In May 2020, the Philippine Society of Medical Oncology published its initial recommendations on the treatment of cancer patients during the SARS-Cov-2 pandemic. The objective of this update is to provide answers to the questions pertaining to the diagnostic testing of SARS-CoV-2 for both cancer patients and healthcare professionals caring for cancer patients, as well as the recommended protective measures and practices that may be instituted in healthcare facilities. Six months into the SARS-CoV-2 pandemic, the Philippines continues to struggle in coping with the increase in cases, especially during the last weeks of July 2020. As the nation went on an enhanced community quarantine in March 2020, the healthcare community learned to cope with the demands of caring for those affected by the virus, adopting and applying effective medical practices as evidence unfolded. To cope with the increasing number of infected individuals, medical facilities were converted into COVID-19 referral centres and Filipinos were advised to stay at home as part of the preventive measures to limit the contagion.Despite the country’s low COVID-19 mortality rate, SARS-CoV-2 continues to impact all Filipinos, particularly those with medical conditions like cancer, cardiovascular, pulmonary and other comorbid diseases. While real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) diagnostic laboratories have been set up throughout the country to identify those affected by the virus, capability and resources to pay for the tests remain very limited relative to the country’s population. Thus, the preventive measures of hand washing, physical distancing, wearing of masks and face shields remain the most cost-effective measures to save all lives.Similar to the situation in different parts of the world The uncertainties brought about by this public health emergency have likewise presented unique challenges to oncologists around the world , 10, witIn May 2020, the Philippine Society of Medical Oncology (PSMO) published its initial article on the treatment of cancer patients during the SARS-Cov-2 pandemic, dwelling on the prioritisation of cancer care, ensuring a safe work environment, organising transition of cancer care and maintaining cohesion in a time of isolation . HoweverThe objective of this article is to provide specific answers to questions pertaining to the diagnostic testing of SARS-CoV-2 for both cancer patients and healthcare professionals caring for cancer patients, as well as the recommended protective measures and practices that may be instituted in healthcare facilities. This article reviews recommendations from the American Society of Clinical Oncology, the European Society of Medical Oncology, and the PSMO’s recommendations on how these practices may be adapted by each medical oncologist providing oncologic care throughout the archipelago.primum non nocere, the identification of SARS-CoV-2 infection among cancer patients became an utmost priority.Multiple studies carried out around the world have shown that patients with cancer are at a higher risk for severe complications and mortality from SARS-CoV-2 infection –19. In tPSMO acknowledges that protocols regarding prioritisation of patients may vary according to institutional resources and local testing capacity. For general guidance, prioritisation of cancer patients for COVID-19 testing was adopted from previous recommendations by international oncologic societies , 22 Tab.Consistent with our previous recommendations, a triage/screening area manned by personnel with appropriate personal protective equipment (PPE) should be in place in all cancer institutions to ensure the safety of both patients and healthcare workers , 23.Obtaining a good history for signs and symptoms of COVID-19 is paramount. Systematic reviews of observational studies showed that the common symptoms of COVID-19 are fever, cough, fatigue /myalgia, dyspnoea, shortness of breath, chest tightness/pain, anorexia, arthralgia, sputum production, chills, headache and sore throat. Less common symptoms (<10%) include diarrhoea, abdominal pain, dizziness, rhinorrhoea, nausea and vomiting, nasal congestion and haemoptysis. Patients presenting with dyspnoea or shortness of breath were noted to be at a higher risk of developing severe cases of COVID-19 or death .Furthermore, the use of a standardised questionnaire  OPD Patient Screening Form) to screen for symptoms and potential exposure is recommended .rRT-PCR assayAn rRT-PCR using nasopharyngeal swab specimens should be carried out to confirm the presence of SARS-CoV-2 infection among cancer patients whenever feasible.The currently recommended test and the ‘gold standard’ to confirm COVID-19 infection is rRT-PCR  assay. Using this assay, SARS CoV-2 viral RNA can be detected in nasal or pharyngeal samples, sputum, bronchoalveolar lavage fluid and other bodily fluids, including faeces and blood .Among the upper respiratory tract specimens, nasopharyngeal and nasal swabs had the highest sensitivity  with a specificity of 100% .Rapid tests based on antigen productionnot currently recommend the use of antigen-detecting rapid diagnostic tests for patient care, although research into their performance and potential diagnostic utility is highly encouraged [It is important to note that the WHO does couraged .However, in centres where rRT-PCR diagnostic assay for COVID-19 is not available, the rapid antigen tests can potentially be used as an alternative among symptomatic cancer patients during the first week of illness. Negative results from an antigen test should be confirmed with an RT-PCR test prior to making treatment decisions to prevent the spread of the virus. Oncologists are advised to interpret the results with utmost care and caution, and to always correlate it with clinical and epidemiologic parameters [rameters .Rapid antigen test detects the presence of viral proteins (antigens) expressed by the COVID-19 virus in a sample from the respiratory tract of a person. The antigen(s) detected are expressed only when the virus is actively replicating; therefore, such tests are best used to identify acute or early infection .Although commercially available rapid antigen tests report a sensitivity of 87% (95% CI 52.9–97.8) and a specificity of 100% (95% CI 96.8–100) based on a small study using direct nasal swabs from sequentially enrolled patients compared to a SARS CoV-2 extracted RT-PCR assay, some studies show a very low overall sensitivity rate of 30.2% .Detection of Antibodies to SARS-CoV-2The use of IgM/IgG rapid test kit is not recommended in the diagnosis of COVID-19 in cancer patients.Two clinical trials showed that there is insufficient evidence to support the use of IgM/IgG rapid test kits for the definitive diagnosis of COVID-19. Diagnostic accuracy varies greatly depending on the timing of the test. Furthermore, the test performed very poorly during the early phase of the disease  , 31.not recommend rapid point-of-care lateral flow immunoassay antibody tests as stand-alone tests for the diagnosis of COVID-19.The PCP-PSMID guidelines also do not currently recommend the use of antibody-detecting rapid diagnostic tests for patient care but encourages the continuation of ongoing research to establish its usefulness in disease surveillance [The WHO also does eillance .An rRT-PCR SARS-CoV-2 nasopharyngeal swab test should be conducted for cancer patients presenting with COVID-19 signs and/or symptoms.An rRT-PCR SARS-CoV-2 nasopharyngeal swab test is recommended for new asymptomatic cancer patients BEFORE receiving their first cycle of immunosuppressive therapy which includes, but is not limited to, cytotoxic chemotherapy, biologic therapy, immunotherapy, high-dose corticosteroids, extensive radiotherapy or stem cell transplantation. Ideally, the test should be conducted 48–72 hours prior to the start of the immunosuppressive treatment if patient resources or institutional logistics allow [If the test is found impractical to do by the attending oncologist because of logistical/financial concerns or the patients’ clinical scenario, please see ‘For Areas where rRT-PCR SARS-CoV-2 Testing is NOT Readily Available’ below.cs allow , 22. If For asymptomatic cancer patients who are on succeeding cycles of immunosuppressive treatment, the oncologist has the option to screen patients using repeat rRT-PCR SARS-CoV-2 nasopharyngeal swab test or the 14-day COVID-19 symptom-based test. A systematic review showed that among asymptomatic individuals with possible exposure to COVID-19, the sensitivity of detecting active COVID19 infection with a 14-day symptom-based test is 92.8% and specificity is 98.3% [is 98.3% . It is iIt is important to note that the sensitivity and specificity of a test vary with time, from symptom onset due to changes over time in the viral load .Using rRT-PCR, the probability of detecting SARS-CoV-2 varies based on time from the exposure, being as low as 0% in the immediate days following exposure, 33% one day before symptom onset, 62% on the day of symptom onset and peaking at 80% on day 3 of symptoms .Symptomatic Cancer Patientsthe recommendations of PCP-PSMID that rapid antigen tests can potentially be used as an alternative among symptomatic cancer patients during the first week of illness may be applied. Negative results from an antigen test should be confirmed with an rRT-PCR test prior to making treatment decisions to prevent the spread of the virus. Oncologists are advised to always correlate with clinical and epidemiologic parameters [In settings where the rRT-PCR SARS-CoV-2 test is unavailable, or the logistical scenario makes its use difficult, rameters .Asymptomatic Cancer Patients who will start or are on active treatmentstrict self-quarantine for 14 days, if logistically possible [One strategy to ensure patients arrive for their immunosuppressive cancer treatment without subclinical SARS-CoV-2 infection is to observe a period of possible .oncologist should discuss the best available evidence (including the risks of chemo if there is undetected COVID-19 infection) to patients prior to making an informed decision. Furthermore, not all patients will have the means to self-quarantine and this strategy may add to the already apparent social and economic burden of cancer treatment.This may be an alternative for screening asymptomatic cancer patients in resource-limited settings since any prior exposure would have sufficient time to enter the symptomatic phase. However, with the data on asymptomatic COVID-19 cases rising, the Cancer patients with confirmed COVID-19 infection should be referred to an Infectious Disease specialist and managed according to the latest PCP-PSMID-PCCP Interim Guidelines [idelines .Immunosuppressive treatment for these patients should be delayed for 10–14 days after symptom onset and/or cleared by infectious disease expert based on clinical parameters [rameters , 22. FurThere is no gold standard ‘test of cure’ for COVID-19 [COVID-19 . Based oCOVID-19 , a test-Currently, the need for documenting two consecutive rRT-PCRs is being questioned in light of recent evidence showing that although viral shedding can last several weeks, the virus is likely to be non-viable by day 8 . The US-If a confirmed case was noted to have entered the clinic or hospital grounds, the area where the patient was noted to have stayed should be disinfected accordingly and contact tracing protocols should be set in place according to the PSMID Unified COVID-19 Algorithms .REPEAT TESTING for patients with an initial negative COVID-19 test result should be carried out if there is a high index of suspicion for COVID-19 infection, despite an initial negative test result [t result .Immunosuppressive treatment for these patients should be delayed until a repeat rRT-PCR result shows a negative result and/or cleared by an infectious disease specialist [ecialist .Cancer patients who are asymptomatic with a negative test result may proceed with the planned immunosuppressive treatment after being clinically assessed by his/her oncologist.Symptomatic patientsThe following ancillary tests are recommended when COVID-19 is suspected to guide management if deemed imperative by the attending physician: complete blood count; metabolic panel: creatinine, liver function tests, sodium, potassium, magnesium, calcium and albumin; inflammatory markers: lactate dehydrogenase, ferritin, C-reactive protein and procalcitonin; prothrombin and D-Dimer; arterial blood gas measurement; blood cultures if concomitant bacterial infection is suspected; respiratory tract specimen for influenza testing; sputum, endotracheal aspirate, or bronchoalveolar lavage fluid culture and sensitivity; chest X-ray; high-resolution chest CT scan plain and ECG .Asymptomatic cancer patientschest X-ray is used as an initial diagnostic tool in some institutions due to its availability and the delay in results of RT-PCR, its universal use as a screening test is not recommended because of its low sensitivity (69% versus 91% for rRT-PCR), especially early in the disease; moreover, abnormalities, if detected, are non-specific [Although specific .A systematic review shows the following chest X-ray findings among laboratory-confirmed COVID-19 patients :Chest X-ray typically shows ground-glass opacities and consolidation in the lung periphery.Initial imaging results may be normal early in the course of illness and in mildly symptomatic patients.Abnormalities are not specific and overlap with other infections and coronavirus types of pneumonia.The universal use of Chest CT scans as a screening tool (for asymptomatic patients) is not recommended.The characteristic chest computed tomographic imaging abnormalities for COVID-19 are diffuse, peripheral ground-glass opacities . Ground-As front liners taking care of immunocompromised patients in the COVID-19 response, healthcare workers (HCWs) are continuously at risk of acquiring the infection. HCWs could get SARS-CoV-2 at work through direct or indirect contact with infected patients or other healthcare workers, or as a result of ongoing community transmission . A studyIn June 2020, a hospital-wide healthcare worker surveillance testing programme conducted at the Philippine General Hospital revealed a relatively low COVID-19 rRT-PCR positivity rate among healthcare workers.Of 4871 HCWs, 99 (2%) tested positive. Twenty-six of 1,794 (1.4%) assigned to the COVID wards and intensive care unit (ICU) tested positive, while 16 of 893 (1.8%) assigned to the non-COVID areas were positive. Ten (1.16%) of 858 HCWs with essential but non-clinical work were positive. Of the 439 HCWs with symptoms, 21 (4.7%) tested positive. Of the 4,432 HCWs without symptoms, 78 (1.4%) tested positive for COVID-19 .Measures to prevent transmission in specialised facilities, such as cancer centres, are paramount and an immediate priority in order to: 1) safeguard and protect immunocompromised patients and the healthcare staff; 2) slow the demand for specialised healthcare, such as use of mechanical ventilators and ICU beds; and 3) minimise the export of cases to other healthcare facilities and the general community. As such, the following recommendations were made to guide HCWs handling cancer patients on immunosuppressive therapy.Workplace risk assessments should be conducted routinely and the appropriate measures to continuously minimise exposure to and transmission of the virus should be implemented. This includes, but is not limited to, the following:Minimise social gathering .Adhere to the minimum standard PPE recommendations and transmission-based precautions set by the respective institutions (See No. 7).Restructure the clinic or facility, as applicable, in accordance with the hospital infection control unit and/or safety and health committee recommendations.Observe proper respiratory/coughing etiquette and disposal of used hygiene materials.Decontaminate the workplace regularly following hospital and local recommendations.Provide alternative ways of doing operations  , 22.Limit the number of visitors or companions during admissions or clinic visits.All HCWs should be updated on the epidemiology of COVID-19 in their respective institutions and localities, including the known risk factors for infection, the presenting clinical signs and symptoms and the procedures for reporting, testing, isolating or transferring co-workers who are probable, suspected or confirmed COVID-19 cases. Emerging evidence and evolving guidance should be taken into account.The staff should be provided with the necessary education, training and assessment on the following , 22:Infection control, proper selection and use and disposal of personal protective equipment and proper use of respirators.Proper use and cleaning of equipment, clinic rooms, chemotherapy infusion facilities, among others.Proper disposal of potentially infectious wastes.Institutions should have established COVID-19 consultation hotlines and health service system to triage, examine and provide immediate dispositions  on symptomatic and/or infected HCWs . An orgaAs much as possible, HCWs working on cancer care facilities should not be mixed with HCWs providing care for COVID-19 patients to avoid cross-contamination by undocumented, asymptomatic medical personnel , 50. AllIdentify the number of staff essential for facility operations and patient care and treatment . As muchAll HCWs handling cancer patients should always adhere to the minimum standard and transmission-based precautions for COVID-19, which include :Use of face shield or goggles .Use of fUse of N95 masks or higher-level respirator based on anticipated exposures and suspected or confirmed diagnoses . A recenObservance of physical distancing of 1 meter or more.Strict hand hygiene after every patient encounter and/or contact with potentially contaminated surfaces.high risk* of exposure or who were exposed to confirmed or suspected COVID-19 cases.Periodic HCW risk assessment should be conducted to allow for early identification, immediate work restriction and monitoring of HCWs either at Self-monitoring of fever, respiratory symptoms and other symptoms related to COVID-19.see below).Recommendations on testing  [If a particular HCW is deemed to have an increased risk for severe complications or death when infected with COVID-19, they should be reassigned away from the 9 wards) . These mHCWs with diabetes.HCWs with predisposed cardiac condition.HCWs with asthma.HCWs who are obese and with obstructive sleep apnoea.All HCWs caring for cancer patients with symptoms compatible with COVID-19 should be immediately relieved from their duties and isolated while symptomatic, and should be prioritised for testing in order to be able to return to work as soon as possible, with clearance from the hospital infection control unit and/or safety and health committee.While molecular testing with rRT-PCR is widely available in the National Capital Region (NCR) and Metro Cebu, testing resource constraints continue in the rest of the archipelago. For this main reason, it is prudent to continue to use an evidence-based approach when making COVID-19 testing priorities.Testing of HCWs working in cancer facilities should be considered in the following situations :HCWs with signs or symptoms consistent with COVID-19.Asymptomatic HCWs with known or suspected exposure to SARS-CoV-2.HCWs who have been diagnosed with COVID-19 to determine when they are no longer infectious, or prior to returning to work, as deemed necessary by the hospital infection control unit and/or safety and health committee.When testing is feasible and available, HCWs should be considered a priority for evaluation . FacilitIn case of limited testing capacity, symptomatic HCWs should be prioritised for testing over low-risk groups .If no testing is available or testing capacity is limited, for the purposes of returning to work, symptom-based strategy must be employed. HCWs should be excluded from work until:At least 10 days since symptoms first appeared, ANDAt least 3 days with no fever without anti-pyretics AND symptoms have improved .True asymptomatic infection is believed to be uncommon. The average time from exposure to symptoms onset is 5 days, and up to 62% of transmission may occur prior to the onset of symptoms. Although studies have described rates of asymptomatic infection, ranging from 4% to 32%, it is unclear whether these reports represent truly asymptomatic infection by individuals who never develop symptoms, transmission by individuals with very mild symptoms or transmission by individuals who are asymptomatic at the time of transmission but subsequently develop symptoms .For asymptomatic HCWs with COVID-19 infection, they may be cleared to return to work using the following:Time-based strategy. Exclude from work until:10 days have passed since the date of their first positive COVID-19 diagnostic test, assuming they have not subsequently developed symptoms since their positive test. If they develop symptoms, then the symptom-based or test-based strategy should be used. Note that because symptoms cannot be used to gauge where these individuals are in the course of illness, it is possible that the duration of viral shedding could be longer or shorter than 10 days after their positive test.Test-based strategy. Exclude from work until:Negative results for SARS-CoV-2 from at least two consecutive respiratory specimens collected ≥24 hours apart . Note, because of the absence of symptoms, it is not possible to gauge where these individuals are in the course of their illness. There have been reports of prolonged detection of RNA without direct correlation to viral cultureProtecting the health of HCWs is paramount. The well-being of HCWs can be promoted by the provision of adequate PPE, as well as by ensuring that infected colleagues are promptly tested and isolated. The scale of asymptomatic HCWs positive with COVID 19 is not fully understood, nor is the full potential for asymptomatic and pre-symptomatic HCWs to transmit infection to patients who do not have COVID-19, other HCWs or the public. However, given that asymptomatic transmission has been documented, utmost caution is urged .Timing of RT-PCR testingSensitivity of testing varies with the timing of testing relative to exposure , 57Day 1 of exposure: 0%Day 4 of exposure: 33%Day 5 of exposure, Day 1 of symptoms: 62%Day 8 of exposure, Day 3 of symptoms: 80%Day 21 of exposure, likely no more symptoms: 34%Care must be taken in interpreting rRT-PCR tests for SARS-CoV-2 infection—particularly early in the course of infection—when using these results as a basis for removing precautions intended to prevent onward transmission. If clinical suspicion is high, infection should not be ruled out on the basis of rRT-PCR alone, and the clinical and epidemiologic situation should be carefully considered .Should there be a case of confirmed COVID-19 among the HCWs tested, the institution should have an established communication protocol or algorithm, as mentioned above.At times of surge or massive infection in the cancer care facility, the recommendations will have to be revisited to allow for adequate workforce support to continue providing optimal, appropriate and compassionate cancer care, while still prioritising the safety of both patients and healthcare staff .Institutions should consider splitting healthcare teams to ensure continuity of cancer care during the COVID-19 pandemic .Should cancer facilities have staffing shortages, the institution may allow asymptomatic HCWs with higher risk exposures to continue to work during their 14-day post-exposure period. If testing is available, carrying out testing during the 14-day post-exposure period can be considered in order to quickly identify pre-symptomatic or asymptomatic carriers. For HCWs with lower risk exposures, symptom screening and source control measures while at work should be in place .Appropriate information and training to HCWs recruited for the temporary replacement of the quarantined workforce should be provided.An adaptable framework for possible transfer of clinical care and/or continuity of management should be in place to allow for quick referral and coordination of affected patients.Cancer centre leaders should be attentive to HCWs who may experience increased stress, anxiety, burn-out or depression due to the COVID-19 pandemic. Psychological support and stress management resources should be made available to all HCWs to maintain physical and emotional well-being and to provide effective coping strategies , 22.This review and recommendations were put together by PSMO for Filipino medical oncologists to provide safe and effective cancer care during the COVID-19 pandemic. As new data emerge, the PSMO fervently supports the dictum of safety and well-being for all cancer patients and healthcare workers.www.psmo.org.ph.Site-specific cancer care guidelines during the COVID-19 pandemic will also be available at This work did not receive any funding.The authors have no conflicts of interest to declare.Data presented here are based on the best current evidence as of this writing. However, information about COVID-19 is rapidly evolving, and new evidence may have emerged by the time this article is published. Information contained in this article does not substitute for the independent professional judgment of the medical oncologist or other physicians in the context of treating an individual patient. This document is for informational purposes only and does not constitute medical or legal advice.


Arising from H. Mergental et al. Nature Communications 10.1038/s41467-020-16251-3 (2020)1. Of 31 initially discarded livers, 22 (71%) met the viability criteria during NMP and were transplanted with a 100% 90-day graft survival; however, three out of ten livers donated after circulatory death (DCD) developed biliary complications (30%) and required retransplantation. Because the trial was already initiated in 2016, more recent insights in viability testing should be considered when discussing the design and results of this clinical trial. Therefore, there are three issues that needs commenting to interpret the high rate of biliary complications reported: (1) the viability criteria used in this trial, (2) production of bile during NMP and (3) the use of end-ischemic NMP alone.The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) for viability testing of high-risk donor livers, were eagerly awaited as in this field different techniques are currently being used1. The first reports on the value of bile composition as a tool to determine bile duct viability were published after the initiation of this study3. In our experience, a substantial number of especially high-risk DCD grafts do not meet the cholangiocellular viability criteria during NMP (Table 4. Transplanting high-risk (DCD) donor livers without monitoring bile composition during NMP poses a risk to the recipient, as other investigators have previously shown a high rate of post-transplant cholangiopathy after end-ischemic NMP of high-risk DCD livers5. Therefore, with the current knowledge it is not a complete surprise that Mergental et al. have noted a high incidence of post-transplant cholangiopathy (30% after DCD transplantation) and need for retransplantation in their series1.In contrast to hypothermic <12 °C) machine perfusion (HMP), livers are metabolically fully active during NMP. This leads to restoration of hepatobiliary metabolism, such as clearance of lactate, production of (coagulation) proteins, and, importantly, bile production. Two types of viability criteria for donor livers during NMP have been distinguished: hepatocellular (‘liver parenchyma’) and cholangiocellular (‘bile duct’) viability criteria , we have monitored bile composition 1. In our experience, we have always been able to explain low or absent bile flow during NMP by a technical issue with the biliary drain. Regularly, the tip of the biliary drain can be stuck against the bile duct wall, leading to obstruction of the lumen and limiting bile flow. We have tested biliary drains extensively in preclinical experiments, and observed that bile flow initiates more rapidly when a small diameter drain is used, as a result of increased capillary force. As a result, we have been using a small feeding tube catheter (8 French) with an open tip and side holes as a biliary drain9.In the study by Mergental et al., 23% of the livers did not appear to produce bile1. Since the VITTAL study was initiated in 2016, other centers shared similar experiences showing high percentages of biliary complications after NMP for high-risk (DCD) donor livers5. End-ischemic NMP exposes a donor organ to ischemia-reperfusion injury, to which the bile ducts are extremely sensible. It has been shown before that a short period of dual hypothermic oxygenated machine perfusion (DHOPE) reduces reperfusion injury of the liver and biliary tree10. Several studies have demonstrated a beneficial effect of performing DHOPE prior to either direct transplantation or NMP15. After combined DHOPE and NMP, hepatic adenosine triphosphate content and biliary bicarbonate and bilirubin were higher in comparison to livers that underwent NMP only15. As a result, in 2017, the DHOPE-COR-NMP trial was initiated with a combination of one-hour DHOPE, followed by one-hour controlled oxygenated rewarming, and subsequent NMP, with the aim to reduce ischemia-reperfusion injury at the start of NMP8. Interestingly, all livers in the DHOPE-COR-NMP trial met the hepatocellular viability criteria used in the VITTAL study, despite the fact that all livers were derived from high-risk DCD donors with a substantially higher median age, compared to the VITTAL study8. This could suggest that a short period of DHOPE prior to NMP is very effective in preventing additional reperfusion injury of the liver parenchyma (hepatocytes) at the start of NMP. Only livers that have suffered too much (warm) ischemic injury of the bile ducts during and after the DCD procedure may no longer be salvageable with DHOPE and will not meet the biliary viability criteria during the NMP phase.In the study by Mergental et al., it was chosen to perform end-ischemic NMP onlyIn conclusion, in a rapidly advancing field of liver machine perfusion, we are all still learning and it is through sharing of our experiences that we can collective determine the most optimal use of the new technology in the benefit or our patients. From the emerging evidence, it becomes clear that end-ischemic NMP is an important tool to assess and select donor livers that, based on traditional criteria, were initially considered not suitable for transplantation. Yet, end-ischemic NMP alone, as applied in the VITTAL study, does not protect the bile ducts against ischemia-reperfusion injury. Therefore, a short period of HMP prior the NMP, as well as the use of cholangiocellular viability criteria during machine perfusion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.


Graphene-based nanostructures, used as potential reinforcement in ceramic composites, have a great tendency to agglomerate. This requires the use of homogenization techniques during the powder processing, posing the need to evaluate how these techniques affect the microstructure and the mechanical properties of the resulting composites. The influence of the processing route on the properties of 3YTZP  ceramic composites with 10 vol % cost-effective GNP (graphene nanoplatelets) has been addressed. Four different powder processing routines combining ultrasonic powder agitation (UA) and planetary ball milling (PBM) in wet and dry media have been used and all the composites were densified by spark plasma sintering (SPS). The mechanical properties at room temperature in the macroscale have been assessed by Vickers indentations, four-point bending tests and the impulse-echo technique, while instrumented indentation was used to measure the hardness and Young’s modulus at the nanoscale. The application of dry-PBM enhances greatly the mechanical and electrical isotropy of the composites, slightly increases the hardness and lowers the elastic modulus, independently of the application of UA. The combination of UA and dry-PBM enhances the flexure strength by 50%, which is desirable for structural applications. Ceramics are still attractive structural and functional materials due to their unique resistance to high temperatures, resistance to corrosion and inertness . TetragoAlthough many studies have been devoted to investigating the mechanical properties of graphene nanoplatelets (GNP)–ceramic composites ,15,16,17The aim of this work is to assess the mechanical performance of ceramic composites with 10 vol % cost-effective GNP (graphene nanoplatelets) densified by SPS from powders subjected to different processing routines, involving either ultrasonic wet powder mixing, planetary ball milling in wet/dry media or combinations of both mixing techniques. These powder processing techniques alter the GNP size, crystallinity and distribution into the ceramic matrix, as it was reported in a previous work . In orde3YTZP-10 vol % GNP composites were fabricated from commercial powders: TZ-3YB-E ceramic powder with 40 nm particle size supplied by Tosoh Europe B.V, Amsterdam, Netherlands and N006-P graphene nanoplatelets with <5 μm lateral size and 10–20 nm thickness supplied by Angstrong Materials, Dayton, OH USA. Four different powder processing routines were followed: (i) UA: wet powder mixing by ultrasonic agitation, (ii) UA-W-PBM: wet powder mixing by ultrasonic agitation followed by wet planetary ball milling, (iii) UA-D-PBM: wet powder mixing by ultrasonic agitation followed by dry planetary ball milling and (iv) D-PBM: dry powder mixing by planetary ball milling. The procedure was covered in detail in a previous paper .Elemental microanalysis was used to assess the GNP  content in the composite powders after processing, by means of a TruSpec CHNS micro LECO elemental micro-analyzer .The composite powder mixtures were densified using SPS with the conditions detailed in : 1250 °C3 (GNP) and 6.05 g/cm3 (3YTZP) given by the suppliers.The sintered composites with cylindrical shape (15 mm diameter × 3 mm thickness) were lapped manually to remove the graphite adhered during sintering, and then grinded to achieve parallel faces. Density was estimated by the Archimedes’ method . TheoretV (GPa) = 1854.4 P/D2 [Standard Vickers indentations  on perpendicular mirror-polished surfaces  were performed to estimate the composites’ hardness at the macroscale and to check for anisotropy effects. The hardness values were calculated averaging ten indentations on each surface, using the equation H4.4 P/D2  where P 4.4 P/D2 . The har4.4 P/D2 .® equipment and software .The impulse excitation technique was used to estimate the Young’s modulus (E) at the macroscale by measuring the acoustical response of the cylindrical-shaped composites to a short mechanical pulse with Sonelastic3) were tested for each composite. The bar surface in tension was polished up to 1 µm diamond paste, while the edges were chamfered with 10 and 2 µm diamond paste. To adapt to the specimen’s small size, a special lab-designed miniature 4-point bending assembly [Four-point bending tests were carried out for the composites processed using dry planetary ball milling (UA-D-PBM and D-PBM). Four bars , Raman spectroscopy, laser granulometry and scanning electron microscopy (SEM) is covered in detail in a previous paper . The mosGNP corresponds to the GNP aggregates lateral size, Dmax is the maximum lateral size value observed, dGNP is the thickness, A.R.GNP is the aspect ratio (DGNP/dGNP) and, finally, d3YTZP is the ceramic grain size, corresponding to the planar diameter. The parameters that have been statistically obtained are followed by their corresponding standard deviations (s.d.). These results are shown because they are important microstructural parameters to explain the mechanical behavior of the different composites.The results of the GNP morphology characterization performed from the analysis of SEM micrographs from polished cross sections of the composites in a previous study  are summmax) for easier comparison. Differences in the GNP surface can also be observed, with crumpling and wavy surfaces in the composites from powders subjected to UA and mostly flat surfaces in the D-PBM composite. The ceramic grain size is lower and more homogeneous (lowest standard deviation) in the D-PBM composite, due to the smaller GNP size which allowed their enhanced distribution around the ceramic grains. It was concluded that the homogenization of the powder mixture by high-energy planetary ball milling in dry conditions without previous ultrasonication resulted in the composite with the best performance in terms of microstructural homogeneity and electrical conductivity [We have to point out that the GNP size is slightly reduced when planetary ball milling is applied to the powder suspension  and considerably reduced when planetary ball milling is applied to the powders . The dry PBM promotes both the fragmentation and the exfoliation of the GNP, and also reduces the aspect ratio of the GNP, producing more isotropic microstructures. Although the GNP morphological parameters for both composites using dry PBM are similar, the most remarkable difference is the maximum GNP size, lower in the D-PBM one, which points to a more effective size reduction with this homogenization routine. This effect was more clearly observed from the dynamic laser scattering performed to the powders. The GNP distribution and morphology can also be visualized in the backscattered electrons (BSE)-SEM micrographs of uctivity .The results of the hardness tests carried out at the nanoscale by instrumented indentation and at a larger scale by Vickers indentations on the composites prepared using the mentioned four different powder mixing routines are listed and compared in All the composites are above 95% of the theoretical density, and the small fluctuations on the experimental density values do not seem to influence the hardness results. Although all the composites had a 10 vol % nominal GNP content, the slight differences in the real GNP content detected by the microanalysis assessment of the composite powders can affect the mechanical properties of the dense materials.The composites prepared from powders mixed with dry planetary ball milling (D-PBM and UA-D-PBM) have similar hardness values and are more isotropic, especially the one which included ultrasonic agitation (UA-D-PBM). The composite D-PBM is the most homogeneous, with the smallest standard deviation. The rest of the composites are more anisotropic, being harder when the indenter hits the cross-section surface, where the GNP lie edgewise. This behavior has been already reported for 3YTZP-GNP composites from powders processed by ultrasonic agitation ,41, and The nano-indentation method was the only one which was carried out on two different orientations of the specimens to obtain the Young’s modulus. According to this method, the Young’s modulus in the i.p.—in plane, where the GNP in the anisotropic composites lie on their main plane—is very similar for all the composites see , no matt3N4 matrix. In the present study, it is also observed that the more aggressive the mixing procedure, with wavier and smaller GNP, the lower the elastic modulus. Our results also indicate that the lateral size reduction of the filler is also related to the decrease of the elastic modulus. The Young’s modulus obtained for D-PBM and UA-D-PBM by this method are very similar.The elastic modulus estimation by the echo-pulse technique is based on the response to a mechanical pulse which impinged on the i.p. surface of the composites, so the results should be compared to the i.p. elastic modulus measured by nano-indentation. According to the impulse-echo technique, the composites with the lowest elastic modulus were UA-D-PBM and the highest elastic modulus was exhibited by the composites UA. Taking into account that the GNP which were only subjected to sonication during the mixing step are larger and less damaged, this result is in line with the results from Seiner et al. , who fouThe four-point bending tests were carried out on rectangular bars whose surface in tension–compression corresponded to the i.p. face, where the GNP in the anisotropic composites lie on their main plane, so the results are related to this configuration. The four-point bending tests were only performed to the composites which displayed a more homogeneous microstructure, the ones that had undergone dry planetary ball milling (D-PBM and UA-D-PBM). The composites D-PBM showed a lower flexure modulus than UA-D-PBM, but taking into account the large experimental uncertainties, the values can be considered similar.Comparing the different mechanical testing methods, the highest elastic modulus values are those measured by nano-indentation, following the same trend than the hardness results. These values are higher due to the different way of measuring. Hardness in nano-indentation is Meyer’s hardness, which use the projected contact area for measuring hardness. In Vickers, the contact area is used instead, so values are always lower. In addition, Young’s modulus can be slightly overestimated due to possible effects of the Poisson ratio in the relationship between stiffness and Young’s modulus ,46.Besides, the results of hardness and elastic modulus for these composites at the nanoscale are fairly dependent on the GNP filler size, and thus they are not so representative of the overall behavior of the material. It is sensitive in a different scale and could be useful to detect the interfacial properties between the filler and the matrix. The flexure modulus values obtained by means of the stress-strain curves recorded from four-point bending tests are the lowest elastic moduli of the three mechanical testing techniques. Although ideally the flexure modulus and the Young’s modulus of a solid should have the same value, they may differ in real conditions due to the non-ideality of the material or of the test conditions . In our The flexure strength was only evaluated in the most homogeneous composites, the ones from powders processed using dry planetary ball milling. The results of the stress to failure (UFS) measured in the specimens from different batches are listed in The results of UFS indicate that the composites which included ultrasonic dispersion of the GNP prior to the dry planetary ball milling exhibit a 50% increase in flexure strength compared to the ones which had not been subjected to ultrasonic agitation. This was a surprising finding since we expected very similar flexure strength results. The reason for this discrepancy can be that the application of ultrasonic agitation effectively disperses the GNP, breaking agglomerates and thus enhances their lubricating effect during the milling with the 3YTZP ceramic powder. This can explain the larger GNP size in the UA-D-PBM composites compared to the D-PBM ones. The larger GNP size is associated with an increase in the flexure strength. The larger GNP anchors strongly to the ceramic composite, effectively bridging cracks , while rIn this work, the hardness and elastic modulus have been estimated in 3YTZP–GNP composites to assess the influence of four different mixing approaches during the powder processing. The mechanical characterization has been carried out with different testing methods at the nano- and the macroscale to compare the results and establish their validity range for these composites.The non-destructive impulse-echo technique gives reliable results for the Young’s modulus in these composites. Nano-indentation also produces reliable and consistent results. Differences in the obtained values are attributed to the different ways of measuring the mechanical properties.The use of dry planetary ball milling (D-PBM and UA-D-PBM) during the powder processing compared to milder mixing procedures produced slightly harder composites with an isotropic response to indentation. However, the more aggressive the mixing procedure, the smaller the GNP size and the lower the elastic modulus.The composites which had included in the powder processing ultrasonic agitation previous to dry planetary ball milling (UA-D-PBM) presented a 50% higher flexure strength than those which were processed by direct dry milling (D-PBM). The use of UA previous to D-PBM enhances the GNP dispersion into the ceramic powder, increasing the GNP lubricating effect during the milling and therefore limiting its size reduction. The larger GNP can provide better crack inhibition mechanisms.


Coronavirus disease 2019 (COVID-19) is a declared global pandemic. There are multiple parameters of the clinical course and management of the COVID-19 that need optimization. A hindrance to this development is the vast amount of misinformation present due to scarcely sourced manuscript preprints and social media. This literature review aims to presents accredited and the most current studies pertaining to the basic sciences of SARS-CoV-2, clinical presentation and disease course of COVID-19, public health interventions, and current epidemiological developments.The review on basic sciences aims to clarify the jargon in virology, describe the virion structure of SARS-CoV-2 and present pertinent details relevant to clinical practice. Another component discussed is the brief history on the series of experiments used to explore the origins and evolution of the phylogeny of the viral genome of SARS-CoV-2. Additionally, the clinical and epidemiological differences between COVID-19 and other infections causing outbreaks  are elucidated.Emphasis is placed on evidence-based medicine to evaluate the frequency of presentation of various symptoms to create a stratification system of the most important epidemiological risk factors for COVID-19. These can be used to triage and expedite risk assessment. Furthermore, the limitations and statistical strength of the diagnostic tools currently in clinical practice are evaluated. Criteria on rapid screening, discharge from hospital and discontinuation of self-quarantine are clarified. Epidemiological factors influencing the rapid rate of spread of the SARS-CoV-2 virus are described. Accurate information pertinent to improving prevention strategies is also discussed.The penultimate portion of the review aims to explain the involvement of micronutrients such as vitamin C and vitamin D in COVID19 treatment and prophylaxis. Furthermore, the biochemistry of the major candidates for novel therapies is briefly reviewed and a summary of their current status in the clinical trials is presented. Lastly, the current scientific data and status of governing bodies such as the Center of Disease Control (CDC) and the WHO on the usage of controversial therapies such as angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen), and corticosteroids usage in COVID-19 are discussed.The composite collection of accredited studies on each of these subtopics of COVID-19 within this review will enable clarification and focus on the current status and direction in the planning of the management of this global pandemic. History of the outbreakOn 31st December 2019, Wuhan health commission in the Hubei province of the Republic of China notified the National Health Commission, China CDC and WHO of a cluster of 27 cases of pneumonia of unknown etiology  and that in 95% of all COVID-19 patients developed illness onset within 10 days . OutlierWang et al. (n = 138) showed that the median time from preliminary symptoms to dyspnea, hospital admission and ARDS was 5, 7, and 8 days, respectively. The median hospital stay was 10 days in patients that were discharged .Figure EpidemiologyAs of March 21, there have been 304,900 cases of which 94,793 have recovered and 13,001 have died . TherefoAs shown in Figure Countries with the highest mortality rates are Italy, Spain, Iran, France, and the USA . MortaliScreening toolThere are two prominent screening tools, one developed by the CDC and the other by the WHO. Both criteria charts have evolved over the progression of the outbreak. Table Diagnostic toolsOn 12th January 2020, the China CDC shared the genetic sequence of the SARS-CoV-2. This enabled countries to develop primers against the SARS-CoV-2 genome and utilize reverse transcriptase polymerase chain reaction (RT-PCR) assays to make a diagnosis of COVID-19. Therefore, RT-PCR has become the gold standard for the diagnosis of COVID-19, but it is only 66-80% sensitive . EssentiThe largest study (n = 1014) showed that CT-chest had a 95% sensitivity in making an early diagnosis of COVID-19 through the identification of ground-glass opacities . This caContrastingly, chest X-rays have poor sensitivity, but if there are ground-glass opacities then the patient must be isolated. The pathophysiology of this radiological finding is that the SARS-CoV-2 virus induces an inflammatory response in the alveolar sacs leading to the accumulation of exudative fluid. In the severe progression of the disease, this moves to the lobes and the radiological finding is a solid white consolidation.Laboratory examinationStandard blood investigations revealed that most patients with COVID-19 have normal or decreased leucocytes, and lymphocytopenia. Furthermore, there is a systemic elevation of the pyrogenic cytokines such as IL-6, IL-10, and TNF-α -24. In cManagementThe management of viral pneumonia is predominantly supportive amidst the absence of validated antiviral drugs. The most primary symptoms managed in COVID-19 are fever and non-productive cough, therefore the first-line antipyretic agent is Paracetamol and antitussive of choice is guaifenesin . SupplemIn the majority of the cases, public health measures are vital for the management of the spread of COVID-19. If public health measures for containment are not adequate, then there will be a patient burden that supersedes the capacity of available ICU beds and mechanical ventilation, as seen in the crisis taking place in Italy. Therefore, the entire objective of the COVID-19 management rests on the premise of social distancing to suppress the rapid emergence influx of new cases in a short time frame. This epidemiological concept is referred to as the “flattening of the curve”. The mainstay of public health must be to identify the infective cases, isolate these cases, attain contact tracing and isolate contacts that present with symptoms.Discharge criteria and quarantine discontinuationFour major discharge criteria exist, and these are from Italy , China (China CDC), USA (CDC), and Singapore . These models differ only in their cutoffs.The China CDC discharge criteria state that all four conditions must be met to satisfy a discharge from the hospital .1. A patient must remain apyrexic for at least three consecutive days.2. All respiratory symptoms  must be resolved.3. Chest CT must demonstrate marked resolution of the exudative lesion.4. Two serial RT-PCRs must be negative for SARS-CoV-2 RNA from the nasopharyngeal collection, these assays must be spaced by 24 hours.Quarantine discontinuation criteriaTwo separate quarantine discontinuation criteria for COVID patients in self-quarantined at home have been developed by Italy  and USA (CDC).The CDC quarantine discontinuation criteria state that both conditions must be met to satisfy the criteria .1. At least two serial RT-PCRs must be negative for SARS-CoV-2 RNA. These swabs must be nasopharyngeal collections, these assays must be spaced by 24 hours.2. The patient must remain apyrexic for at least 72 hrs without antipyretic medication use, and resolution of respiratory signs and symptoms. A minimum of seven days have passed since the preliminary symptom appeared.Prevention strategiesSelf-ProtectionHand washing for at least 20 seconds after visiting public spaces. Soap or hand sanitizer with at least 60% of ethanol is recommended . It is aAll healthcare workers managing COVID-19 patients require full personal protective equipment (PPE) containing surgical masks, double gloves, full-sleeved procedural gowns, and eye shield . The N95Containment of community transmissions is achieved by the closure of educational institutions, businesses, airspace, and sports events. High-risk individuals such as those older than 65 or having chronic comorbidities without any symptoms are also required to self-quarantine to decrease the likelihood of COVID-19 contraction .Herd ProtectionOn the development of any symptoms, the potential patient should remain quarantined in self-isolation away in a separate room with a separate bathroom for at least 14 days. This self-isolation must be extended to pets as well, as there is a recorded case of a human-to-dog transmission . If therRole of vitaminsVitamin CVitamin C (L-ascorbic acid) has a pleiotropic physiological role, but there is evidence supporting the protective effect of high dose intravenous vitamin C (HDIVC) during sepsis-induced ARDS. Vitamin C reinforces the maintenance of the alveolar epithelial barrier and transcriptionally upregulates the protein channels  regulating the alveolar fluid clearance . HDIVC hVitamin DVitamin D is known to mitigate the scope of acquired immunity and regenerate endothelial lining. This may be beneficial in minimizing the alveolar damage caused in ARDS. Level I evidence  showed that there is a 12% overall protective effect of vitamin D supplementation against bacterial and viral acute respiratory tract infection  . These pVaccinationUnfortunately, there is no approved vaccine against COVID-19 as of March 2020. One of the leading candidates is the mRNA-1273 vaccine manufactured by ModernaTx Inc . The mRNA-1273 is encapsulated within a lipid nanoparticle and encodes for a full-length, prefusion stabilized spike glycoprotein (S) of the SARS-CoV-2 virus. This vaccine is currently in Phase I, Open-Label, Dose-Ranging, clinical trial (NCT04283461) to evaluate the safety profile, reactogenicity, and immunogenicity in healthy subjects. The estimated completion time is June 2021.Novel therapeuticsCurrently, multiple avenues for therapies are being explored. Summarized below are some of the more prominent candidates.RemdesivirRemdesivir (GS-5734) is a nucleoside inhibitor that is the strongest candidate from COVID-19 treatment. Remdesivir is a monophosphoramide prodrug that causes premature termination of viral RNA replication and was originally developed against Ebola, MERS-CoV, and SARS-CoV. Furthermore, an in vitro study on human cell line (human liver cancer Huh-7 cells) showed potent interference of remdesivir with the NSP12 polymerase of SARS-CoV-2 despite intact ExoN proofreading activity . There aLopinavir and RitonavirThe protease inhibitors lopinavir and ritonavir combination is usually a part of the HAART regimen to treat HIV. The lopinavir and ritonavir combination has also been shown to be effective against SARS in vitro . The curUmifenovirUmifenovir is a non-nucleoside broad-spectrum antiviral licensed for influenza treatment and prophylaxis in Russia and China. It has not received FDA approval yet. Umifenovir is a membrane fusion inhibitor. Current regimens of Umifenovir used in China include a PO dose of 200 mg TDS for a duration of 10 days . One larChloroquineChloroquine is an anti-malarial medication. In viruses, chloroquine can inhibit pH-dependent stages of replication. Furthermore, chloroquine’s immunomodulation is dependent on the suppression of cytokines (IL-6 and TNF-α) production and dissemination. Moreover, experiments with monkey cell line (Vero E6) showed that chloroquine interferes with the receptor glycosylation and thereby affects the entry mechanism of SARS-CoV-2. This treatment was especially successful in the in vitro experiments with SARS-CoV-2 infection of a human cell line (human liver cancer Huh-7 cells) . InteresSecondary COVID-19 rates can be minimized with pre-exposure prophylaxis and post-exposure prophylaxis in an individual with document exposure to SARS-CoV-2. Therefore, hydroxychloroquine has been hypothesized to be an adequate chemoprophylaxis candidate to reduce secondary COVID-19. There are six clinical trials currently underway in Mexico NCT04315896), South Korea (NCT04307693), China , Spain (NCT04304053), Norway (NCT04316377), and USA (NCT04308668). The first Chinese study (NCT04261517) has shown positive outcomes in its preliminary data. Although the sample size is small (n = 30), this is still promising. The current Chinese guidelines recommend dosing of chloroquine as PO 300 mg or 500 mg (Chloroquine phosphate) BID for a duration of 10 days [15896, SoACE Inhibitor (ACEi) and Angiotensin Receptor-1 Blocker (ARBs)SARS-CoV-2 enters the type II pneumocytes via the ACE2 receptor, and this is also a functional receptor. The functional role of the ACE2 receptor has a reciprocal physiological action to ACE1, it converts the angiotensin II back into angiotensin I. Therefore, patients taking ARBs will have an increased plasma level of angiotensin II. Contrastingly, patients taking ACEi will have low levels of angiotensin II. There is an upregulation of ACE2 receptors in the kidney and heart in response to ACEi or ARB dosing in rats and humans -48. TherAntipyreticsIbuprofen has shown to upregulate ACE2 receptors . There iSystemic CorticosteroidsThe use of systemic corticosteroids such as glucocorticoid in the management of ARDS secondary to viral pneumonia is controversial. The rationale behind this approach is that the corticosteroids prolong the viral shedding time and maintain a systemic anti-inflammatory state that will minimize the precipitation of ARDS, dyspnea, and severe pneumonia. The WHO states that the use of corticosteroid is not recommended outside of clinical trials (NCT04273321) or otherwise indicated . MoreoveThis COVID-19 pandemic is a reminder of the volatility in the ongoing planning to manage the primary and secondary infection of SARS-CoV-2. This planning can be improved by accurate modeling of current data and by eliminating the misinformation in our era of data surplus. Additional variables that can strengthen countermeasure to this pandemic are rapidly updating surveillance data, availability of robust accredited information, and a multidisciplinary approach that bridges the gap in knowledge between basic sciences and clinical sciences.This literature review comprehensively summarizes the most relevant study relating to the individual parameters that influence the clinical course and management of COVID-19. Due to the lack of available and validated therapeutics, most of the countermeasures rely on the usage of public health containment and quarantine approaches. Primary learning points from this COVID-19 pandemic are to upheld transparency to prevent delays in threat identification. Secondly, delays in travel restriction and self-quarantine measures led to a logarithmic expansion of cases. Lastly, there is a need to increase investments towards research and development in COVID-19.


On 21 February 2020, ‘Luigi Sacco’ Hospital was identified as a Covid-19referral Hospital in Lombardy. The Department of Urology of our HealthcareInstitution consists of two Urology Units, one at ‘L.Sacco’ Hospital and one at ‘Fatebenefratelli’Hospital . The HealthcareSystem’s Administration communicated to all personnel the implementation ofa planned ‘biological risk protocol’ at the Covid-19 hospital, while theCovid-19-free hospital followed regular government recommendations. Weevaluated the risk of Sars-Cov-2 infection in the patients treated forsurgical or invasive urologic procedures during the epidemic in the twodifferent hospitals.At the Covid-19 hospital, 12 patients underwent surgery and 51 patientsinvasive diagnostic procedures between 22 February and 8 March 2020; in thesame period, at the Covid-19-free hospital, 21 patients underwent surgeryand 56 patients invasive diagnostic procedures. We compared the incidence ofSars-Cov-2 infection among the patients who were accessed in the two UrologyUnits in the period of different restrictive measures after the outbreak ofthe epidemic.We registered no cases of Sars-Cov-2 infection in the patients hospitalizedin that period in Covid-19 hospital, despite three cases of swab positivityin the Covid-19-free hospital.The early implementation of extraordinary measures to restrict the spread ofthe virus offers a good protection also in a Covid-19 referral Hospital. Theadoption of safety measures may be considered even after the end of thepandemic in all the health systems. An ‘Infectious Emergencyand Bioterrorism Unit’ was created in order toAfter the SARS epidemic (2003), ‘Luigi Sacco’ University Medical Center wasidentified as referral hospital of Northern Italy for activities regarding thebiological risk of infective epidemics, caused by natural events or bioterrorism,which might represent serious hazards to the population.Coordinate all the procedures for emergencies like Sars or Ebola;Keep an update inventory of the equipment useful in case of crisis;Organize courses for health care professionals;envelope filled withanthrax).Identify a 24-h available group of quick intervention in case of suspectedbioterrorism  is provided with 17 recovery beds adjacent to the 12operative theatres.Coronavirus disease 2019 (Covid-19) is a clinical syndrome caused by a novelcoronavirus called severe acute respiratory syndrome coronavirus 2 (Sars-Cov-2).2 On the night between 20th and 21st of February, ‘Luigi Sacco’s’ InfectiousEmergency and Bioterrorism Unit was sent to Codogno’s hospital to evaluate theso-called ‘Italian patient 1’. On the morning of 21 February, we were informed that‘Luigi Sacco’ Hospital was identified as a Covid-19 referral Hospital in Lombardyand thus all the planned procedures for an emergency were activated.On the evening of 20 February, the first Italian Covid-19 case was diagnosed inCodogno’s hospital, in Lombardy region.The 25 beds in the negative pressure rooms of the Infectious Diseases Department werefreed up moving all the patients to other departments. The ICU adjacent to the mainoperative theatres was closed and transferred to the ground floor of the InfectiousDisease Department and the ‘Covid-ICU’ became operational in few hours.In the early afternoon, two patients were admitted to the Covid-ICU . During the weekend, the InfectiousDisease Department only admitted Covid-19 patients coming from the wholeLombardy.37:Since then, the Hospital Administration has been communicating to all health carepersonnel the implementation of a ‘biological risk protocol’ with the followingmeasures to restrict the spread of the virusDedicated pathways in the Emergency Department for patients with fever orrespiratory symptoms (suspected Covid-19 cases);Proper use of individual protection devices (IPDs), like surgical masks,covers, gloves and so on for all doctors and nurses during the outpatientactivities and for patients coming from outside;Recommended frequent hands washing with antiseptics;Specific droplet precautions with the use of filtering face piece masks (FFP2or FFP3), water-repellent coats, safety visors/goggles, double gloves whenvisiting patients with clear or suspected respiratory syndrome, depending onthe specific medical activity;Restriction of visitors for hospitalized patients;Measuring the body temperature of all the patients hospitalized for surgicaland invasive procedures;Recommendations for patients’ transfer to the operating room ;Reduced activity of all surgical specialities with the suspension ofnon-urgent activities and the restrictions in scheduling the procedures thatare non-deferrable or urgent, mainly owing the availability ofanaesthesiologists who are engaged in the Covid-ICU.The Department of Urology of our Healthcare Institution  in Milan consists of two Urology Units, oneat ‘Luigi Sacco’ University Medical Center  and one at ‘Fatebenefratelli e Oftalmico’ Hospital , both led by the same Chief of Staff (A.G.). In bothunits, there are six Consultant Urologists.During the first 15 days, after the first Italian case of Covid-19, the planned‘biological risk protocol’ was immediately applied at the Covid-19 hospital, whilethe Covid-19-free hospital followed regular government recommendations.We included in this report all the patients who underwent to surgical or invasivediagnostic procedures in the two urology Units between 22 February and 8 March.At the Covid-19 hospital, 12 patients underwent a surgical procedure and 51 patientsunderwent invasive ambulatory procedures; in the same period, at the Covid-19-freehospital, 20 patients underwent a surgical procedure and 56 patients underwentinvasive ambulatory procedures. 8We evaluated the Sars-Cov-2 infection more than 15 days after the hospital discharge,considering that the average incubation period of COVID-19 is reported to be over5 days and 97.5% of people who develop symptoms do so within 11.5 days from infection.Between 23 and 27 March, we contacted by phone all the patients treated with surgicalor invasive procedures in the two Urology Units during the period when differentrestriction measures were adopted by the two hospitals.We interviewed the patients in order toAssess their health status after the urological procedures;To find out about possible respiratory symptoms, fever and an eventualdiagnosis of infection by Sars-Cov-2, appeared after hospital discharge.The aim of the evaluation was to compare the risk of infection between a Covid-19hospital adopting a strict biological risk protocol and a theoreticallyCovid-19-free hospital adopting standard safety procedures.10; consequently, none of themwere swab-tested, because swabs are only used on symptomatic patients according tothe regional diagnostic policy.No cases of Sars-Cov-2 infection were registered among the 63 patients who wereaccessed in the selected period in the Urology Unit of the Covid-19 hospital. Allpatients were free of symptoms attributed to Sars-Cov-2 infection Among the 76 patients hospitalized in the Covid-19-free hospital, 3 patients werepositive for Sars-Cov-2 infection.Two cases had mild symptoms and were sent home in quarantine, with activesurveillance. They underwent bilateral nephrostomy for advanced bladder cancer andureterolithotripsy for complicated renal colic, 6 and 9 days before the Sars-Cov-2positivity, respectively. One patient, who underwent transurethral resection of abladder tumour was re-hospitalized 11 days after discharge with a diagnosis ofCovid-19 pneumonia. Finally, we registered two cases of Sars-Cov-2 infection among the urologists fromthe Covid-19-free hospital .Today, all the north of Italy, in particular the Lombardy region, is fighting a realwar against a terrible enemy. The medical specializations gradually lost importance,because in several hospitals like ours, due to the shortage of specific specialists,such as infectious diseases’ specialist, pneumologist and anaesthesiologist,Covid-19 patients are managed also by other specialists such as general surgeons,urologists, orthopaedics, ophthalmologists and so on.When the virus out broke in northern Italy, probably the health care systemunderestimated the risks, and the initial idea of the local governments was toconcentrate the Covid-19 cases in just few hospitals. A few weeks later, due to theoutburst of the number of patients needing hospitalization and intensive care, itwas clear in Lombardy region that all public and private hospitals had to play acentral role in the management of the epidemic.We were wondering if the access to a Covid-19 hospital represented a severe risk ofinfection for patients hospitalized for other pathologies. We expected a higher rateof Sars-Cov-2 infection in patients who entered the Covid-19 hospital, than in thosewho entered the Covid-19-free hospital.Conversely, our evaluation indicates that we had more infections in a Covid-19-freehospital, with a late implementation of the security protocols. In fact, patientsoperated in the Covid-19-free hospital underwent also deferrable procedures, did notwear surgical masks during the hospitalization and the transportation to theoperating theatre, and had fewer limitations for visitors.That may suggest that the early adherence to strict safety protocols and the correctuse of IPDs can guarantee a safer pathway for the patients being hospitalized forurologic problems, even in a Covid-19 referral hospital.11Moreover, a lack of preparedness within the health care settings may be considered afactor promoting superspreading events.Possible biases of this report may be represented by the low number of patients andthe impossibility to demonstrate that Sars-Cov-2 was contracted during hospitalrecovery.However, in our opinion, it is mandatory to start defining protocols for all thepatients who will enter hospitals in the next future mainly for two reasons:First, hospitals can become an important spreading factor of the epidemic,especially in many countries still not following World Health Organisation’srecommendations on containment;Second, there is no defined scientific prediction to the end of the pandemic,and therefore it is necessary to restart a normal surgical activity, alsowith elective procedures, trying to guarantee patients a low infective riskduring the hospital stay.Relying on a wider range of cases with the design of surveillance models could ensuresafer pathways for all patients accessing hospitals, especially for those hospitalsnot directly involved in the treatment of Covid-19. This may improve ourpreparedness to fight the Sars-Cov-2, as well as future infectious diseaseoutbreaks.


The COVID-19 epidemic may elevate mental distress and depressive symptoms in various populations in China.This study investigates the levels of depression and mental distress due to COVID-19, and the associations between cognitive, behavioral, and psychosocial factors, and depression and mental distress due to COVID-19 among university students in China.A large-scale online cross-sectional study (16 cities in 13 provinces) was conducted among university students from February 1 to 10, 2020, in China; 23,863 valid questionnaires were returned. The Patient Health Questionnaire-9 was used to assess depression. Structural equation modeling was performed to test mediation and suppression effects.Of the 23,863 participants, 47.1%  reported high or very high levels of one or more types of mental distress due to COVID-19; 39.1% (n=9326) showed mild to severe depression. Mental distress due to COVID-19 was positively associated with depression. All but one factor  were significantly associated with mental distress due to COVID-19 and depression. Mental distress due to COVID-19 partially mediated and suppressed the associations between some of the studied factors and depression (effect size of 6.0%-79.5%).Both mental distress due to COVID-19 and depression were prevalent among university students in China; the former may have increased the prevalence of the latter. The studied cognitive, behavioral, and psychosocial factors related to COVID-19 may directly or indirectly  affect depression. Interventions to modify such factors may reduce mental distress and depressive symptoms during the COVID-19 epidemic. COVID-19 started in Wuhan, China in December 2019 . In ChinAlthough a number of studies have looked at the factors of depression during the COVID-19 period, fewer studies were conducted in the initial phase of the outbreak, which started after the Chinese government announced the disease’s person-to-person transmission property on January 20, 2020, and started the first controversial Wuhan lockdown 3 days after . To our Furthermore, the first COVID-19 outbreak occurred in China during the CNY, which involved high mobility, as billions of people were returning to their hometowns and, hence, created a high risk of spreading the virus to the entire country. Mobile populations have special relevance in this specific time and country context, one of which was university students, as the majority of students were studying in cities away from their hometowns. This study investigates psychological responses of depression and associated factors among university students in China from 10 to 20 days since COVID-19 was believed to involve person-to-person transmission. Our literature search found only four similar university student studies conducted during the same time period -14. ThreAlthough factors of depression during the COVID-19 period have been widely reported. There are still substantial research gaps that are being filled by this study besides the aforementioned fact that such studies were scarce during the initial weeks. Cognitive, behavioral, and psychosocial factors related to COVID-19 were all found to be potential determinants of depression -17. AlthAccording to the fear appeal theory, perceived threat comprises perceived susceptibility and perceived severity . The theMisconceptions that H1N1 could be transmitted via some unconfirmed modes of transmission such as waterborne transmissions increased perceived susceptibility, which was associated with mental distress . The assCOVID-19–related behavioral factors of depression are also important, as behavioral responses would occur during initial outbreaks of new emerging infectious diseases. An important and unprecedented response was staying at home during the CNY in China, keeping in mind that there were then no clear strict social distancing policies in China, and there was no penalty for going out in most Chinese cities. It is important to understand the level of staying at home during the critical initial outbreak phase, as it had contributed to the control of COVID-19 in China by reducing social contacts. Research has found that quarantine was positively associated with depression , but staPotential psychosocial factors related to COVID-19 may be associated with mental distress at the community level. For instance, perceived discrimination is a risk factor of depression  and has Mental distress due to COVID-19  is potentially associated with depression. It is understood that prevalence of depression among university students prior to the COVID-19 outbreak was not low; not all depressive symptoms were caused by COVID-19 although the pandemic could have inflated the risk of depression. This study thus has the novelty of measuring both general depressive symptoms and the level of self-reported mental distress directly attributed to COVID-19, based on a scale used in understanding mental distress due to SARS and H1N1 ,34,35. IAnother research gap is that few studies have looked at the mechanisms between COVID-19–related factors and depression during the pandemic period. According to the common sense model of illness representation, cognitive perceptions, how a person feels about a disease , and their coping responses such as behavioral responses would determine health outcomes, including mental health status ,37. Thuscognitive factors , behavioral factors , and psychosocial factors  related to COVID-19. We further tested the hypothesis that mental distress due to COVID-19 would mediate between the aforementioned cognitive, behavioral, and psychosocial factors, and depression. The literature has not reported similar studies.This study investigates the level of depression among 23,863 university students of 26 universities located at 16 cities in 13 provinces of China 10 days after the official recognition of person-to-person transmission by the Chinese government and during the 8th to 17th days of the CNY in China, which was the initial rising phase of COVID-19. Based on the literature search, besides background and contextual factors, this study investigates the associations between the following factors and both mental distress due to COVID-19 and depression: lucky money (red pocket) of ¥1 (about US $ 0.15).This cross-sectional study was conducted during the 8th to 17th days of the CNY . Data were collected from 26 universities of 16 cities in 13 out of the 32 provinces, municipalities, and autonomous regions in the country. A total of 681 classes were sampled by convenience within a number of faculties . The median number of students selected per university was 1165 (IQR 2271). All students of the selected classes were sent a QR (Quick Response) code through Wechat to access an anonymous online questionnaire that took about 10-15 minutes to complete. They were informed about the study’s background, anonymity, restriction to academic use, and that return of the completed questionnaire implied informed consent. A lucky draw gave out five prizes of ¥50-¥200 (about US $7-$28) per city, while half of the students randomly received a symbolic CNY A total of 36,560 invitations were sent out; 25,647 completed questionnaires were returned, 1197 (4.7%) of which did not pass the consistency checks and were excluded from data analysis together with 47 (0.2%) others who were diagnosed COVID-19 positive, 515 (2.0%) who were quarantined, and 25 (0.1%) who were outside mainland China. The effective sample size was 23,863 (93.0%). The response rate was 70.2% .The study was approved by the Survey and Behavioral Research Ethics Committee of the Chinese University of Hong Kong (No. SBRE-19-400).Personal background information included sociodemographic data , school-related information , and self-reported physical health status.shut down by the local government during the CNY, and the number of confirmed COVID-19 cases detected in the provinces that the participants’ localities belonged to.Contextual factors included living arrangement during the CNY , whether staying with their families at the time of the survey, whether their localities of stay were Depression was assessed by using the Patient Health Questionnaire-9 (PHQ-9). It has been validated in Chinese populations and has shown good psychometric properties . The iteThree items were used to assess the levels of mental distress due to COVID-19 . The items were rated with a four-point Likert scale ; higher levels of the summative score indicate higher levels of mental distress due to COVID-19. The summative scale has been used in a number of H1N1 studies ,8. The Cairborne transmission stated “COVID-19 can be transmitted long distance through air” ; the responses were recoded into two groups . Second, three items were used to assess the levels of perceived infection risk of COVID-19 in the coming year for oneself, family members, and classmates ; the responses were recoded into two groups . The Perceived Infection Risk Indicator was then formed by counting the number of ones (range of 0-3). Third, the item on perceived permanent bodily damage stated “COVID-19 will easily cause severe permanent bodily damage” ; the responses were recoded into two groups . Fourth, the item perceived chance of controlling the COVID-19 epidemic in China stated “What is the chance that the COVID-19 epidemic will be controlled in China in the coming six months” ; the responses were recoded into two groups .First, the item on staying at home item assessed the total number of hours spent out during the 7-day CNY . Second, the item close contacts with people who had visited Wuhan asked “Have you closely contacted people who had visited Wuhan within the two weeks before CNY?” The response was recoded into two groups .First, the One item assessed the level of perceived discrimination encountered due to COVID-19 .P<.05.The summative score of the PHQ-9 was used as the continuous dependent variable. The associations between the background personal variables, contextual variables, and depression were analyzed by simple regression models; Spearman correlation coefficients were derived to assess the correlations among the studied cognitive, behavioral, and psychosocial factors; the potential mediator ; and the dependent variable . Collinearity diagnosis of the aforementioned independent variables and mediators was conducted by examining the variance inflation factor (VIF); a VIF value greater than five would suggest existence of collinearity. By using structural equation modeling (SEM) with maximum likelihood estimation, the potential mediation and suppression effects of mental distress due to COVID-19 between the cognitive/behavioral/psychological factors and depression were tested, adjusting for all studied background personal and contextual variables. Three latent variables were created for the SEM analysis: perceived infection risk , mental distress due to COVID-19 , and depression . The random parceling approach has been recommended for SEM analysis . Other iDescriptive statistics are presented in Regarding psychological responses, 47.1%  reported high or very high levels of one or more types of mental distress, panic , anxiety , or emotional agitation  due to the COVID-19 epidemic; the composite variable of mental distress due to COVID-19 summed up the item scores of these three types of responses. The mean was 6.9 . Furthermore, about 40% of the participants showed mild to severe depression . The mean of the PHQ-9 score was 4.6 . Several contextual factors were significantly associated with lower risks of depression, including staying in the city of the university, staying with family, and self-perceived physical health, while the number of confirmed cases (>300 cases) detected in the province where the participants were staying at the time of the survey was positively associated with depression symptoms . Whether the city had been shut down was, however, not associated with depression. The background variables were adjusted for in the SEM analysis.The associations between background variables and depression are presented in r=0.11, P<.001), having close contacts with people who had visited Wuhan 2 weeks prior to the CNY , perceived discrimination due to COVID-19 , and mental distress due to COVID-19 . Some variables were negatively correlated with depression, including perceived chance of getting the epidemic under control in China within 6 months  and staying at home . Perceived airborne transmission  and perceived permanent bodily damage  were not significantly associated with depression; mediation analyses were hence not performed for these two associations . No collinearity was detected with the VIF values of all studied variables ranging from 1.00 to 1.37 (VIF>5 indicates the existence of collinearity). In P<.001), between perceived discrimination and depression , between perceived chance of epidemic control and depression , and between staying at home behavior and depression . The nonsignificant mediator was close contacts with people who had visited Wuhan (Sobel test P=.32). The beta values are shown in The SEM model’s fit index was satisfactory ; the range of factor loadings for the three latent variables was 0.70-0.97 . This study identifies a number of significant COVID-19–related cognitive , behavioral , and psychosocial  factors of both mental distress due to COVID-19 and depressive symptoms; nonsignificant factors included perceived airborne transmission and perceived permanent bodily damage. As expected, mental distress due to COVID-19 was significantly and positively associated with depressive symptoms; it further mediated the associations between some of the cognitive/behavioral/psychosocial factors and depressive symptoms. The findings present a rough snapshot of what happened in the country and shed light on how people may react emotionally to new emerging infectious diseases and how various types of responses  would be associated with such emotional responses.The COVID-19 pandemic has affected people’s mental health. The findings of this study reveal prevalent mild to severe depression in 40%  of university students in China, according to the PHQ-9. The prevalence obtained from studies among university students in China prior to the COVID-19 period seemed lower , but suDepressive symptoms were prevalent among university students at the initial phase of the COVID-19 outbreak in China; this can be seen from the high levels of self-reported mental distress directly attributed to COVID-19, which is understandable, as uncertainties and the Wuhan lockdown were alarming and worrisome. Furthermore, mental distress due to COVID-19 was positively associated with depressive symptoms. Thus, the mental distress directly attributed to COVID-19 might have increased the already high level of depression among university students during the initial phase of the epidemic in China. As mental distress and depression affect preventive behaviors , and acuuniversity’s city or with family members were less likely than others to be depressed. They might have received better support from their significant others, and social support and coping resources are protective against mental health problems [province they were located in was positively associated with depression; it is plausible that the perception might increase perceived susceptibility and perceived severity of the epidemic and thus depression. It is interesting that travel restrictions on entering and exiting from the city of stay, which was then a new preventive measure, was not significantly associated with depression. The findings suggest that such drastic restriction, if implemented orderly and with good support, does not necessarily cause substantial panic or negative impacts on mental distress. A number of countries implemented even more severe lockdowns such as bans on going out soon after the completion of this study , which was followed by many other countries . In some countries, the strict social distancing measures were associated with depression [new measure and identify ways to minimize its adverse mental health effects. This study hence documents the initial responses to preliminary lockdown measures in the COVID-19 pandemic.The context of this study was unique and relevant, as it was conducted during the CNY and soon after the first outbreak and lockdown in Wuhan. It can be seen that students who stayed in the problems ,46. The pression ,47. FutuThis study has interesting findings that involve interpretations in the context of the initial outbreak and in comparison with other studies. Spearman analysis and the SEM showed that some COVID-19–related cognitions (perceived chance of controlling COVID-19 and perceived risks of infection) were significantly associated with both mental distress due to COVID-19 and depressive symptoms; such findings corroborate with other studies ,20-23. HThe behavioral factors of self-reported mental distress due to COVID-19 and depressive symptoms also illustrated the uniqueness of this study. The duration of staying at home during the CNY was protective against depression, which has not been reported in the global literature . HoweveWuhan virus. Travelers might be regarded as potential carriers of the virus; discrimination found a fertile ground to grow and might have a powerful negative effect on mental distress. It is imperative to investigate whether perceived discrimination related to epicenters has caused mental distress in the later phase of the pandemic. For instance, there were over 22 million detected cases in the United States as of January 10, 2021, and a new viral strain of higher infectivity was found in the United Kingdom where the incidence of COVID-19 is soaring. The level of perceived discrimination and its association with depression might be country specific due to politicization. When facing outbreaks of new emerging infectious diseases in the future, stigma needs to be removed from the location of the outbreak. The effects of the generalized perceived discrimination need to be investigated.This study also investigated the psychosocial factor of perceived discrimination. Over half  of the participants perceived discrimination related to COVID-19, possibly because of their traveler status. Associations between perceived discrimination and depression were similarly reported in previous studies related to SARS and H1N1 . In factThis is one of the few studies that looked at the mechanisms behind the associations between COVID-19–related factors and depression during the COVID-19 period. The findings suggest that COVID-19–related cognitive, behavioral, and psychosocial factors, and mental distress directly attributed to COVID-19 were all associated with depression, while the relationships between some of the COVID-19 cognitive, behavioral, and psychosocial factors, and depression may be partially mediated and suppressed through mental distress due to COVID-19. Specifically, perceived risk and perceived discrimination may have an indirect effect on depression via mental distress due to COVID-19; such risk factors might have increased mental distress due to COVID-19, which would in turn increase risk of depression. In addition, confidence in controlling the epidemic and staying at home could potentially be protective against depression via reduction of mental distress due to COVID-19, which was in turn positively associated with depression. Interventions to improve these cognitions or preventive behaviors may thus reduce depression directly or via reduction of mental distress due to COVID-19. Moreover, the mediation and suppression model presented in national scenario. This study has some limitations. First, it did not have national coverage. Selection bias may exist, as classes and departments were not randomly selected. Second, we did not cover important interpersonal factors , which were associated with many health-related behaviors [This study has the strength of covering a large number of university students who were staying in most of the provinces in China. The data thus presents a crude ehaviors ,51. ThirThe findings suggest that mental distress due to COVID-19 and depression were prevalent among university students in China during the initial COVID-19 outbreak period. The former may have further increased the prevalence of the latter. Various cognitive, behavioral, and psychosocial responses to COVID-19 showed both direct and indirect effects  on depression. Thus, interventions to improve such multidimensional factors might reduce mental distress during the initial COVID-19 outbreak period. The associations between some of the studied factors and depression may change over time as more information and experiences were obtained by the public, signifying early investigation of community responses to avoid mental distress, which would carry over to later phases and affect prevention behaviors. Some of the findings may shed light on handling new emerging infectious diseases that occur in the future. It is important to validate the findings in general and specific populations in China and in other countries.