Bio-secure bubble protocol and investigate the consequences of spectators/fan attendance at such mass events during the ongoing COVID-19 pandemic in Qatar.Background: Elite professional sports events involving mass gatherings carry a high risk of viral transmission during the coronavirus disease of 2019 (COVID-19) pandemic. We describe the potential impact of resuming professional football leagues involving international participants adhering to a strict Bio-secure bubble protocol. It included extensive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RT-PCR (reverse transcription-polymerase chain reaction) every 3–6 days and clinical symptom monitoring on and off the field. Target variables included positive RT-PCR results and clinical symptom monitoring among participants, and rapid antigen testing for fan attendance to examine their safe return to the stadiums.Methods: We conducted a descriptive cohort study involving football players, referees, match officials, local organizing committee (LOC) members, hotel and security staff working in close coordination, and over 10,000 spectators from the Asian Football Confederation (AFC) Champions League (East) and the final match. The study covered almost four weeks of the event  under a robust Bio-secure bubble were done over one month for all the AFC (East) matches, including the final match. Overall, 44 matches involving 16 teams were played. During the championship, only five individuals  returned positive for COVID-19 infections. Four individuals  had reactive results. None of the players tested positive for COVID-19 infection. All individuals testing positive were asymptomatic or had mild symptoms, with no one requiring hospitalization other than symptomatic treatment. The overall positivity rate was 0.15% for the entire duration of the AFC (East) Champions League. For the final match, a total of 10,320 rapid antigen tests were done for spectators, of which only one test was positive for COVID-19.Results: A total of 12,250 RT-PCR tests involving 3158 individuals in the Bio-securebubble protocol has been implemented.Conclusions: This report shows a very low incidence rate of COVID-19 infections during mass gathering events at the international level. For the resumption of football with spectators, careful mitigation strategies should be considered to reduce the risk of transmission to a sufficiently safe level. This may require proper coordination and measures . Based on this, during the ongoing COVID-19 pandemic, the supervised and controlled resumption of football matches with spectators can be done safely provided that a strict  COVID-19 is an infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus with various symptoms ranging from mild to severe illness. Following the COVID-19 outbreak, by April 2020, the health authorities and governments of several countries declared confinement measures to decelerate the disease propagation, which resulted in the suspension of all professional sports training and elite competitions..In March 2020, the World Health Organization (WHO) declared the coronavirus disease of 2019 (COVID-19) a pandemic. while producing having significant health and socioeconomic effect on the host nation(s), including an increased risk of infectious disease transmission. Therefore, pandemics like COVID-19 have brought an added earnestness to assess the impact of hosting large sporting events. Due to the global outbreak of the COVID-19 pandemic, Qatar's professional football leagues were also interrupted after March 2020. With each passing day, more information about viral transmission mechanisms is emerging and becoming more apparent. Preventive measures have become the mainstay of addressing individual-level risk control. However, these measures sometimes become impractical and difficult to implement when dealing with sports involving mass gatherings and elite athletes, making physical distancing challenging to follow. It also involves international travel and spectators, further potentiating the risk of viral spread.There has been increasing debate about the desirability of professional football resumption during the COVID-19 pandemic. These professional football tournaments involving international participants provide mass spectacles for the public Qatar, a country in the Arabian Gulf with a total population of 2.8 million, has also played an instrumental role in building confidence among players and spectators alike. It safely hosted a couple of football tournaments with players and spectators in attendance with infection control measures. In May 2020, the Qatar government created a task force composed of sports physicians, scientists, and healthcare professionals under one umbrella to allow the resumption of the football league and implement a return-to-competition protocol. It was a massive challenge considering that the WHO suggested that hosting an event involving a mass gathering during the active phase of the ongoing pandemic be of very high risk.Over almost one and a half years, the global football community has worked diligently to find solutions for the sport's safe return amidst the global COVID-19 pandemic, and in the second half of 2021, it appears that the great sports freeze has thawed.Bio-secure bubble system by including many team competitors for several sports events with spectators during 2020 and 2021. The successful and safe return of the continental football league in Asia was marked by the initial west group stage matches of the AFC competition, played without spectators, under strict adherence to Bio-secure bubble protocol. A Bio-secure bubble is a sanitized area that operates in a strictly controlled environment involving the interaction between a specific set of people, all of whom need to test negative for COVID-19 by the reverse transcriptase-polymerase chain reaction (RT-PCR) test. The isolated space remains closed to outsiders. Nobody can leave or enter once the bubble is in effect. The Bio-secure bubble system included regular COVID-19 testing, safe transportation methods, and regular disinfection of tournament venues, including training and media facilities for the safe and efficient return of the first professional football league involving spectators. Under this protocol, Qatar hosted 60 West Zone matches in the 2020 AFC Champions League successfully and safely. It boosted the organizers’ confidence to host 44 AFC Champions League (East) matches in November and December 2020, apart from the final, which saw more than 10,000 spectators’ safe attendance. The event welcomed and marked the safe return of spectators to the sporting arena. Requirements expected of the spectators included double vaccination (second vaccine at least 14 days before), a recent negative PCR test, recovery from COVID-19 infection (14 days before), physical distancing , Qatar has hosted the Asian Football Confederation (AFC) Champions League West and East Zone matches, including the final, the Amir cup in 2020. In February 2021, it concluded with hosting the FIFA  Club World Cup (FCWC), with spectators permitted to attend and stadiums operating at 30 percent capacity. Qatar has become one of the first countries to implement an expanded Bio-secure system. We also report the consequences of the operational plans undertaken for the resumption of the international football league with spectators in stadiums for the first time in Qatar during the active phase of the COVID-19 pandemic.There is a gap in the existing literature about the impact of mass outdoor events like football matches involving intercontinental participation and patterns associated with spectator attendance on the possible spread of COVID-19 infections. From a public perspective, the resumption of football and other mass gathering events along with spectators by implementing multifaceted infection risk mitigation approaches is imperative, as football represents such a significant mass outdoor hobby across many Middle Eastern countries and worldwide. This study describes the success of the return-to-competition protocol, involving the clinical and safety measures implemented in the Supplementary Table).This is an observational cohort study including players, staff, and referees of the AFC Champions League 2020 (East Zone), Qatar Football Association (QFA), along with local organizing committee (LOC) staff, hotel staff, state security personnel outside the Bio-secure bubble system and the spectators. The AFC Champions League (East) and its final match were held from November 18 to December 19, 2020, in Qatar. Each team typically consisted of 45–60 persons, including players, staff, and family members. The AFC (East) Champions League included 16 teams over 30 days, with the first match on November 18 and the last game played on December 13, 2020, and the final match played between the champions of the AFC (West) and the AFC (East) on December 19, 2020. This article follows the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist , created a task force composed of sports physicians, scientists, and government officials to develop guidelines to resume football activities. This task force established a framework based on scientific evidence to reduce the health risks of returning to international professional football amidst the ongoing COVID-19 pandemic. A robust and strict protocol was implemented wherein players, and officials were part of a strict “Bio-secure bubble.” This limited their movement only to and from their designated accommodations, stadiums, and training sites. Each team was assigned a dedicated meeting room with a seating arrangement plan to ensure physical distancing for team meetings. Food and refreshments were served to each player/official/staff in their rooms. Every team had a pre-scheduled time for gym sessions for physical training-related activities. All pieces of equipment were sterilized before and after use. Individuals under the same bubble were not permitted to contact anyone outside their bubble.Upon arriving at Hamad International Airport, all international players and tournament officials were tested for COVID-19 infections. Participants completed their immigration process through dedicated counters and were transported to their accommodations. Participants were quarantined in their hotel rooms until their test results were confirmed as negative to participate in the event. After they arrived at their designated accommodation/hotels, players and tournament officials were placed in a “The bubble protocol mandated that all teams be transported in small groups at a maximum of 50 percent vehicle capacity using alternate seats and maintaining the 1.5 meters separation distance. All stadiums were equipped with medical clinics and a medical staff team to ensure a swift and well resourced, frontline response during the tournament. All medical staff was tested for SARS-CoV-2 virus by RT-PCR, 24 hrs. before the match and were not a part of the Bio-secure-bubble protocol. Stadiums also had a dedicated isolation facility to hold individuals exhibiting COVID-19 symptoms or requiring medical assistance. Players and team officials underwent regular temperature checks throughout the tournament before entry into tournament-related venues. All players, support staff, and officials were required to adhere to these measures; violations were subject to disqualification from the league. The test is highly sensitive and specific to SARS-CoV-2 viral RNA. All international participants  were required to have a negative PCR test for COVID-19 infection within 48–72 hours before entering the country. For national participants, testing was performed 1–2 days before entering the bubble hotel or 1–2 days before the competition. Subsequent swabbing for COVID-19 PCR testing was undertaken from all participants every 3–6 days until the individual participated in the event.The current gold standard for detecting the presence of COVID-19 infection is the PCR test.The AFC (East) Champions League marked the partial return of spectators. Ticket allocations were limited to 30% of the overall capacity of each stadium. Crowd management poses the most significant challenge during sporting events. The AFC (East) Champions League made special arrangements to mitigate COVID-19 transmission during the event by implementing physical distancing measures, such as reducing the overall number of attendees, using mobile ticket sales, and staggering and controlling the arrivals and departures. All spectators had to undergo rapid antigen tests up to 72 hours before each match at approved facilities designated by the MoPH. Only spectators with negative SARS-CoV-2 antigen tests were allowed to attend the match. Before entering the stadium, an initial health screening such as a temperature check was conducted on each spectator. All spectators had to wear a facemask throughout the event. Seating inside the stadiums was staggered to provide adequate physical distancing, and spectators were spaced apart by at least 1.5 meters in all directions to avoid crowding . Family  was used on a Hamilton Microlab STAR , and aliquots were tested with the AccuPower SARS-CoV-2 Real-Time RT-PCR Kit  on an ABI 7500 FAST, or loaded directly into a Roche Cobas® 6800 system. Next, they were assayed with the Cobas® SARS-CoV-2 Test . The results were interpreted as per the manufacturer's instructions based on the respective cycle threshold (cT) of the gene target amplified. Results were reported based on the cT value either positive (cT < 30), reactive (40 > cT > 30), negative, or inconclusive. Reactive samples were defined as cases where the possibility of transmitting the infection was relatively low. The average time required from when the sample was taken for PCR testing to the validation and availability of results was approximately six hours.Following standardized protocols, all PCR analyses were performed at the Communicable Disease Centre Laboratory. Nasopharyngeal or oropharyngeal swabs  were collected. All assays were pre-validated before routine use. PCR testing was performed on aliquots of Universal Transport Medium. Aliquots were extracted on the Qiagen (QIA) symphony platform  and tested with real-time reverse transcription PCR (RT-qPCR) using the TaqPath COVID-19 Combo Kit  on an ABI 7500 FAST . Then, a custom protocol The test provides specificity of 99.2% and a sensitivity of 95.5%  with a testing time of 15–30 minutes. Test results were analyzed and interpreted as per the manufacturer's instructions. In the current study, the sampling was conducted to diagnose COVID-19 through rapid antigen testing among the spectators. All antigen testing was performed at two approved facilities designated by the MoPH, i.e., the Al Shahaniya Workers Camp and Qatar National Convention Centre, maintaining proper physical distancing. All the testing arrangements for spectators were organized for them by the Supreme Committee of delivery and legacy. An outline of the Rapid Antigen Testing protocol is illustrated in The SARS-CoV-2 rapid antigen test is a reliable, chromatographic immunoassay for the qualitative detection of specific antigens of SARS-CoV-2 in the human nasopharynx. Additionally, team physicians also communicated the test results to the players and team officials. If any player/team official, LOC, or hotel staff was positive for COVID-19 infection at the hotel, they were immediately isolated in their room. The compliance officer, a medical doctor, and an accommodation lead were informed about ascertaining contact tracing. Anyone tested positive for COVID-19 infection inside the stadium or en route to the stadium was immediately removed, transported to an isolation facility, and PCR tests were repeated within 48–72 hrs. The COVID-19 positive individuals were retested on day three and day nine and, if tested negative or reactive, were released from the isolation facility on day 10. However, if the results were positive, the patient continued in isolation until 14 days. Discharge certificates and negative PCR certificates were issued to the participants before their departure. In cases of inconclusive reports, players and event officials continued to the matches and training sites until the availability of the retest results. The departure protocol required all participants to take a COVID-19 test 48 h before departure. The test results and certificates were emailed individually to team doctors, the AFC committee, referees, and individual email addresses for media and guests.All COVID-19 specific PCR results for the event officials  were made available via the national COVID-19 tracking phone application (EHTERAZ), which is mandatory for all Qatari citizens and residents as one of the measures implemented in Qatar to control the spread of the virus.data.gov.qa), which furnishes open access to important statistical information from government entities.By the time the AFC (East) championship and final matches were organized, the incidence of ongoing COVID-19 infections in Qatar had stabilized, with a gradual decline in the daily COVID-19 positive cases being recorded . During The incidence of COVID-19 infections, if any, during the AFC (East) Champions League was documented to determine the effectiveness of the Bio-secure bubble protocol on the recommencement of professional football tournaments. Besides, some players and team members regularly joined and left the team as the championship progressed. The AFC conducted 12,250 PCR tests over one month by working closely with the QFA, the medical teams, and the LOC. Altogether, 3158 individuals were tested at least once, with an average of four tests per person throughout the championship.There were five PCR positive and three reactive cases during the championship involving match officials (n = 2) and LOC (n = 3) members. None of the players and referees tested positive for COVID-19. Local medical authorities and team doctors followed up on all positive cases. The overall positivity rate for COVID-19 among the individuals involved in the championship was 0.15% during the tournament, as shown in In the current study, to diagnose COVID-19 among the spectators, all the rapid antigen testing was performed at two approved facilities designated by the MoPH in which proper physical distancing was maintained. A total of 10,320 rapid antigen tests were done for the final match. Only one (n = 1) spectator returned a positive result for COVID-19 infection during the final event.Notably, no spike in COVID-19 cases was detected within a week after the football match. Hence, there might not have been any significant (if any) transmission of the virus among spectators.Bio-secure bubble protocol, by successfully hosting the AFC Champions League West and East Zone matches up to the final itself.Qatar was one of the first among Middle Eastern countries to implement a robust Bio-secure bubble protocol for the resumption of intercontinental professional football with spectators. Qatar set the benchmark in hosting tournaments involving multiple international teams, across various venues, and under a strict Bio-secure bubble protocol and a gradual return of a limited number of spectators in stadiums were not associated with COVID-19 infections under the epidemiological circumstances prevailing during November and December 2020 in Qatar. A comprehensive safety net of expert planning, vigorous testing, and medical protocols was implemented for the AFC Champions League (East) held in Qatar to ensure the health protection of all stakeholders, including players, match officials, and spectators. The extensive PCR-based surveillance during the Bio-secure bubble protocol demonstrated no evidence of club-to-club or community transmission. During the entire championship, our extensive surveillance program proved that elite intercontinental football could be safely resumed during a pandemic with strict adherence to a Bio-secure bubble protocol that mitigates the transmission risks among players, staff, and local personnel, Implementation of this protocol also had significant financial implications regarding the high costs involved for performing all Bio-secure bubble-related operational measures.This is the first study from the Middle Eastern region to report the consequences for the players, spectators, and hosting country of a controlled resumption of the international football championship league amidst the COVID-19 pandemic. Our study demonstrated that the resumption of professional football under strict adherence to the  The authors reported eight positive cases of COVID-19 infections among 1079 players (0.74% positivity rate) and four positive cases among 623 match officials over nine weeks (May to July 2020). Overall, they reported only 12 positive cases (0.7%) among 1702 regularly tested individuals. They also observed a population infection rate of only five per 100,000 per week among the general population during the event. In our study, none of the players returned positive test results. We found five PCR positive or reactive cases (0.15% positivity rate) among 3158 individuals tested during the championship period.Our findings are consistent with those from the German Bundesliga professional football league. They reported a successful return of the game under a controlled environment with a diminished risk of viral transmission., and there may be a possibility of involvement of some indirect methods. However, we must acknowledge that even in countries where the surge of COVID-19 infections has initially been contained, a subsequent wave of new infections involving new strains has been reported. The Bio-secure bubble protocol ensures more robust infection mitigation measures in such a scenario. It assumes greater importance in creating the safest possible environment for the return of professional football competitions.It should be noted that the football league was organized at a time when there was low community incidence rate , and the incidence of the COVID-19 had stabilized in Qatar since March 2020. Furthermore, the incidence in the community steadily declined to six per 100,000 persons at the end of the tournament . Also, it is worth mentioning that more than 99% of the participating players and other officials maintained their negative COVID-19 status during the championship league, indicating that no transmission of SARS-CoV-2 had occurred. This agrees with the observation that disease transmission during match play itself is not very high had reported that 85 subjects (6.4% positivity rate) returned positive for COVID-19 among 1337 participants , of which 36 (2.7% positivity rate) were players. As a part of the Qatar Sports League, this event was hosted without spectators between June 8, 2020, and September 2, 2020, in Qatar. The infection rate of COVID-19 was high at that time  and was consistent with that of the general population during the same period. The high positivity rate of COVID-19 infection among players and others in this study could be because the event was being played during the very active phase of the COVID-19 pandemic when the transmission risk was relatively higher. In mid-May–July 2020, COVID-19 cases in Qatar were doubling every week, suggesting that Qatar was on a transmission trajectory similar to many European countries. In late June 2020, however, daily case numbers began to plateau in Qatar, and by early November 2020, cases were dramatically reduced. We cannot extrapolate our study's findings to other settings, as the data presented in our study corresponded to when the COVID-19 incidence rate had stabilized in Qatar. The risk of infection transmission was relatively low in the general population. Nevertheless, it is imperative to pinpoint the importance of following a close vigil on the hosting country's prevailing safe epidemiological conditions when implementing a return-to-play protocol designed to mitigate the risk of SARS-CoV-2 transmissions.A previous prospective cohort study in Qatar by Schumacher et al. In the present study and a previous report, most individuals who tested positive for COVID-19 were young, asymptomatic, experienced mild symptoms, and had no significant comorbidities.In our study, no player, staff member, or match official required hospitalization or urgent medical treatment following the diagnosis of COVID-19 infection other than symptomatic treatment. They only manifested mild symptoms . Our data are consistent with the findings from previous sports events conducted in Qatar. other than football have documented the transmission of COVID-19 cases during these events. As such, evidence is still lacking on whether COVID-19 measures and the impact of the virus on fan presence can mitigate the super-spreader nature of mass sporting events. One study showed that following a day after an indoor hockey match in Florida, USA (July 2020), a player was infected with COVID-19 infection, ultimately transmitting it to other players and staff. Fifteen of 22 players and one rink staff member tested positive or experienced symptoms. Another study revealed a cluster of five COVID-19 cases linked to playing squash at a sports venue in Maribor, Slovenia. It was assumed that the transmission occurred indirectly through contaminated objects in changing room or squash hall or via aerosolization in the squash hall. A US study found that each National Basketball Association and National Hockey League game in March 2020 contributed to 380 more COVID-19 cases and 16 more deaths per one million people in the counties where these events occurred. AFC Champions League resulted in only a few COVID-19 positive cases because matches were played in outdoor settings, where physical contact between the players was limited and brief.Since the outbreak of the COVID-19 pandemic in 2019, few reports of sporting events and Cardazzi et al. determined the impact of sporting events as super-spreaders. Ahammer et al. looked at mass indoor events during the COVID-19 pandemic and found that these events led to around 380 more COVID-19 cases and 16 more deaths per one million people. Currently, there is a lack of evidence on the impact of spectators’ attendance under a controlled environment on the mass sporting events during the COVID-19 pandemic. During the championship league's final event, only one spectator returned with a positive result for COVID-19 infection after rapid antigen testing. The case was detected before he/she could attend the match and hence never went to the stadium. A study with a similar intent looked at the impact of the virus's spread from English football matches played in February and March 2020, before the first national lockdown. The evidence suggested that regardless of how full the stadiums were, the health outcomes after an English football match in March were consistent; for every 100,000 people in the same local area, there were six COVID-19 cases, two deaths, and three overall deaths. In contrast to the above findings, our study has shown that when multilayered protection involving physical distancing, disinfection, communication, and crowd control is strictly implemented, it is possible to resume professional football with limited spectators in stadiums amidst the COVID-19 pandemic. Also, results suggest caution in returning to spectator attendance at matches. In our setting, the final match of the AFC East Championship was played with 30% attendance.Outdoor events, such as professional football involving mass gatherings, can act as super-spreaders of an airborne virus like COVID-19. Moreover, there are unprecedented challenges to COVID-19 mitigation strategies in stadiums due to the involvement of many factors, such as the high number of spectators, seating proximity, and the high level of contact between athletes. Ahammer et al.Despite studies showing that antigen testing is accurate for detecting positive COVID-19 cases, no factual inference can be drawn from the current data regarding the potential risk of SARS-CoV-2 transmission during activities involving spectators due to the possibility of false-negative results. The latter is likely to raise testing concerns. Any positive antigen result will necessitate a PCR confirmation test, but a false-negative antigen test could theoretically open the door for the overlooked spread of the infection. Other spot confirmatory tests  on random negative antigen samples can be a safeguard; however, it is cost-ineffective to do both tests for almost all spectators. Daily testing should be done as an added layer of surveillance protection when we intend to include spectators in sports events.When the COVID-19 pandemic first emerged at the end of 2019 into the start of 2020, few could have anticipated that the COVID-19 crisis would stretch into 2021. The resumption of sports involving mass gatherings amid the COVID-19 pandemic remains debatable. The pandemic continues to surge, and many experts remain concerned about forging a safe environment for the athletes and staff. Nevertheless, many international sporting events are forging ahead. Qatar has demonstrated a safe and gradual resumption of international football tournaments and other sports activities, like tennis, equestrian, golf, and the Qatar motorcycle Grand Prix, by collaborating across local and international sports bodies at a time when a professional sports activity without spectators seemed to be the norm everywhere .Bio-secure bubble sports system for the AFC Champions League tournament with and without spectators will lead to new ways of conceptualizing how sports involving mass gatherings can be organized during a pandemic.Perhaps the robustness and effectiveness of Qatar's expanded  The vaccination program remains the biggest hope to direct a series of pilot and research projects like the one discussed in the current study (the Bio-secure bubble protocol). It is expected to serve as a model for sports leagues to resume with spectators. In addition, it will ensure safety and provide a scheme for the public to overcome the fear of being in large crowds after such an extended period of being physically distanced. It could act as a catalyst to win back the support of an increasingly skeptical football fan. Nevertheless, we have demonstrated that the return of spectators to the stadium is possible. However, it would depend on the transmission rates of the virus and the epidemiological milieu of the hosting country.The current manuscript was written when much about the future of sports involving spectators remains uncertain, as seen from a specific set of perspectives and circumstances arising from the COVID-19 global pandemic. At this manuscript writing, a vaccination program has already been initiated in Qatar, and 88.3% of the Qatar population aged 16 years and above had already received two doses of the vaccine, with more than 6.4 million doses administered.One limitation of the current study was its retrospective nature. Also, we could not follow up with the spectators to determine the post-event transmission rate. The post-event epidemiological data did not show any spike in the local transmission of COVID-19 cases . NeverthBio-secure bubble protocol and the gradual return of spectators in stadiums is not associated with a substantial spread of COVID-19 infection. The safety of this protocol will be fortified further by the current vaccination programs. Qatar's recent preparation, strategies, and successful experiences for mitigating infection during professional football tournaments involving international participants were critical in restarting sporting events with or without spectators. The game's safe and infection-free hosting marks an important milestone in Qatar's preparations for the FIFA World Cup 2022. It provides an opportunity to test its operational plans further and ensure its readiness for football's showpiece event in 2022 amidst the world's uncertain epidemiological circumstances.This report demonstrates that the resumption of professional football activities at the international level under strict adherence to the This study was granted ethical approval from the medical research center and institutional review board of Hamad medical corporation, Doha, Qatar (IRB#MRC-01-21-431).not applicableAll data generated or analyzed during this study are included in this article. Data are accessible upon agreement with the Medical Research Centre, Hamad Medical Corporation, Doha, Qatar.NoneNone


Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales  to measure 18 participants’ response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC. Post-acute sequelae of COVID (PASC), commonly referred to as long COVID, is an emerging public health syndrome that continues to devastate and debilitate adult and pediatric survivors of acute SARS-CoV-2 infection. The World Health Organization (WHO)-led Delphi consensus defined PASC as a syndrome starting 3 months from onset of probable infection with symptoms lasting over 2 months and could not be explained by an alternative diagnosis . Over 20Here, we describe an 18 participant case series investigating the combination of the CCR5 receptor antagonist maraviroc, and pravastatin, which targets fractalkine, as a potential therapeutic approach in addressing and treating the potential pathology of PASC. The CCR5 receptor is a seven-transmembrane G protein-coupled receptor (GPCR) that is found on macrophages and T-lymphocytes and functions to regulate trafficking and effector functions of these cells . The rolThe records and immunological lab reports from 18 adult PASC patients treated with maraviroc 300 mg per oral twice daily and pravastatin 10 mg per oral daily from our virtual medical clinic were collected and analyzed.The 18 participants selected for this case series were from a pool of patients who reported symptom improvement while on maraviroc and pravastatin and who fit the inclusion and exclusion criteria we set below.All the participants in the case series were COVID-19 survivors with documented FDA EUA approved RT-PCR SARS-CoV2 positive test and/or were positive for anti-SARS-CoV2 antibodies using FDA EUA approved tests. All participants had one or more new onset symptoms that persisted greater than 3 months after the diagnosis of acute COVID-19 infection. These symptoms included cognitive impairment (brain fog), migraines, post exertional malaise (PEM), myalgias, arthralgias, severe fatigue, tachyarrhythmias, postural orthostatic tachycardia syndrome (POTS), and shortness of breath. All participants displayed either isolated or combinations of elevated pro-inflammatory markers: RANTES, TNF-alpha, IFN-gamma, sCD40L, VEGF, IL-6, IL-2, and IL-8 on the IncellKINE panel. The IncellKINE cytokine panel is a set of 14 cytokines that was constructed from a previous machine-based learning algorithm that identified potential markers of PASC , arrhythmias, bleeding disorders, and anticoagulation therapy.When patients reported that their post-COVID symptoms improved by 80% of greater, we initiated discontinuation of both maraviroc and pravastatin. Bi-monthly follow-ups were conducted for 12 weeks post-treatment to monitor if symptoms reappeared or worsened.A challenge in studying and defining PASC is the heterogenous clinical presentation and multisystem involvement. Thus, we categorized the main participant symptoms into 5 groups: neurological/autonomic function, cardiac, respiratory, overall functionality, and fatigue. Since there are no validated scales for PASC, we used five validated scales for other organ systems  to measure subjective participant responses to treatment –5. PartiNew York Heart Association (NYHA) functional classification was used to classify severity of PASC associated cardiac symptoms.The Composite Autonomic Symptom Scale 31 (COMPASS 31), a self-rating questionnaire consisting of 31 items and evaluating orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor function, was used to measure autonomic dysfunction and the subsequent therapeutic effects of maraviroc and pravastatin. A sub raw score for each of the six domains was calculated and converted into a weighted sub-score. The sum of this weighted sub-score gave a total score which ranged from 0 to 100, with 0 meaning no autonomic symptoms and 100 reflecting the most severe autonomic symptoms.The Medical Research Council (MRC) Dyspnea scale is a validated method comprised of five statements that aims to measure perceived feeling of breathlessness.Modified Rankin scale for neurologic disability is a validated scale to measure degree of disability after suffering a stroke or neurological insult.The Fatigue Severity Scale (FSS) questionnaire is a nine-statement validated scale that rates the severity of fatigue symptoms. Participants were asked how accurately each statement reflected their condition before and after treatment with maraviroc and pravastatin and the extent to which they agreed or disagreed based on a scale of 1 (strongly disagree) to 7 (strongly agree).The Fresh plasma was used for cytokine quantification using a customized 14-plex bead based flow cytometric assay  on a CytoFlex flow cytometer as previously described  using thEnd points for the study were when the patients reported improvement in post-COVID symptoms that led to increases in daily functionality and quality of life. We checked in with the patients every 2 weeks to monitor progress.python programming language (version 3.9) and the pandas library  we compared the datasets by implementing the non-parametric Wilcoxon’s paired test. The implementation of this test was done using the python library scipy . The selIn order to identify potential statistically significant relationships between the biomarkers present in the dataset and the subjective scores, we imported the full dataset into the R programming language (version 4.1.1)  and condp-value was calculated. We defined that correlation coefficients were statistically significant if their p-value was equal or less than 0.05. In order to properly interpret and convey the correlation relationships and their statistical significances, we constructed a modified correlation matrix using a dot plot with the python programming language. We implemented additional functions and arguments that allowed us create a diagram only showing statistically significant correlations. Additionally, because correlation plot is constructed using a matrix, there is a mirror-image effect between the left and right side of the diagonal. We used the arguments of the plot to avoid this effect, in order to improve plot interpretability.The Pearson correlation coefficient has the advantage that its values are highly interpretable, always ranging from −1 (strong negative correlation) to +1 (strong positive correlation). Correlation coefficients were calculated for both the before and after data points, and to validate their statistical significance, their The dot plot implemented a color and size code. In this system, positive correlation coefficient were associated with shades of blue, whereas negative correlation values where associated with red correlation values. Regarding the size of the dot, it represented statistical significance, with greater sizes being indicative of greater statistical significance, smaller dots representing lesser values of significance, and no dots indicating no significance.To determine the state of individuals in the dataset as Post-acute sequelae SARS-CoV-2 (PASC) we classified them using a machine learning model. This model, which consisted of a random forest classifier, developed in a previous report  and usedp-value = 2.20e-17) between the cytokine profiles of the two treatment groups (before and after). Group 1 was defined as the before treatment and group 2 was after treatment. These results support that the medians of both groups are different and that a one-sided test was required to define the difference between group 1 and group 2. For the one-sided test, we focused on determining if the medians values for the biomarkers in treatment group 1 (before) were greater than those of group 2 (after). The results indicated that before treatment had statistically significant greater  magnitudes for the cytokines than the after-treatment group. The statistical analysis using a two-tailed and a one-tailed Wilcoxon test of the individuals from the maraviroc and pravastatin group indicated that there were statistically significant differences between the before and after treatment. The two-tailed test indicated that there were differences in the medians of these two groups . The one-sided test  indicated that before treatment had greater magnitudes for the cytokines (biomarkers) than the after treatment.The Wilcoxon paired test to contrast the before and after treatment groups using a two-sided hypothesis revealed the existence of statistically significant differences (The correlation dot plot indicates the presence of significant correlations based on color and size of the dot (circle) on the right of the diagonal. The correlation value is indicative of the joint correlation for both the before and after treatment groups when compared to each variable. The diagonal correlation values are the values of each marker or subjective score compared against itself, and thus the coefficient will be equal to 1 (dark blue) and have the largest size possible dot. For the observed correlation coefficients, the intensity of the color was indicative of values of r (correlation coefficients) including various negligible positive and negative correlations, and instances ranging from low positive to moderate positive correlation, however we also identified the presence of negative correlation. Identification of correlation values was done by comparing with color scale in Additionally, it is possible to see that for the subjective scores  there were multiple significant correlations with biomarkers. These significant correlations followed the trend of being mostly low positive or moderate positive, as indicated by the color of the dot . The preWe analyzed the linear relationship between the cytokine biomarkers and the modified Rankin score . In brier values between 0.30 and 0.50. The linear association between IL-8 and GM-CSF indicates that there appears to be a weak linear association between both treatment groups (before and after) where the levels of both cytokines appear to be positively associated with the NYHA score. When subsequently analyzed the correlation values for the Medical Research Council (MRC) Dyspnea scale score (Applying the New York Heart Association (NYHA) Functional Classification, which labels individuals in one of four categories, we were able to identify two statistically significant biomarkers in the joint correlation . The cytle score , which i1 provides a 9-item scale allowing the measurement of the effects of fatigue on an individual. The scores range from a value of 9 (lowest possible score) to 63 (highest fatigue effects). Our analysis identified that various biomarkers showed statistically significant correlations  were classified as belonging to the PASC class. This labeling or classification was achieved using the random forest classifier previously published  and descAlthough we observed differences between the before and after treatment conditions , with the one tailed-test indicating that the magnitudes in the before condition are greater than after, these changes are not sufficient to lead to a difference in classification using the machine learning model. Although the before and after groups are different when undertaking a statistical comparison, the magnitude in the shift between the groups could not be large enough to be captured as change in state, reflected by the statistical comparison and the subjective scores. Additionally, it is possible that individuals in the after group presented cytokines patterns similar top PASC at the time of sample collection, but if we were to analyze the progression of these samples in a defined time period, we could potentially observe a change in classification, as cytokine profiles continue to change.via the fractalkine pathway (via glycoprotein 1b-IX-V-receptor (GPIb-IX-V) with collagen-bound von Willebrand factor (vWF) (The discovery of CD16+ monocytes containing persistent S1 proteins from PASC patients may help further understand its pathophysiology and identify targets for therapy . Both CD pathway . This su pathway . This in pathway  and coulor (vWF) . Activator (vWF) , thus acor (vWF)  and actsor (vWF) . While tor (vWF) , the proor (vWF) . Hence, r = 0.4, p = 0.02) and sCD40L  , along with neuropathy and weakness, necessitating the need for assistance in performing daily tasks. CD14+ CD16+ monocytes are known to transmigrate across the blood brain barrier and play an important role in central nervous system (CNS) immune surveillance. These monocytes were implicated as HIV reservoirs in the CNS causing neuroinflammation, neuronal damage, and cognitive defects . We hypo = 0.01) , suggestr = 0.6, p = 0.0005), sCD40L , and TNF-alpha , suggesting that pro-inflammatory macrophage activation may be triggering vascular endothelialitis. Interestingly, elevations in sCD40L have also been associated with sympathoadrenal activation and targeting these vascular markers may address PASC associated dysautonomia  and light sensitivity has also been associated with PASC. POTS is a syndrome consisting of unexplained tachycardia, dizziness, light-headedness, fainting, and abdominal pain. While the true etiology of POTS has yet to be defined, endothelial dysfunction has been suggested as the pathophysiology . There iutonomia .r = 0.4, p = 0.03) and GM-CSF . Interestingly, endothelial cells are main producers of IL-8 , GM-CSF , sCD40L , and TNF-alpha . Intriguingly, CD16+ monocytes are known to produce large quantities of TNF-alpha and could be activated by the retained S1 proteins  , VEGF , TNF-alpha , IL-2 , and GM-CSF , again suggesting that targeting the monocytic-platelet-endothelial axis can alleviate PASC associated fatigue.Cardiorespiratory complaints leading to exertional intolerance and limitation of physical activity are very commonly reported by PASC patients. Many PASC patients with cardiac and pulmonary symptoms have undergone extensive workup  which has not detected any abnormalities or pathologies. Subsequently, current clinical approaches have only been used to treat symptoms with antiarrhythmics, bronchodilators or alpha-adrenergics, instead of addressing the underlying pathophysiology. We observed an improvement in exertional tolerance and physical activity as evidenced by a decrease in NYHA functional classification . This im of IL-8  and stat of IL-8 . Additio of IL-8 . These m of IL-8 . These ron (PAH) , while Ion (PAH) . We prevon (PAH) , 43, whion (PAH)  after mavia glucuronidation. However, the therapeutic benefits with other statins have also been observed and should be considered.Despite a black box warning for hepatoxicity, maraviroc has demonstrated a strong safety profile in adult, pediatric, and neonatal populations , 45. AnaDue to rising numbers of post-COVID symptoms and lack of studies and approved therapeutics, many patients have been on different therapeutics. This was reflected in the participants of this case series where some were previously on other therapeutics including ivermectin, fluvoxamine, and prednisone. This presents a significant limitation in this case series because what is unknown is whether these patients were already getting better from these medications before commencing maraviroc and pravastatin. After starting maraviroc and pravastatin, some participants saw symptom relief after 6 weeks, while others needed treatment up to 12 weeks before discontinuing medications. We recognize that studies will need to be conducted to understand this variation in length of treatment between participants. We followed up bi-monthly with these 18 patients for up to 12 weeks post-treatment and no one reported that their symptoms worsened or returned during this period.Other limitations and weakness of the study were no in-person, objective assessments due to the virtual nature of our clinic, the lack of the control arm and the open label nature of the study. Since immune subset assays were not available for this study, in the future, we would also like to study CD4/CD8 ratios and the amount of S1 proteins in CD16+ monocytes before and after treatment. The results we present in this case series do not replace the need for a double-blinded placebo controlled randomized trial to understand drug efficacy. However, we do believe this study sets the framework for our future clinical trial designs to further investigate the efficacy and usefulness of maraviroc and pravastatin to treat PASC.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by CCTC Ethics and IRB Committee. The patients/participants provided their written informed consent to participate in this study.RY, EO, and MZ conceptualized the study. RY organized the study. JG-C and RM-R performed the bioinformatics. RY, JG-C, and RM-R wrote the draft of the manuscript. All authors contributed to revising the manuscript and approved the submitted version.


The role of fibrates as a repurpose to treat SARS-CoV-2 is under investigation in at least three ongoing RCTs.Obesity, diabetes, hypertension and dyslipidaemia, individually or clustered as a discrete phenotype, the metabolic syndrome, typically associate with a more severe course of COVID-19.Fibrate treatment seems to be most advantageous among patients who have been taken fibrates before SARS-CoV-2 infection and are continuing to take them during the infection.We recommend that the clinicians encourage their patients who are already taking fibrate to continue using the drug throughout the COVID-19 illness.Based on separate protective mechanisms related to lipid metabolism, viral cell entry and inflammation, fibrate treatment might be advantageous among patients who have been taking fibrates before SARS-CoV-2 infection and continue taking them during the infection. Based on published data on hospitalized COVID-19 patients, we recommend that the clinicians should ask their patients with metabolic syndrome who are already taking fibrates to continue fibrate treatment during the COVID-19 illness. This recommendation applies to both outpatients and hospitalized patients. However, results from the ongoing randomized controlled trials (RCTs) using fenofibrate treatment for the prevention or treatment of COVID-19 have yet to prove that fenofibrate is clinically significant for this indication. In this research letter, we will briefly address the importance of continuing fibrate treatment in patients with metabolic syndrome who are taking fibrates already before any clinical symptoms of SARS-CoV-2 infection. The role of fibrates as a repurpose to treat SARS-CoV-2 is under investigation in at least three ongoing RCTs . While tMore than a decade ago, fenofibrate therapy was shown to increase survival by about 30% in mice infected with the influenza A virus . A recenn = 1411) by Masana et al. examined the clinical significance of varying plasma lipid levels during the infection [An observational cross-sectional study of hospitalized COVID-19 patients  had diabetes, including 21 newly diagnosed diabetes, the newly diagnosed diabetes was a powerful predictor of COVID-19 severity . HoweverInsulin resistance usually associates with metabolic syndrome and type-2 diabetes, and by downregulating the enzymatic activity of lipoprotein lipase it affects the levels of circulating lipoproteins towards a profile characterized by increased triglycerides and decreased HDL-cholesterol . During Many underlying comorbidities, such as obesity, diabetes and hypertension have been identified in the progression of COVID-19 into a severe and critical stage, and accordingly, patients with these cardiometabolic conditions have a poorer prognosis than those without them . In a reBased on separate protective mechanisms related to the fibrate effects on the cellular entry of the SARS-CoV-2 virus, inflammation and lipid metabolism, treatment with this drug seems to be most advantageous among patients who have been using fibrates before and during SARS-CoV-2 infection. We recommend that the clinicians inform their patients with metabolic syndrome and an ongoing fibrate treatment that there is no reason to stop taking fibrate during a SARS-CoV-2 infection. Rather, continuing the fibrate treatment is likely to be beneficial. Our recommendation applies to both outpatients and hospitalized patients. The availability of the results from the ongoing RCTs using fenofibrate treatment for a milder SARS-CoV-2 infection and ensuing COVID-19 illness are needed to demonstrate any potential benefit of this drug . Meanwhi


BackgroundIn light of the ongoing coronavirus disease 2019 (COVID-19) pandemic, vaccination is one of the most important defensive strategies in combating the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccine hesitancy or anti-vaccination attitude has become a barrier to the nationwide vaccination program, potentially sabotaging the effectiveness of vaccination. Thus far, Google Trends (GT) has been used extensively for monitoring information-seeking behavior during the pandemic. We aimed to investigate the association between Google search, the vaccination rate, and the number of vaccinated and infected cases among the Malaysian population.Material and methodGT’s customizable geographic and temporal filters were applied to include results for predetermined keywords from January 1, 2021, to December 31, 2021. Both Malay and English languages were used to reflect the multi-racial and multi-lingual community in Malaysia. The search volume index (SVI) derived was compared with the numbers of vaccinated and infected cases which were extracted from the open-access database  within the same period. Both analyses were performed independently by two authors to ensure accuracy of the data extraction process. A descriptive analysis was used to compare GT analyses and the number of daily vaccinations and positive COVID-19 cases.ResultsThe information-seeking behavior in the public fluctuated from time to time. The interest surged during the initiation of vaccination program and upon the outbreak of COVID-19 in Malaysia. The surge in interest prior to the peak of vaccination rate also indicated that the public tended to get information online prior to getting the vaccines. ConclusionThis observational study illustrates the ability of GT to monitor the interest of vaccination among the Malaysian population during the pandemic. By monitoring the dynamic changes in Google Trends, healthcare authorities can get a glimpse of public perceptions such as attitude towards COVID-19 vaccine, hence potentially identify and stymie any dangerous online anti-vaccination rhetoric swiftly. Since the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic, there has been a monumental toll on the healthcare system .To defend against COVID-19, the COVID-19 vaccination program was initiated in Malaysia on February 24, 2021 . RealiziOne of the hurdles faced by the Ministry of Health is vaccine hesitancy or anti-vaccination attitude among a small Malaysian population. Aided by easy access to unverifiable internet sources, the fear of vaccine’s side effects is spreading like a virus. Highlighted by Gunther Eysenbach, one of the four pillars to fight an infodemic is information monitoring (infoveillance) . Ergo, nWe aimed to conduct an infodemiological study to find the association between Google search, the rate of vaccination, and the number of infected cases in Malaysia. This study will provide an insight into whether the number of infected cases and the rate of vaccination in Malaysia are influenced by the search behavior of the Malaysian population.There were two parts in this study. The first part included an analysis of Google Trends (GT) while the second part involved an analysis of vaccination rate among the Malaysian population via an open-access database. Both analyses were performed independently by two authors to ensure accuracy of the data extraction process. Any discrepancy was resolved by re-evaluation of GT or open-access database analyses by the study team.In the first part of GT analysis, GT’s customizable geographic and temporal filters were applied as outlined by Mavragani . The seaIn the second part, the number of individuals receiving vaccines in Malaysia was obtained from the open-access database  . The numCOVID-19 vaccinesThere was a surge in SVI for both English and Malay language searches for COVID-19 vaccines in mid-February 2021 (Figures There was another surge in Google search for COVID-19 vaccination between June 2021 and July 2021, possibly related to the increasing number of people infected with COVID-19 during that period Figures , 4. In tVaccine boosterCOVID-19 booster vaccination was implemented in Malaysia since September 2021. Since the announcement of COVID-19 booster vaccine being inaugurated, there was a steadfast increase in Google search for COVID-19 vaccine booster Figures , 6. ThisConsidering the ongoing COVID-19 pandemic, this is the first study in Malaysia that investigates the behavior of public interest in COVID-19 vaccination using GT analysis. A 10-year GT analysis by Kow et al. reveals that GT is a viable platform to track healthcare interest among the Malaysian population, despite a geographical variation in the language used . SimilarThere were two major surges of the number of Google searches for COVID-19 vaccines Figures . The firCharacterization of information-seeking behavior via Google searches is crucial and it may be helpful in planning by healthcare authorities. GT has been found to be able to predict COVID-19 outbreaks in India and Italy ,11. In tLimitationsThis study has several limitations. First and foremost, this study uses Google Trends which only analyses the search behavior of people using the Google search engine. Nevertheless, as previous studies have indicated, Google is an overwhelming search engine of choice among Malaysians, hence the risk of bias will be kept to a minimum . In addiThis study augments the belief that the Malaysian population routinely uses Google search to obtain information on COVID-19 vaccines. Nevertheless, there is a dynamic change in the interest based on timing and the number of infected cases. By monitoring Google Trends, healthcare planners in Malaysia can get a glimpse of public perceptions such as attitudes toward COVID-19 vaccines. In the same vein, by tracking Google Trends, healthcare authorities can quickly identify and stymie any dangerous online anti-vaccination rhetoric.


A significant gap exists between high rates of antenatal care attendance and low uptake of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) in Senegal. This study aims to investigate whether IPTp-SP is delivered per Senegal’s national guidelines and to identify factors affecting the delivery of IPTp-SP at antenatal care visits. A secondary analysis was conducted using the 2014 and 2016 Senegal’s Service Provision Assessment. The study sample consists of 1076 antenatal care across 369 health facilities. Multiple logit regression models were used to estimate the probability of receiving IPTp-SP during the antenatal care visit based on prior receipt of IPTp-SP and gestational age during the current pregnancy. At an antenatal care visit, the probability of receiving IPTp-SP is 84%  among women with no IPTp-SP history and 85%  among women with one prior dose. Women who visit a facility in the top quintile of the proportion of IPTp trained staff have a nearly 4-fold higher odds of receiving IPTp compared to those who visit a facility in the bottom quintile . The dose and timing of IPTp-SP provided in antenatal care settings in Senegal did not always conform with the national guideline. More training for providers and patient engagement is warranted to improve the uptake of IPTp-SP in antenatal care visits. Plasmodium falciparum parasite.[Pregnant women are among the most vulnerable populations to malaria infection. In 2020, approximately 34 million pregnant women were at risk of exposure to the parasite. For pregparasite.,2 Other parasite..Intermittent preventive treatment in pregnancy (IPTp) is a core intervention recommended by the World Health Organization (WHO) for the prevention of malaria in pregnancy . IPTp wiWhile 33 moderate-to-high transmission Sub-Saharan Africa (SSA) countries have adopted IPTp into their national malaria control guidelines, the gap between the actual implementation of IPTp and target coverage levels remains large. According to the WHO Malaria World Report 2021), 74% of pregnant women report using ANC at least once; yet, only 57% of pregnant women receive at least one dose of IPTp, which is far below the recommended target level (90%) [, 74% of Countries such as Senegal have made great strides in strengthening their health care infrastructure and reducing malaria transmission. Senegal has an annual malaria incidence rate of 50.5 cases per 1000, ranking it in the lowest 33rd percentile among malaria-endemic countries in the African region . The natPrevious studies have shown that the coverage of IPTp was affected by factors at the health system level, facility level, provider level, and individual level. Key health system issues affecting the provision and uptake of IPTp included the discordance between malaria control and maternal health policies, human resource shortages, and medication stock-outs ,18. At tThis is a secondary analysis of cross-sectional data obtained from Senegal’s 2014 and 2016 SPA surveys. The SPA, a component of the DHS program, is a comprehensive nationally representative health facility-based survey that generates health service delivery data from low-to-middle income countries. The overall goal of SPA is to evaluate whether the overall availability and readiness of different health services in a country are in accordance with United States Agency for International Development’s and WHO’s service readiness indicators . For SPAFor our analyses, we combined data collected from the ANC consultation observation protocol, antenatal client exiting interview questionnaires, SPA facility questionnaires, and provider questionnaires administered during the 2014 and 2016 SPA survey waves. Only ANC visits with complete information for facility-level and individual-level characteristics are included in this complete-case analysis. As shown in This study examines the key factors associated with women receiving IPTp at their current ANC visit. The outcome variable is defined by whether a pregnant woman receives a dose of IPTp-SP during her current ANC visit in the ANC protocol observation survey of the SPA. Visits where providers “gave malaria prophylaxis medicine (SP) to client during the consultation” or “prescribed malaria prophylaxis medicine (SP) to client to obtain elsewhere” were coded as 1 and 0 otherwise.The main explanatory variables of interest to predict the probability of receiving IPTp were gestational age and IPTp-SP history prior to the focal ANC visit (the ex-ante SP history). These are factors used by health care workers to determine whether a pregnant woman should receive IPTp-SP at her ANC visit ,16,27. TUsing data from ANC visit protocol observations, we examine the probability that a pregnant woman would be prescribed SP during her ANC visit, conditioning on the number of SP dose(s) she has received prior to the focal visit. We first grouped ANC visits into three groups based on the ex-ante IPTp-SP history: (1) pregnant women who never had any SP dose before (IPTp-SP0), 2) pregnant women who had 1 SP dose before (IPTp-SP1), and (3) pregnant women who had at least 2 SP doses before (IPTp-SP2+). According to Senegal’s national malaria treatment and prevention guideline, IPTp-SP0 women ought to receive their first IPTp-SP dose at the ANC visit if they are at least 16 weeks of pregnant or active movements of the fetus are detected. Hence, in this category, we expect the probability of receiving IPTp-SP to be close to 100% for ANC visits after 16 weeks of pregnancy. Similarly, ANC visits of the second category should have a probability of receiving an IPTp-SP prescription near 100% conditioning on the last IPTp-SP dose at least a month earlier. Additional IPTp-SP doses are recommended by the WHO and Senegal’s national guidelines but are not required  pregnant , we conducted post-estimation to generate the predicted probabilities of receiving IPTp-SP with other covariates at means as well as their 95% confidence intervals (CI) to help interpret the results. The sample is weighted by facility weights provided by the SPA assuming equal individual weights throughout to ensure that the contribution of facilities to the total is proportionate to their existence in the total. Sensitivity analyses were conducted with clustered standard errors at the regional level to account for the possibility of clustering at the regional level. All analyses are conducted using Stata17 .No patients were involved in the process of generating the research question, designing the study, and implementing the study. No patients were asked to advise on writing up or interpretation of results. There are no plans to disseminate the findings to study participants or the relevant patient community.On average, pregnant women in our final sample were 27 years old and 27 gestational weeks see . Among tFor the conditional probability of IPTp-SP prescription for each ANC visit category along with gestational age, we collapsed the ANC visits at the 4-week interval to compute the mean likelihood and 95% CI see . In addiThe blue line visualizes the probability curve for ANC visits that required the second dose of IPTp-SP. Unlike the previous category, women of 4-month pregnancy or longer all had SP prescription probability that was not statistically different from 100%. However, this result is primarily due to the wide CIs of the sample means. The probability ranges from 71% in the fourth month of pregnancy to 96% in the ninth month.Lastly, the green line depicts the probability curve for ANC visits that IPTp-SP prescription was optional according to the national guideline. Interestingly, ANC visits in this category had a high chance of receiving SP prescriptions. For instance, women who were 4–6 months pregnant in this category all received the optional SP prescriptions. Furthermore, among all women who already had the required 2 IPTp-SP doses, 60.8% received the SP prescriptions at the ANC visits.We predict the probabilities that a pregnant woman receives an IPTp-SP prescription using our logit regression results  does not significantly impact IPTp-SP provision. Different types of hospitals also have similar effects, except that providers in private for-profit facilities shrink the likelihood of treating with or prescribing IPTp-SP by a factor of 0.05 compared to providers in other types of facilities . Lastly, a higher share of care providers who ever received IPTp training is positively correlated with the likelihood of IPTp-SP treatment and prescription.The sensitivity analyses with clustered standard errors at the regional level showed similar results to the main findings (results not shown).Despite the national guideline requiring care providers to prescribe at least two doses of IPTp-SP .) to pregnant women at scheduled ANC visits, a significant proportion of pregnant women in Senegal did not receive IPTp-SP prescriptions per the guideline. Specifically, IPTp-SP0 pregnant women who are the prime target of IPTp intervention have a chance as low as 52% to receive their first IPTp-SP dose at ANC visits in the 4th month of pregnancy (84% throughout the course of pregnancy). A similar gap also presents among the IPTp-SP1 women, who only have an 85% chance on average to be prescribed the second required SP dose by ANC providers throughout the course of pregnancy.Notably, this gap could not be explained by the lack of proper infrastructure for malaria services at the facility level. The national malaria treatment and prevention guidelines are available to 92% of facilities . There iThe positive association between a pregnant woman’s accumulative IPTp-SP history and her likelihood of receiving an IPTp-SP at an ANC visit during the second trimester highlights the importance of the interaction between care providers and pregnant women in improving IPTp-SP delivery and broadly the prevention of malaria in pregnancy. On average, women who never received IPTp-SP before have a 75% chance of receiving an IPTp-SP prescription at their second trimester ANC visits. The probability increases to 80% for IPTp-SP1 women, 78% for IPTp-SP2 women, and 94% for IPTp-SP3 women (results not shown). Although IPTp-SP history is an important reference for providers to prescribe SP in ANC settings, how IPTp-SP history predicts the uptake of IPTp-SP was rarely documented in previous literature. Although the SPA surveys do not document the interactions leading to whether or not to provide IPTp-SP, the higher likelihood among pregnant women to whom the IPTp-SP is optional suggests IPTp history-dependent disparity. This disparity might possibly be explained by the characteristics of care providers and pregnant women. For instance, pregnant women who had received IPTp-SP before could be more aware of the risk and the adverse consequence of malaria infection; thus, they could be more likely to be proactive and initiate the conversation regarding IPTp-SP with ANC providers. Conversely, pregnant women with no or low IPTp-SP history may be less aware of the importance of IPTp-SP and rely on ANC providers to complete the required IPTp-SP doses. Further data collection and research would be warranted to examine those hypotheses.After the IPTp intervention has been adopted in Senegal for nearly a decade, converting guideline recommendations at the policy level to care delivery in the field remains challenging. These findings raised the question: what steps can further close the gaps to the IPTp policy targets? As Crawley et al. pointed out, collaboration with reproduction health programs is the key step in implementing a malaria prevention policy targeting pregnant women at risk.  One areaWhile improving training for the provider side is necessary, dissemination of IPTp education among pregnant women such that more women at risk are aware of the IPTp-SP as an integrated part of ANC will help accelerate the improvement of IPTp-SP provision ,36,37. IThis study has several limitations. First, our results draw from a cross-sectional analysis using a convenience sample. They are thus prone to non-response bias if pregnant women who participate in the survey differ from those who do not. Moreover, with insufficient panel data to track individual pregnant women’s ANC and IPTp-SP history, we can only draw an association, rather than temporal causality, between the likelihood of receiving IPTp-SP at ANC visit and explanatory variables. Particularly, the time interval between receiving the last IPTp-SP and this ANC visit is unknown in the SPA data. As a result, it is possible that not all women with at least one IPTp-SP dose before need to be prescribed SP at this ANC visit. However, women with one prior IPTp-SP dose had SP prescription probability not statistically different from 100% starting from their 4-month pregnancy. Thus, the omitted variable of time to the last IPTp-SP should not be a major threat to our findings. Other omitted variables due to data limitations (such as the distance to the ANC facility) could also potentially threaten the findings.Second, we use IPTp-SP treatment or prescription by care providers to approximate IPTp-SP administration. This approximation may be problematic if the patient compliance level is low, which would negatively bias our estimations, and is likely to have a differential effect on IPTp history ,40. ThusThird, we recover the IPTp-SP history for each interviewed pregnant woman based on the interviewers’ observations and records from pregnant women’s ANC cards, assuming that the ANC cards were updated timely and accurately. Although we remove observations with IPTp records that occurred too early in pregnancy (<8 weeks), recall bias/measurement error could bias our results away from the null. On the other hand, if those erroneous observations are a truthful reflection of IPTp history, they raise a concern about over-provision. Future IPTp policy shall address this issue to avoid adverse outcomes such as SP resistance.This study shows that the dose and timing of IPTp-SP provided in antenatal care settings in Senegal did not always conform with the national guideline. Specifically, women with no previous IPTp-SP history have a chance significantly lower than 100% to receive the first IPTp-SP prescription at an ANC visit. More research on the interaction between care providers and patients is warranted to explain this phenomenon further. Moreover, more training for care providers could be integrated into future interventions aiming at improving IPTp-SP uptake.


Despite the existence of effective medicines, heart failure continues to be the largest cause of illness and death worldwide. As a prospective family of drugs with potential cardiovascular advantages in non-diabetic patients, sodium-glucose co-transporter 2 inhibitors (SGLT2-I) have recently come to the forefront. In this comprehensive study, we assessed the favorable cardiovascular outcomes of SGLT2-I in three sizable, randomized trials with both diabetic and non-diabetic populations. The results from these studies revealed a substantial reduction in heart failure hospitalizations and cardiovascular and all-cause deaths. To further support our assertion that SGLT2-I has the potential to be a novel addition to the standard treatment plan for heart failure, we also tried to assemble several post hoc and prespecified studies of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. The details of two clinical investigations that supported their use in acute decompensated heart failure were also examined, along with the most plausible mechanism of action generating their cardioprotective effects. Additionally, positive cardiovascular advantages were addressed in chronic heart failure with both preserved and reduced ejection fractions. The role of SGLT2-I in ST-elevation myocardial infarction (STEMI) and hypertrophic cardiomyopathy (HOCM) patients is currently being studied, and this research has the potential to be revolutionary. The purpose of this systematic review is to compile all information that supports the use of this life-saving drug in patients who do not have diabetes so that cardiac care can be improved globally. The need for innovations in heart failure (HF) therapy is critical due to the enormous morbidity and death linked to the condition. Worldwide, the number of instances of cardiovascular disease nearly quadrupled from 271 million to 523 million between 1990 and 2019. Cardiovascular mortality increased as well, from 12.1 million in 1990 to 18.6 million in 2019 [First identified as a novel anti-diabetic medication, sodium-glucose cotransporter-2 inhibitors (SGLT2-I) were introduced into the market after multiple clinical trials proved their magical role in appropriate diabetic control. Canagliflozin (CANA) was approved by the Food and Drug Administration (FDA) in March 2013 as the first SGLT2 inhibitor, followed by dapagliflozin (DAPA) and, empagliflozin (EMPA) in 2014 . The mecIn recent years, studies have been done to see if SGLT2-I treatment has any favorable cardiovascular effects, even in individuals with HF who are not diabetic. Beginning with two large, randomized trials, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) , which included both diabetic and non-diabetic population, showed a significant reduction in the incidence of heart failure events -12. AddiThis systematic review's goal is to compile all the information that supports SGLT2-I's favorable therapeutic effects on non-diabetic heart failure patients so that it can be utilized as a standard for future studies and enhance the quality of care for cardiac patients globally.MethodsThe inclusion and exclusion criteria, the search method used, the bias calculation in each research, and the selection of studies are discussed in this section.Inclusion and Exclusion CriteriaTable Search StrategyTwo research databases including PubMed and Cochrane library were extensively used to find literature on the subject. All databases were last accessed on June 28, 2022. As shown in Table To eliminate duplicate references, the ones retrieved from databases were alphabetically sorted using Microsoft Excel 2022 . The studies were further scrutinized using the titles and abstracts to filter out any that did not fit the inclusion criteria. Based on the titles and abstracts, the records were examined, removing studies that were not relevant. Retrieval of the full-text articles came next, after reviewing.Quality Appraisal of Individual StudiesAll publications that satisfied the inclusion requirements underwent risk of bias assessment using instruments designed specifically for the original study type. As shown in Table Selection of Individual StudiesTwo authors (Paghunda Ehsan and Rawia N. Aburumman), who participated in the study selection process, performed an initial screening of all papers that satisfied the inclusion criteria by reading their titles and abstracts. Studies in English and those which included non-diabetic heart failure patients taking SGLT2-I for heart failure treatment were accepted. In the second stage of screening, the papers that were determined to be pertinent to the research issue were further examined. RCTs and NRCTs that met the requirements for inclusion and demonstrated minimal bias risk on the quality assessment tools were then subjected to full-text review.This systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and the search strategy is outlined in Figure ResultsA total of 2833 studies were obtained after searching using two databases, namely PubMed and Cochrane Library, using the search strategy described. 6663 duplicates were removed using Microsoft Excel 2022 version. Of the 2833 studies, 127 articles were screened after duplication removal and removal of records marked ineligible owing to exclusion criteria. Nine studies were excluded as their topics were irrelevant. The abstracts of the remaining 118 articles were thoroughly read by the author to select the studies which fit the research question better. Out of 118 articles, only 16 articles managed to match the inclusion criteria of the study and were included in this systematic review, out of which characteristics of 14 articles are outlined in Table DiscussionThis comprehensive review firmly supports the claim that, regardless of diabetes status, treatment with SGLT2-I lowers the risk of CV death or a composite of deteriorating heart failure . In this section, we will address the most likely mechanism of action and the most recent data on the positive cardiovascular benefits of SGLT2-I in nondiabetic patients. The variations in cardiovascular outcomes across trials, their flaws, and suggested next steps will also be discussed. In the end, it will be clear what must be done more in this area to enhance the cardiovascular outcome for individuals with heart failure.SGLT2-I Cardioprotective Mechanism of ActionWhile the precise mechanism of SGLT2-I is unknown, multiple studies have validated a myriad of hypotheses. The advantages of SGLT2-I in the treatment of HF are mostly due to the stimulation of natriuresis and osmotic diuresis which these drugs induce, which improves cardiac output and reduces afterload and preload ,19,27-29From March 6, 2018, to September 10, 2019, Omar et al. enrolled 70 patients with stable euvolemic HFrEF (54 non-diabetic patients) to receive either 10 mg of EMPA or a matching placebo once daily based on a standard heart failure treatment regimen for 12 weeks to evaluate the hemodynamic effect of SGLT2-I using right heart catheterization (RHC) at rest and during exercise. The ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at maximum exertion after 12 weeks was the main result. In contrast to the placebo, the PCWP/CI ratio did not change during exercise or at rest, but PCWP was reduced across the board in all hemodynamic parameters, lowering LV filling pressures [In 2021, Kolwelter et al. randomized 2:1 participants with HF New York Heart Association (NYHA) II-III and an ejection fraction of 49 percent or less to receive EMPA 10 mg once daily or a placebo for three months to determine the impact of EMPA on vascular function. Vascular metrics such as central systolic blood pressure (cSBP), central pulse pressure (cPP), forward pressure height (FPH), and reflected pressure pulse height (RPH) under basal conditions decreased in the EMPA therapy group (n = 45) after one and three months. The decreased afterload of the left ventricle caused by greater arterial and aortic compliance perhaps led to a better prognosis seen in HF patients taking SGLT2 inhibition [Evidence Presently Available, Issues, as well as Future Suggestions for SGLT2-I's Cardiovascular BenefitsThe impact of SGLT2-I in chronic heart failure patients in a handful of trials will be reviewed in the upcoming paragraphs.DAPA-HF TrialThe Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, which involved 4,744 patients, 2,605 of whom did not have diabetes, was the first notable groundbreaking RCT of SGLT2-I to include both diabetic and non-diabetic patients . The triA 2020 exploratory analysis of the DAPA-HF trial by Petrie et al. showed a substantial reduction on in the primary composite outcomes of worsening HF or cardiovascular death in patients without diabetes  . MartineThe risk of cardiovascular mortality or worsening heart failure rapidly decreased, with particularly high absolute and relative risk reductions in those with more recent heart failure hospitalizations, according to Berg et al. in a secondary analysis of the DAPA-HF study in 2021 .Owing to sex-related variations in pharmacokinetics and pharmacodynamics, women may react to certain HF therapies differently than the male population ,32,33. IEMPEROR-Preserved TrialImproved health status and quality of life as judged by the Kansas City Cardiomyopathy Questionnaire, across all areas and at all measured periods , were shown by Butler et al. to extend to HFpEF in the "EMPEROR-Preserved study" in 2021 .EMPEROR-Reduced TrialIn 2019, the results of DAPA-HF were mirrored by the "Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction (EMPEROR-Reduced)", with EMPA's effects being similar in diabetics and non-diabetics  .DEFINE-HF TrialIn the clinical trial entitled "Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF)", Nassif et al. included 236 adult ambulatory patients with or without type 2 diabetes mellitus. Compared to the placebo, a significantly higher percentage of patients receiving dapagliflozin for 12 weeks showed clinically significant changes in their functional status, quality of life, or natriuretic peptides . The impEMPULSE TrialIn 2022, Voors et al. in the "EMPA in patients hospitalized for acute heart failure (EMPULSE) trial" randomly assigned 524 non-diabetic patients with a primary diagnosis of acute or decompensated chronic heart failure, regardless of LV ejection, to receive either 10mg EMPA or placebo when they were clinically stable , and they were treated for up to 90 days. The main goal was met by EMPA curing more patients than placebo . A five-point or greater difference in variation from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, or death from any cause, the number of heart failure events, and the time since the first heart failure event, as a hierarchical composite, were deemed clinical benefits .EMPA RESPONSE-AHF TrialTrials were conducted to determine SGLT2-I's positive effects on individuals with acute heart failure as well, considering growing evidence of its benefits for people with chronic heart failure. In a multicenter pilot study, Damman et al. randomly assigned 80 patients with acute HF with and without diabetes (EMPA RESPONSE-AHF) to receive either EMPA 10 mg/day or a placebo for 30 days. Results revealed that EMPA was safe, increased urine output, and decreased a composite endpoint of worsening HF, rehospitalization for HF, or mortality at 60 days, but it did not affect change in visual analog scale (VAS) dyspnoea, diuretic response, N-terminal {NT}-prohormone brain natriuretic peptide (NT-proBNP), or length of hospital stay .Recent GuidelinesIn the past years, numerous guidelines have been added that recommended the use of SGLT2-I in non-diabetic heart failure patients. For instance, In September 2020, UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite the use of appropriate primary agents, whether they have type 2 diabetes or not . SGLT2-IOngoing TrialsCurrently, new clinical trials are being conducted worldwide to check the efficacy of SGLT2-I in numerous cardiovascular issues like ST-segment elevation myocardial infarction (STEMI), atrial fibrillation, and hypertrophic obstructive cardiomyopathy (HOCM). An interventional clinical trial, namely "Impact of Dapagliflozin on Cardiac Function Following Anterior Myocardial Infarction in Non-Diabetic Patients (DACAMI)" has recently been conducted by Omar Younis at National Heart Institute, Egypt, and completed on June 30, 2022, checking its role in anterior wall ST-elevation myocardial infarction (MI) .Similarly, there is a new clinical trial "Empagliflozin in Hypertrophic Cardiomyopathy (EMPA-REPAIR)", started on June 1, 2022, in Warsaw, Poland, for EMPA administration at the recommended dose of 10 mg per day for 12 months to patients with hypertrophic cardiomyopathy as the suggested intervention. Diabetic patients will not be included in the trial. A total of 250 patients will be randomized in a double-blind method to either EMPA or a placebo. The study's main outcome measure will be the variation in maximum oxygen uptake (VO2 max), as determined by a cardiopulmonary exercise test. Before and after receiving EMPA or a placebo, VO2max, an objective measure of physical performance, will be measured. Secondary outcomes include modifications to the maximal LV wall thickness, LV mass, measures of diastolic dysfunction, degree of myocardial fibrosis, and improvement in the heart's energy status . This stAll the precedent data point to the enormous potential that SGLT2-I has outside of its current use in diabetic control and point to positive results in several cardiovascular health measures in both diabetics and non-diabetics. As a result, this miraculous medication should be further investigated for its undiscovered advantages.LimitationsWe limited our search to just two databases that contained English-language studies published during the last five years; as a result, good publications from earlier years and in other languages would have gone undiscovered. Grey literature and other databases were not incorporated. As far as we are aware, there are no larger clinical trials with a purely non-diabetic population only. Furthermore, non-diabetic populations had a smaller sample size in recent studies. Most of the studies we discussed were post hoc analyses or prespecified subgroup analyses on previously completed bigger RCTs with a significant proportion of diabetes participants. Finally, we didn't discuss much of the side effects of SGLT2-I.In addition to its ability to lower blood glucose levels, SGLT2-I has been shown in various studies to improve patients' cardiovascular health. Therefore, this systematic review aimed to learn more about its application in non-diabetic cardiac patients, whether they had acute or chronic HFs. Even though no significant clinical trial has been carried out solely on the non-diabetic population, recent studies have demonstrated cardiovascular benefits in the cohorts of both diabetic and non-diabetic populations and have demonstrated a significant reduction in HF hospitalization and mortality from cardiovascular causes. The above-stated efficacy in both populations is identical, which is surprising. The outcomes of present and upcoming RCTs in patients with MI, atrial fibrillation, and hypertrophic cardiomyopathy will likely expand the clinical indications for SGLT2-I in a variety of patient categories, enabling us to explore their potential beyond anti-glycemic effects. Future research will, however, require more trials with bigger non-diabetic sample size.


Wire-based coronary physiology pullback performed before percutaneous coronary intervention (PCI) discriminates coronary artery disease (CAD) distribution and extent, and is able to predict functional PCI result. No research investigated if quantitative flow ratio (QFR)–based physiology assessment is able to provide similar information.index) (quantitative method). QVPindex calculation was based on the maximal QFR drop over 20 mm and the length of epicardial coronary segment with QFR most relevant drop. Then, the ability of the different functional patterns of CAD to predict post-PCI QFR value was tested.In 111 patients (120 vessels) treated with PCI, QFR was measured both before and after PCI. Pre-PCI QFR trace was used to discriminate functional patterns of CAD . Functional CAD patterns were identified analyzing changes in the QFR virtual pullback trace  or after computation of the QFR virtual pullback index  was present in 22 (18%) vessels. Its occurrence differed across functional patterns of CAD . Similarly, QVPindex was correlated with post-PCI QFR value .By qualitative method, 51 (43%), 20 (17%), 15 (12%), and 34 (28%) vessels were classified as focal, serial focal lesions, diffuse disease, and combination, respectively. QVPOur results suggest that functional patterns of CAD based on pre-PCI QFR trace can predict the functional outcome after PCI.ClinicalTrials.gov, number NCT02811796. Date of registration: June 23, 2016.The online version contains supplementary material available at 10.1007/s10557-021-07162-6. In the HAWKEYE  study, 16% of investigated vessels had a post-percutaneous coronary intervention (PCI) quantitative flow ratio (QFR) ≤0.89, which was associated with adverse outcome , 3. WhetWe therefore performed a proof-of-concept analysis of the HAWKEYE study  to assesThis is a post hoc analysis of the HAWKEYE study , which pAll cases were reviewed by two trained members of the core lab and required agreement of both reviewers to be selected for inclusion in the present study. Then, pre-PCI QFR computation and the identification of the functional pattern of CAD by the QFR virtual pullback were performed. Finally, the relationship between functional pattern of CAD and PCI outcome (as assessed by post-PCI QFR) was assessed.Quantitative coronary analysis (QCA) and QFR were performed offline, using the software package QAngio XA 3D  in agreement with the step-by-step procedures validated in previous studies , 4, 5. Iindex) (quantitative method).Identification of the functional pattern of CAD was performed by the analysis of the trend of pre-PCI QFR virtual pullback  and by calculation of the QFR virtual pullback index  focal (presence of single drop ≥0.05 in 10 mm); (ii) serial lesions ; (iii) diffuse disease ; (iv) combination of previous patterns. Divergences between the reviewers were solved after consensus and with the involvement of a third supervisor.index validated by Collet and colleagues  in the lowest, 0.94 [0.91–0.97] in the intermediate, and 0.99 [0.97–1] in the highest (p<0.001) . A QVPindex ≤0.57 predicted suboptimal PCI outcome with sensitivity of 77% and specificity of 72%  in 22 (18%) vessels. Post-PCI QFR values significantly differed across the functional patterns of CAD  Table . After cThe present post hoc analysis of the HAWKEYE study showed that the functional pattern of CAD evaluated both qualitatively and quantitatively on the basis of pre-PCI QFR trace has a strong correlation with post-PCI QFR value and can predict post-PCI suboptimal functional outcome.Since the first years of interventional cardiology, several attempts to discriminate the distribution of coronary atherosclerosis have been made. The primary aim was to classify the pattern of CAD to discriminate the preferred treatment strategy, and estimate the risk of PCI complications and long-term prognosis. Intracoronary physiology has been introduced into daily practice to discriminate between vessels that would benefit from revascularization vs. those with diffuse disease where percutaneous intervention may not be useful. FFR pullback has been shown to be feasible and reproducible in the discrimination of the CAD pattern , 3. Simiindex.The present post hoc analysis of the HAWKEYE trial utilized pre-PCI QFR virtual pullback for the identification of the functional pattern of CAD. The discrimination was performed both by the analysis of drops and/or progressive decline in the pre-PCI QFR virtual pullback and by a quantitative method, namely the QVPThe major clinical implication of the identification of the functional pattern of CAD is related to the possibility to plan PCI in advance or to avoid it when an optimal functional result is unlikely. In the HAWKEYE trial, we found that post-PCI QFR values ≤0.89 were associated with an increased risk of vessel-related cardiac events . Lower pindex, was strongly associated with suboptimal PCI functional outcome. Stent implantation within a portion of the most highly diseased diffuse area tends to increase residual QFR value, but frequently it is not enough to achieve good functional results. If surgical revascularization or different secondary prevention strategies may be effective or preferable for these patients is unclear and future trials are warranted. In daily practice, we may speculate that a careful analysis of the pre-PCI QFR virtual pullback will help operators in the development of the proper revascularization strategy and in the optimization of PCI results.The focal pattern of CAD, evaluated both qualitatively and quantitatively, showed the highest probability to achieve an optimal result with PCI and stent implantation. In contrast, suboptimal PCI was more frequent in vessels with diffuse disease or a combination of patterns. The amount of vessel length with diffuse disease, which is well described by lowest QVPindex computation can be automatized should be properly investigated. Third, a complete validation of the QVPindex requires a head-to-head comparison with the original PPGindex derived by motorized FFR pullback. However, the present analysis should be considered proof-of-concept of an alternative, quick, easy tool for the assessment of the functional pattern of CAD and further studies are necessary to validate its application in daily practice. Finally, the idea of “QFR-guided virtual PCI” should be considered a hypothesis and prospective appropriate studies are needed to validate its feasibility and effectiveness in daily practice.The present investigation has several limitations that should be considered. First, pre-PCI QFR was not mandated by protocol. Therefore, it was available in a relatively low percentage of patients from the HAWKEYE study. The primary reason for inability to perform QFR pre-PCI was that most of the participating centers utilized 7.5 fps as default angio setting with 15 fps required to perform QFR. Further other QFR requirements such as 2 angiographic projections greater than 25° apart were not observed. It should be emphasized that the relatively smaller study population should not be considered as a technical failure to obtain QFR but rather to the fact that pre-PCI QFR was not mandated by the study, and angiographic views and use of 15 fps were not performed pre-PCI routinely based on the study protocol . CAD, coronary artery disease; QFR, quantitative flow ratioESM 1(DOC 1660 kb)