, three mitochondrial fission/fusion proteins OPA1, FIS1, Drp1, and the autophagy-associated protein Beclin1 as well as Beclin1/p62 ratio, while the anti-apoptotic protein Bcl-2 was increased. VPA significantly increased levels of the complex II protein SDHA, while decreasing levels of the pro-apoptotic protein CASP3 and Beclin1. Clozapine increased levels of Bcl-2, while decreasing levels of Drp1. Olanzapine decreased levels of CASP3, the fusion protein MFN1 and Beclin1. Risperidone significantly increased the levels of both pro- and anti-apoptotic proteins BAX and Bcl-2, respectively, as well as levels of Beclin1 and Beclin1/p62 ratio, while decreasing levels of OPA1. Haloperidol increased levels of Bcl-2 and BAX. However, this drug significantly decreased the levels of the ETC complex I subunits NDUVF1, NDUVF2 and NDUVS1, CASP3, Drp1, Beclin1 and Beclin1/p62 ratio.Hierarchical clustering dendorgram revealed a specific fingerprint for each of the drugs with typical antipsychotics clustering separately from the atypical drugs. The mood stabilizers clustered with the typical drugs, albeit in different subgroups, with lithium clustering with perphenazine and VPA with haloperidol Fig. B.In contrast with the results obtained for protein levels, psychotropic drugs treatment failed to induce any significant change at the level of mRNA expression of the assessed proteins . Each patient was assigned to receive one of the study drugs chosen by the psychiatrist to be used for the patient's treatment. Clozapine was not included since it is not routinely prescribed as a first choice drug. Unfortunately, the amount of blood withdrawn from some of the patients was insufficient to analyze all parameters. Therefore, the effect of all six drugs was monitored for mitochondrial respiration parameters and of haloperidol, lithium, risperidone and olanzapine for protein levels. For each of the mitochondria-related parameters a correlation between the in-vitro and the in-vivo drug-induced changes was analyzed for responding and non-responding patients. In responding patients, a significant correlation between the in-vitro and the in-vivo drug-induced effects was observed for nine out of 20 parameters, including proton-leak, reserve capacity- and non-mitochondrial-OCR, COX2, Bcl-2, MFN1, OPA1, Drp1 and Beclin1. In contrast, in most patients who failed to improve clinically following treatment (non-responders) no correlation was observed for any of the parameters Fig. , suggestAlthough preliminary, it is of interest to note a qualitative similarity  between risperidone's profile in controls, and the drug's in-vitro effect in two untreated, eventually responding patients on 60% (12/20) of the parameters studied . In contrast, in an eventually non-responder there was only 25% similarity. Another patient who eventually did not respond to haloperidol exhibited only 20% similarity, while an eventually lithium responder showed 54% similarity to the drugs' profile in controls.In untreated, eventually responding patients, basal levels of 13 out of the 20 mitochondrial parameters assessed, differed from those of healthy subjects. Basal-, ATP-linked-, maximal- and reserve capacity-OCR were significantly lower, while proton leak and levels of the proteins NDUFV1, NDUFV2 NDUFS1, CASP3, MFN1, FIS1, Drp1 and p62 were significantly higher in these patients as compared to controls Fig. . Short-t42. Studies of the genetic basis of the response to treatment in SZ suggest that DNA sequences related to drug metabolism and target sites can predict treatment response (reviewed in Ref.43). The authors advocated that pharmacogenetics of this disorder may assist personalized treatment and lead to a molecular-based sorting of response to adverse effects of psychotropic drugs. They further alleged that "clinicians may soon be using a patient's genotype to decide initial choice of antipsychotic drug treatment in SZ". Ten years later these expectations have only partially ripened. Namely, quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy, designated therapeutic drug monitoring (TDM), has been extensively developed44. However, TDM does not indicate the optimal drug for a given patient. An alternative emerging approach for personalized medicine suggests mining existing clinical trials' data to build statistical models to predict drug response45. One such example is a study in which machine learning was applied to patient-reportable pre-treatment data from 334 patients of the European First Episode Schizophrenia Trial in order to provide useful insight into individualized outcome trajectories and to optimize treatment selection46. Such an approach does not take into account individual biological factors, while the genetic approach ignores factors affecting drug response such as environmental parameter, epigenetic status and microbiome. Indeed, it was recently claimed that "Environmental factors  and co-medication are usually more important factors than inherited determinants of drug metabolism and response"47. Together, genetic and environmental factors culminate in functional manifestations, which were the focus of the present study. In particular, based on multiple lines of evidence suggesting that mitochondrial dysfunction is a key component in the neurobiology of neuropsychiatric disorders including SZ and BD48 and a target of psychotropic drugs49, we studied twenty mitochondrial function parameters. We addressed two main issues: the relevance of mitochondrial function parameters to psychotropic treatment and the predictability of these parameters for personalized medicine in psychosis.In quest for a rational basis to predict the appropriate drug for an individual, recent intensive research focuses on developing tools predicting individual’s response to psychotropic drugs based on genetic fingerprints (pharmacogenomics)vs. atypical antipsychotic drugs support the relevance of mitochondrial function parameters as a tool for personalized treatment prediction. The profiles are comprised of respiration parameters and mitochondrial function-related proteins but not of their mRNA, which was not affected by the 24 h drug treatment. The latter is in line with a previous study reporting lack of haloperidol effect on mRNA expression of complex I subunits in a human neuronal cell line50 and with the comprehension that mRNA and protein levels are not always affected to the same extent by intra and/or extra-cellular processes52. Alternatively, this lack of effect could indicate that short-term in-vitro exposure to psychotropic drugs affects post-transcriptional mechanisms.Here we show an in-vitro drug-specific mitochondria-related effect profile in healthy controls-derived lymphocytes. This, along with disparate clustering of typical 35. As for the typical drugs, about 25% of the parameters were affected only in the patients, with haloperidol affecting mitochondrial-related proteins, while perphenazine—respiration parameters. Drug-specific induced differences between patients and controls may result from intrinsic disease-dependent differences in drugs' interaction sites. Haloperidol and perphenazine are prone to participate in redox reactions but in a different manner. Haloperidol has oxidation potency53 while perphenazine is an oxidation substrate54. Our data suggest that the patients are more susceptible to oxidoreductive load. Nonetheless, the resemblance in drug effect profiles between untreated patients and controls supports the notion that mitochondrial drug effect profiles may be useful in predicting response to psychotropic drugs.The in-vitro profile of drugs' effect obtained in untreated patients was similar to that in healthy controls. By-and-large our data demonstrate high similarity in the extent of change following drug exposure between the two diagnostic groups. Seemingly, this similarity is counterintuitive given the strong evidence of mitochondrial deregulation in psychotic disorders. This apparent conundrum may be conciliated if the protein-domain targeted by a drug is not impaired in patients. Supporting the latter are the findings that antipsychotic drugs affect complex I-driven respiration to the same extent in lymphocyte-derived cell lines of SZ patients and healthy controls although complex I activity is abnormal in the patientsin-vitro response profile to two drugs in eventually responding untreated patients resembles the profile of controls, as opposed to eventually non-responders, are in favor of the predictability potential of mitochondrial function parameters.The predictability is further supported by the significant correlations between the in-vitro (before treatment) and in-vivo (after ~ 1 month treatment) drug response in treatment-responding patients as opposed to lack of correlation in non-responding patients. The correlation was observed for all five drugs used to treat these patients and for almost half of the studied parameters, implying that the in-vitro response of several parameters can foresee the in-vivo effect and indicate a predictive relationship. The lack of significant correlation for the rest of the parameters may reflect either their irrelevance to the predictive profile, or be due to the small sample size of patients we managed to recruit. A greater sample size is essential in order to support the potential of the in-vitro drug profile as a predictor for in-vivo drug-response. Although anecdotic, our results showing that individuals' 57. Long-term treatment did not normalize the high proton leak in patients indicating an increased uncoupling between oxidative phosphorylation and ATP synthesis, and corroborates with dissipation of the mitochondrial membrane potential (Δѱm) in SZ59. Protons leak through uncoupling proteins (UCPs) on the mitochondrial inner membrane. Interestingly, association of mitochondrial UCP genes with SZ was reported61.The findings of the in-vivo drug treatment effects in patients provide additional evidence for mitochondria being a relevant target for psychotropic drugs. Notably, in responding patients, short-term treatment was not sufficient to ameliorate mitochondrial dysfunction, while a prolonged drug treatment restored mitochondrial function. This is in line with numerous reports of duration-dependent mode of action of drugsIn conclusion, the present proof-of-concept study was aimed to set the ground for using lymphocyte mitochondrial function parameters as a tool to predict the drug of choice for a given patient with psychosis . Using an array of mitochondrial parameters we found an in-vitro drug–specific effect-profile and suggest its applicability by demonstrating a correlation between pre-treatment in-vitro and in-vivo effect of antipsychotic drugs on mitochondrial parameters only in patients eventually responding to treatment. An additional novel finding is that antipsychotic treatment amends the levels of mitochondrial parameters to almost those of healthy controls, but prolonged medication is required.Our study is not devoid of limitations including the small sample size in the untreated patients' group and the retrospectivity of the chronically treated patients study. The current results pave the road and calls for a big data replication study in order to embed this tool into real-world healthcare. Regardless, this study contributes to the understanding of the role of mitochondria in psychosis and its treatment.Supplementary file 1