The EX-PRESS glaucoma filtration device appears to be an effective addition to our options to treat refractory glaucoma. The possibility to create a sclerostomy without tissue excision provides a safe and reliable outflow pathway for aqueous that is standard in size, reducing much of the variability associated with a surgical procedure. Prospective randomized studies comparing EX-PRESS implantation with trabeculectomy show encouraging results. However, complications usually encountered in filtration surgery have been reported, and EX-PRESS implantation can also lead to specific device-related complications. This article reviews the most common complications associated with this procedure. The EX-PRESS glaucoma filtration device  has gained increasing recognition as an alternative to trabeculectomy. The shunt consists in a non-valved biocompatible stainless steel device 2.64–2.96 mm long with a 400 micron external lumen diameter and options of a 50 micron or 200 micron internal lumen diameter. The device connects the anterior chamber to the intrascleral space to divert the aqueous humor to the subconjunctival space, with aqueous shunted from the anterior chamber to beneath a partial thickness scleral flap. Mitomycin C (MMC) use at a concentration of 0.2–0.4 mg/mL during the procedure is recommended to prevent scarring. MMC can be applied to tissues using surgical sponges, while an alternative method involves the irrigation of MMC directly in the subtenon space; the different MMC application route may lead to changes in surgical outcomes .The shunt is available in different versions with an inner lumen of 50 μm  and 200 μm (P-200). Originally, the EX-PRESS shunt was implanted under the conjunctiva, but this unguarded technique resulted in several complications such as hypotony and extrusion and erosion of the implant ,4,5. To Similarly to all filtration surgeries, failure caused by episcleral and subconjunctival fibrosis remains a challenging problem. Although success criteria definition may differ between studies, many comparisons between EX-PRESS and standard trabeculectomy showed similar failure rates ,11,12,13A recent meta-analysis based on four randomized controlled trials of 292 eyes confirmed that EX-PRESS implantation and trabeculectomy have similar efficacy in intraocular pressure (IOP)-lowering, medication reduction, vision recovery, and qualified operative success rates. EX-PRESS implantation is associated with higher rates of complete operative success and fewer hyphemia cases when compared to trabeculectomy .In our series of 248 consecutive patients with uncontrolled glaucoma who underwent EX-PRESS implantation over a period of 9 years (with a maximum follow-up of 7 years), we found a complete success rate decline from 83% at 1 year to 57% at 5 years [Another recent study evaluating Japanese patients found that advanced age, higher postoperative IOP, pseudo-exfoliation glaucoma, and simultaneous cataract surgery negatively influence the volume of the filtration bleb 2 years after surgery . It mustFailure of EX-PRESS shunts implanted under a scleral flap is normally a consequence of episcleral or bleb scarring, despite the use of anti-metabolites. Growth of fibrotic tissue between the external flange of the device and the inner portion of the scleral flap has been shown in vivo  and in eThe first option to consider in case of failure is a bleb needling or revision with antifibrotic agents, which have been proven to be a safe and efficacious procedure in eyes with an EX-PRESS shunt . AnotherIn case of definitive failure, the EX-PRESS shunt does not need to be removed to proceed to additional glaucoma surgery. Conventional tube surgery can be performed avoiding the area of the failed bleb.Most studies show no significant difference in intraoperative or postoperative complications, but some do note a lower incidence of postoperative hypotony and choroidal effusion with use of the EX-PRESS ,11,20,21This finding might be related to the smaller and standard outflow pathway created by insertion of the shunt. However, postoperative hypotony has been reported after surgery, with a transient decrease in the anterior chamber depth, probably due to a transient overfiltration through the EX-PRESS implant .Nonetheless, management of postoperative hypotony can be achieved in the same manner as in the classic filtration procedures.A significant reduction in the axial length, with an important hyperopic refractive shift, was recently observed in a highly myopic patient 18 months following hypotonia after glaucoma filtering surgery with EX-PRESS .EX-PRESS shunt malpositionThe EX-PRESS shunt is designed with a flange that fixes the implant to the sclera and prevents it from penetrating the anterior chamber. It also has a small spur-like extension to prevent movement extrusion.To avoid shunt movement after the insertion, it is essential to perform the pre-incision with the correct needle size. A 25-gauge needle track for the newer P series shunts is required, because of the slightly squared off shape. EX-PRESS glaucoma shunt dislocation into the anterior chamber has been described by Teng et al. twenty-one days after the procedure with no evidence of corneal decompensation . MoreoveThe original technique of implantation under a conjunctival flap was associated with high rates of implant dislocation and subsequent erosion .Traverso et al. showed, in a series of 26 eyes of 25 patients using the sub-conjunctival technique, two cases (7.7%) of device rotation (one treated by reposition) and three cases (11.5%) of conjunctival erosion at 2 and 3 years . ErosionTo remove the device, after an accurate dissection of the overlying conjunctiva and identification of the scleral flap, any fibrotic tissue should be dissected to allow for lifting of the flap. Once the shaft is fully exposed, the device should be gently lifted and rotated to dislodge the distal spur and allow removal. Creating a wider incision for removal is not needed to perform a safe extraction of the shunt.If the integrity of the scleral flap allows a tight closure, a tissue punch can be used to further enlarge the original entry site and convert to traditional trabeculectomy. If the scleral flap has eroded significantly, a patch graft should be used to close the opening and secured tightly to prevent filtration through this site.The EX-PRESS glaucoma filtration device distal portion contains an accessory orifice which serves as an alternative route in case of obstruction of the main central lumen. In a case series of 345 EX-PRESS shunt implantations, Kanner et al. reported that the most common device-related complication was shunt obstruction  . Only onIt has already been shown that the application of MMC may play a role in the pathogenesis of bullous keratopathy after filtrating surgery ,34. TherIn the first study that has compared endothelial changes after trabeculectomy, EX-PRESS shunt and Ahmed valve implantation, Casini et al. did not find significant modifications either at 1 month (0.2% decrease) or at 3 months (0.3% decrease), suggesting that EX-PRESS might represent the treatment of choice in patients with significant low corneal endothelial cell density before surgery or other risk factors for corneal damage . The lowRecent studies evaluating longer follow-ups demonstrate a statistically significant reduction of the corneal endothelium cell density, which was found by Ishida et al. 24 months after EX-PRESS implantation , compareOn the other hand, Omatsu et al. found no effects on the corneal endothelial cells until at least 24 months after the initial EX-PRESS surgery, supporting the benefit of using this procedure in patients who have a lower corneal endothelial cell density prior to the surgery .The physiopathological mechanism underlying the damage to the corneal endothelial cells following EX-PRESS implantation remains unknown, with recent data suggesting that it might be different from that of corneal endothelial cell loss after trabeculectomy. The corneal superior area, where the EX-PRESS device was inserted, was found to have significantly more severe corneal endothelial cellular density reduction than the inferior area 2 years after surgery, whereas no area dependency was observed in patients who underwent trabeculectomy .Possible reported causes of endothelial cell loss after EX-PRESS are MMC , foreign body reaction or immune reactions due to the stainless material used for the tube, changed flow of the aqueous humor around the tip of the tube, and mechanical ablation between the corneal endothelium and the tube.To reduce the risk of a postoperative contact between the tube and the endothelium, the insertion of the device should be performed while the anterior chamber is inflated by a continuous infusion or secured with viscoelastic. The needle entry point is at the grey line (junction between sclera and cornea) to avoid corneal stroma. Tojo et al. reported a case of partial decompensation following filtering surgery with EX-PRESS of the corneal endothelium adjacent to the filtering bleb 9 months after the surgery. Specular microscopy also revealed a marked reduction in the endothelial cell density at the center of the cornea. However, the authors underlined that the device was erroneously inserted from the cornea, not from the trabecular meshwork .Corneal surgery  may be taken into consideration in cases of severe endothelial cell loss, and patients presenting lower endothelial cell count should be carefully evaluated and informed before EX-PRESS implant surgery.Trabeculectomy bleb-associated infections are a serious and vision-threatening complication whose incidence varies among different studies; however, there is cumulative evidence that the incidence of bleb-associated infections has reduced over time . The ColWhile evaluating longer follow-ups, a paper on 460 eyes which underwent trabeculectomy reported cumulative probabilities of blebitis and bleb-associated endophthalmitis of 2% and 5%, respectively, during the 20 postoperative years .Little has been published regarding the incidence of blebitis and endophthalmitis after EX-PRESS implantation. Few cases of bleb-related endophthalmitis following EX-PRESS implantation have been reported ,47, inclThe aim of every glaucoma surgeon is to minimize complications while maximizing outcomes. The EX-PRESS glaucoma filtration device appears to be an effective addition to our surgical options to lower IOP in patients with refractory glaucoma. The possibility to create a standard sclerostomy without tissue excision provides a safe outflow pathway for aqueous with a standard size, reducing much of the variability associated. Prospective randomized studies comparing EX-PRESS implantation with standard trabeculectomy show encouraging results. However, the usual complications encountered in filtration surgery have been shown, and the implant of the EX-PRESS can also lead to specific device-related complications. The correct positioning of the implant is crucial for preventing these complications.


Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents an unprecedented healthcare challenge. Various SARS-CoV-2 outbreaks in healthcare facilities have been reported. Healthcare workers (HCWs) may play a critical role in the spread of the virus, particularly when asymptomatic. We examined four healthcare-associated outbreaks of SARS-CoV-2 infections that occurred at a university hospital in Berlin, Germany. We aimed to describe and analyze the spread of the virus in order to draw conclusions for effective containment of SARS-CoV-2 in healthcare facilities.Healthcare-associated outbreaks of SARS-CoV-2 infections were defined as two or more laboratory confirmed infections with SARS-CoV-2 where an epidemiological link within the healthcare setting appeared likely. We focused our analysis on one of three sites of the Charité-University Medicine hospital within a 2 month period (March and April 2020).We observed four healthcare-associated outbreaks of SARS-CoV-2 infections, with a total of 24 infected persons (23 HCWs and one patient). The outbreaks were detected in the departments of nephrology and dialysis (n = 9), anesthesiology (n = 8), surgical pediatrics (n = 4), and neurology (n = 3). Each outbreak showed multiple unprotected contacts between infected HCWs. A combination of contact tracing, testing, physical distancing and mandatory continuous wearing of face masks by all HCWs was able to contain all four outbreaks.HCW to HCW transmission represented the likely source of the four outbreaks. Ensuring proper physical distancing measures and wearing of protective equipment, also when interacting with colleagues, must be a key aspect of fighting COVID-19 in healthcare facilities. In December 2019, first reports emerged from Wuhan, China about a cluster of pneumonias with a suspected epidemiological link to a seafood wholesale market . The disDroplets have been described as the main vector for human-to-human transmission of SARS-CoV-2 . AsymptoIn this article, we report and examine four healthcare-associated outbreaks of SARS-CoV-2 infections that occurred at one of the sites of a university hospital in Berlin, Germany. We aim to describe and analyze the spread of the virus to draw conclusions for the effective containment of SARS-CoV-2 in healthcare facilities.Charité-University Medicine Berlin is a large tertiary care university hospital with three separate sites and more than 3000 beds. As a first response to the spread of the COVID-19 epidemic in China, the hospital required all return travelers from China to abstain from any activities at the hospital  and recommended isolation at home for 14 days. This regulation was put into effect on 14 February 2020, and subsequently extended to other risk areas (i.e. countries or other areas of the world with assumed widespread community-transmission of SARS-CoV-2 as defined by the German Robert Koch-Institute) as the spread of the disease continued. Reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 was offered to all return travelers and explicitly recommended for those showing signs of infection. On 1 March 2020 the first COVID-19 patient was hospitalized at Charité’s Virchow campus. Personal protective equipment (PPE) recommended by Charité’s infection prevention and control (IPC) team for the care of COVID-19 patients consisted of a medical face mask, gloves and gowns, and in case of exposure to aerosols, of a filtering facepiece mask 2 or 3  plus goggles or a face shield. On 3 March 2020 an outpatient SARS-CoV-2 RT-PCR-testing facility was opened at the Virchow campus. Designated testing sites for employees were established at all three campuses on 17 March 2020. Tests were analyzed in the routine laboratory work. Sampling for SARS-CoV-2 testing was done by a combined oro- and nasopharyngeal swab.direct contact with potentially infectious body fluids (e.g. respiratory tract specimen) without proper PPE (patient to HCW contact),exposure to aerosols without proper PPE (patient to HCW contact),face-to-face contact under two meters without at least one person wearing a face mask , orsharing the same patient room (patient to patient contact).Continuous surveillance of SARS-CoV-2 was initiated in the beginning of March 2020. New cases of laboratory confirmed SARS-CoV-2 infections among patients and HCWs were evaluated by the IPC team. Contact persons, both patients and staff, with relevant exposure to infected individuals were identified. Contact tracing was conducted for a period of 48 h prior to the onset of symptoms, or 48 h before sample collection in case of asymptomatic infections. The definitions applied for contact tracing were oriented towards the SARS-CoV-2 contact categories by the German Robert Koch-Institute . ContactA healthcare-associated outbreak of SARS-CoV-2 infections was defined as two or more infections where an epidemiological link appeared likely, and where acquisition of the pathogen in the healthcare setting was assumed. Only laboratory-confirmed cases with a positive RT-PCR for SARS-CoV-2 were counted. We focused our analysis on the Virchow campus of the Charité-University Medicine hospital within a 2 month period (March and April 2020).Hospitals in Germany are required by the German Protection against Infection Act to conduct continuous surveillance for healthcare-associated infections . All datBetween 1 March and 30 April 2020 we detected four healthcare-associated outbreaks of SARS-CoV-2 infections, comprising of 24 infected persons (23 HCWs and one patient). The outbreaks occurred in the departments of nephrology and dialysis (NEPH) (n = 9), anesthesiology (ANAE) (n = 8), surgical pediatrics (SPED) (n = 4), and neurology (NEUR) (n = 3).Table Table The SPED outbreak which consisted of four HCWs is displayed in Table Details of the NEUR outbreak that consisted of three HCWs infected with SARS-CoV-2 are summarized in Table In all four outbreaks, positive HCWs were exempt from work and sent into quarantine at home. Contact staff were allowed to continue working, but were instructed to closely monitor their health and continuously wear a face mask when in contact with patients or other personnel. In case of symptoms developing, contact HCWs were instructed to leave work immediately and undergo testing for SARS-CoV-2. The requirement to continuously wear a face mask was extended from contact staff to all HCWs in the hospital on 25 March 2020. All meetings had to be reduced to the minimum number of people necessary. Furthermore, HCWs were instructed to practice physical distancing during breaks and take meals separately. The public health authorities were notified of all four outbreaks. Outbreaks were considered contained if for a period of 28 days no new cases were noted. For all four outbreaks this was achieved.Four outbreaks of SARS-CoV-2 infections in four different departments emerged at our campus within a short period of time. Two of the four outbreaks (NEPH and ANAE) were interlinked. With the exception of one patient in the NEPH outbreak, all infections occurred in HCWs. As the primary finding of our investigation we therefore conclude that HCW to HCW transmission can represent a critical factor in the spread of SARS-CoV-2 outbreaks in hospitals and may in some cases outweigh the risks posed by infected patients.Interactions between HCWs in the hospital setting are frequent and an important aspect of a functioning team . PhysicaSteadily wearing a face mask can help reduce the spread of pathogens, including SARS-CoV-2 –24. We bAnother observation was that unprotected contacts between HCWs often occurred in lunch and smoker breaks or in office situations, where masks were taken off and the physical distance between people was overestimated. The hospital IPC team frequently addressed this issue and emphasized the importance of continuous face mask wearing in office situations and recommended spending breaks and taking meals separately. Rising case numbers of SARS-CoV-2, both in the community and specifically among employees, might have also increased awareness on the matter and thereby facilitated adoption of mitigation measures by HCWs.An aspect of similar importance for containing all four outbreaks was the identification and testing of personnel that had been exposed to SARS-CoV-2 carriers. Especially in the early stages of an outbreak it is crucial to quickly gain an overview about the number of cases. In this context, the long lag between the onset of symptoms and the testing of case one of the SPED cluster is noteworthy. Although speculative, it is conceivable that the other infections of the SPED cluster might have been avoided had case one been identified as SARS-CoV-2-positive sooner. The existence of a designated, readily accessible testing site for staff can facilitate rapid and systematic screening of HCWs. We believe that the employee testing site that commenced its operations on 17 March 2020 at our campus, was a key tool for successful outbreak management.Various limitations have to be acknowledged when interpreting our findings. The COVID-19 pandemic is a dynamic situation with community-transmission occurring almost in all parts of the world. Therefore and due to the fact that molecular typing of the isolated SARS-CoV-2 strains was not performed, it is possible that some infections that were counted as part of the nosocomial clusters occurred outside the healthcare setting. Undetected SARS-CoV-2 infections among patients might have represented another source of infection. If such patients had been treated at our campus, it would have been possible that HCWs might have acquired the virus from patients rather than other HCWs. To the best of our knowledge, however, no such cases of undetected HCW exposure to COVID-19 patients occurred during the time of the reported outbreaks. Although the outbreak management was carried out in a sensitive and blame-free manner, some questions related to it may have been perceived as potentially compromising by some of the affected HCWs. Thus, not admitting to not using proper PPE or not acknowledging other unprotected contacts cannot be ruled out. Due to the possibility of false negative SARS-CoV-2 tests and the fact that not all HCWs in the entire hospital were tested, cases of SARS-CoV-2 infections in HCWs and potentially even outbreaks in other departments may have been missed. Compliance with measures, such as mandatory and universal wearing of face masks, might have varied between individuals. Therefore, the effect of such measures should be assessed with caution.PPE places a focus on protecting HCWs from infected patients. Undoubtedly, this represents a key aspect of reducing the spread of SARS-CoV-2 and maintaining HCWs’ health. The threat of infection from colleagues, however, might be underestimated by many HCWs. Increasing awareness of this potential source of infection, i.e. ensuring proper physical distancing measures and wearing of protective equipment when interacting with colleagues, must be a primary focus of infection prevention strategies in times of the COVID-19 pandemic. Since transmission of SARS-CoV-2 by asymptomatically infected individuals is possible, this aspect gains additional relevance.


A dose of 30 mg/kg of azithromycin is recommended for treatment of yaws, a disease targeted for global eradication. Treatment with 20 mg/kg of azithromycin is recommended for the elimination of trachoma as a public health problem. In some settings, these diseases are co-endemic. We aimed to determine the efficacy of 20 mg/kg of azithromycin compared with 30 mg/kg azithromycin for the treatment of active and latent yaws.Treponema pallidum ssp pertenue in PCR testing. We used a non-inferiority margin of 10%. This trial was registered with ClinicalTrials.gov, number NCT02344628.We did a non-inferiority, open-label, randomised controlled trial in children aged 6–15 years who were recruited from schools in Ghana and schools and the community in Papua New Guinea. Participants were enrolled based on the presence of a clinical lesion that was consistent with infectious primary or secondary yaws and a positive rapid diagnostic test for treponemal and non-treponemal antibodies. Participants were randomly assigned (1:1) to receive either standard-dose (30 mg/kg) or low-dose (20 mg/kg) azithromycin by a computer-generated random number sequence. Health-care workers assessing clinical outcomes in the field were not blinded to the patient’s treatment, but investigators involved in statistical or laboratory analyses and the participants were blinded to treatment group. We followed up participants at 4 weeks and 6 months. The primary outcome was cure at 6 months, defined as lesion healing at 4 weeks in patients with active yaws and at least a four-fold decrease in rapid plasma reagin titre from baseline to 6 months in patients with active and latent yaws. Active yaws was defined as a skin lesion that was positive for Between June 12, 2015, and July 2, 2016, 583 (65·1%) of 895 children screened were enrolled; 292 patients were assigned a low dose of azithromycin and 291 patients were assigned a standard dose of azithromycin. 191 participants had active yaws and 392 had presumed latent yaws. Complete follow-up to 6 months was available for 157 (82·2%) of 191 patients with active yaws. In cases of active yaws, cure was achieved in 61 (80·3%) of 76 patients in the low-dose group and in 68 (84·0%) of 81 patients in the standard-dose group . There were no serious adverse events reported in response to treatment in either group. The most commonly reported adverse event at 4 weeks was gastrointestinal upset, with eight (2·7%) participants in each group reporting this symptom.In this study, low-dose azithromycin did not meet the prespecified non-inferiority margin compared with standard-dose azithromycin in achieving clinical and serological cure in PCR-confirmed active yaws. Only a single participant (with presumed latent yaws) had definitive serological failure. This work suggests that 20 mg/kg of azithromycin is probably effective against yaws, but further data are needed. Treponema pallidum ssp pertenue, remains an important public health problem in remote communities of 14 countries in Africa, Asia, and the western Pacific.2 Yaws is closely genetically related to syphilis, but these diseases can be differentiated on the basis of clinical features and through molecular testing. Yaws predominantly affects children younger than 15 years and transmission occurs by direct contact with a person with an early infectious lesion. The early lesions of primary and secondary yaws predominantly manifest as chronic cutaneous ulcers and papillomas.1 A serological diagnosis of yaws requires the detection of both treponemal and non-treponemal antibodies.1 Alongside clinical improvement, non-treponemal titres are expected to fall following treatment with effective antibiotics. More recently, point-of-care serological tests and PCR assays have become available to aid diagnosis.6 If left untreated, yaws can progress to destructive lesions of the bone and soft tissues.Yaws, a neglected tropical disease caused by 7 in Papua New Guinea showed that a single dose of 30 mg/kg of azithromycin (maximum 2 g) was non-inferior to benzathine benzylpenicillin for the treatment of yaws. Following this finding, which was later confirmed by a similar study in Ghana,8 WHO developed a new eradication strategy for yaws that involved mass treatment of the community with azithromycin.9 Pilot studies10 suggest that azithromycin mass treatment is very effective at reducing the prevalence of infection and disease.Long-acting injectable penicillin has been the mainstay of yaws treatment since WHO and the United Nations Children’s Fund led campaigns in the 1950s. In 2012, a randomised controlled trial (RCT)11 however, the dose of azithromycin used in trachoma programmes  is lower than the recommended dose for treatment of yaws. This difference in recommendations is potentially problematic because, in areas where trachoma and yaws are co-endemic,12 although mass treatment for trachoma elimination programmes might aid efforts to eradicate yaws if the dose used is effective against yaws, it could have negative consequences if the lower dose for trachoma treatment is subtherapeutic and results in more rapid selection of macrolide-resistant strains of T pallidum ssp pertenue. Azithromycin resistance spread rapidly in syphilis, caused by the genetically related T pallidum ssp pallidum.15 Establishing definitive data on the efficacy of low-dose azithromycin has therefore been identified as a priority by the International Task Force for Disease Eradication and partners.17 Studies19 in the Solomon Islands have shown that mass administration of azithromycin to eliminate trachoma has significant effects on the prevalence of both active and latent yaws; however, to date, no formal trials have compared the efficacy of the two doses. If a 20 mg/kg dose was shown to effectively treat yaws, this finding could potentially reduce both the costs of eradication and the incidence of adverse events associated with mass drug administration. This result might also allow synergistic treatment of yaws via trachoma elimination programmes (or vice versa) in areas where the diseases are co-endemic.16Mass treatment of the community with azithromycin is also key to WHO’s SAFE strategy for the elimination of trachoma as a public health problem;1 Since treatment of both active and latent yaws is crucial for yaws eradication,20 it is important that the efficacy of treatment with a low dose of azithromycin be established both for active and latent yaws.Although a lower dose of azithromycin might be effective at treating the relatively more metabolically active treponemes in a skin lesion, it might be less effective in latent infections, in which the bacteria are postulated to be less metabolically active.2 to determine whether the efficacy of low-dose azithromycin was non-inferior to standarddose azithromycin in the treatment of yaws.We therefore conducted an RCT in Ghana and Papua New Guinea, the countries that report the most cases of yaws globally,We did a randomised, controlled, open-label noninferiority trial in four districts of Ghana and one district of Papua New Guinea . Partici21 We collected a finger-prick blood sample from each child. A rapid diagnostic test  was done, which detects both treponemal and non-treponemal antibodies.22 Children with a clinically suspicious lesion and a dual-positive rapid diagnostic test  with a clinical lesion that was consistent with infectious primary or secondary yaws, which comprised at least one ulcerative lesion or papilloma, as described in the WHO yaws booklet.Before study commencement, teams underwent standardised training in clinical diagnosis of yaws, performance of the rapid diagnostic test, collection of blood and lesion samples, management of adverse events, and completion of documentation in line with the Good Clinical Practice guidelines.Written informed consent was obtained from the parent or guardian of each participant. Consent was also obtained from children who could provide it. The study was approved by the ethics committees of WHO (RPC 720), the London School of Hygiene & Tropical Medicine , the US Centers for Disease Control and Prevention , the Ghana Health Service , the Papua New Guinea National Department for Health , and the Papua New Guinea Institute of Medical Research . The study was done in accordance with the Declaration of Helsinki and was monitored by an independent Data and Safety Monitoring Board.Eligible children were randomly assigned to either a low-dose  or standard-dose  group. Randomisation was performed in blocks of four, by use of a computergenerated random number sequence that was generated by the trial statistician (CB) at the London School of Hygiene & Tropical Medicine. Allocation was concealed from investigators by use of opaque, sealed, sequentially numbered envelopes that were opened after the study team had enrolled a participant. Health-care workers assessing clinical outcomes in the field were not masked to the patient’s treatment group but patients and investigators performing statistical or laboratory analyses of samples were masked to treatment allocation. Study allocations are listed in 23Children were seen at baseline for enrolment, initial data collection, and treatment, and again for follow-up at 4 weeks and at 6 months. At each visit, children received a standardised skin examination, during which the type and location of any yaws-like lesions were recorded. In participants with more than one yaws-like lesion, the largest lesion was identified as the lesion-of-interest for sample collection and determination of healing at followup. Photographs were taken of the lesion-of-interest and the DPP results at each timepoint. All clinical data were collected directly into smartphones with the LINKS software package.3 At 4 weeks, if there had been no healing of the lesion, a repeat swab sample was obtained and the participant was offered treatment with benzathine benzylpenicillin. At 6 months, if the lesion was still not fully healed, a repeat swab sample was obtained and the participant was offered treatment with benzathine benzylpenicillin, or referred to the local health facility for further management, or both.A 5 mL sample of serum was obtained from all enrolled participants at baseline and at the 6-month follow-up. Additionally, at baseline, a single swab sample was collected from the target lesion and placed into 1·2 mL of AssayAssure transport medium  as previously described.T pallidum passive particle agglutination test  and a quantitative rapid plasma reagin (RPR) test . Because Haemophilus ducreyi commonly causes skin lesions that can be clinically difficult to distinguish from the lesions of yaws infections, and Buruli ulcer is co-endemic in both countries,25 two real-time multiplex PCR assays for the presence of T pallidum ssp pertenue, H ducreyi, and Mycobacterium ulcerans were done on swab samples, as previously described.24 The T pallidum PCR used has previously been shown to have an analytical sensitivity of ten copies per sample.3 The multiplex PCR assays also incorporated an amplification of the human RNA polymerase gene to confirm the integrity of samples and the absence of PCR inhibition. Additionally, all samples were tested by use of an additional multiple PCR for mutations associated with azithromycin resistance.26 The use of PCR in the current study allowed delineation of the effect of the two dosing strategies in both participants with active yaws  and in participants with presumed latent yaws and a different cause of the current skin lesion .Serum and lesion samples were transported on dry ice to the CDC laboratories in Atlanta, GA, USA. Serum samples were tested with the Serodia All participants were treated with azithromycin, which was administered as a single oral dose. WHO purchased azithromycin from Medopharm (India) and DPP syphilis screen and confirm rapid diagnostic tests from Chembio Diagnostics. Other study materials were provided by WHO and CDC. A small snack was provided so that individuals could eat before treatment. The study team directly observed treatment. Participants were observed for 1 hour following treatment to monitor for immediate adverse events. If vomiting occurred within this time, the child was treated again. Children who did not meet inclusion criteria for the study also received a standard 30 mg/kg dose of azithromycin, in accordance with WHO recommendations, and their ulcers were dressed. Any side-effects were monitored and managed by the study team or patients were referred to the district hospital for further treatment. Immediate adverse events were documented at the time of drug administration while the participant remained under observation. Participant-reported adverse events were documented at the 4-week follow-up visit.The primary endpoint was cure at 6 months of treatment. Cure was a composite outcome of both clinical cure and serological cure. Clinical cure was defined as complete or partial resolution of the lesion by 4 weeks. Clinical failure was defined as no evidence of healing at the 4-week follow-up visit . SerologSerological cure and clinical cure were analysed separately as secondary outcomes. Serological failure was defined as an increase in RPR titre between baseline and 6 months of at least 4-fold . Participants with a negative RPR at baseline were excluded from the analyses of both the composite primary outcome and the secondary outcomes because serological outcomes could not be assessed in this patient group. Participants with a missing baseline or 6-month RPR result or a missing baseline lesion PCR result were also excluded from all analyses.T pallidum ssp pertenue at baseline. A prespecified non-inferiority margin of 10% was used. Non-inferiority was defined as an upper bound of the two-sided 95% CI for the difference in proportions  of less than or equal to 10%. This margin was selected to reflect the maximum difference in efficacy that would allow the lower dose to remain acceptable for use in yaws eradication efforts. For secondary outcomes, non-inferiority was also assessed with the use of a two-sided 95% CI for the between-group difference. All confidence intervals were calculated by use of the Agresti-Caffo method.27The study was designed to assess whether treatment with 20 mg/kg of azithromycin (maximum 1 g) was non-inferior to treatment with 30 mg/kg (maximum 2 g) of azithromycin for the primary outcome in participants who were PCR-positive for T pallidum ssp pertenue at baseline. We did pre-planned secondary analyses of this population  by country of recruitment. Further pre-planned analyses were done on the following secondary study populations: (1) all study participants, regardless of baseline PCR status; and (2) participants who had a negative T pallidum ssp pertenue PCR result at baseline. Among participants with a negative T pallidum ssp pertenue PCR result at baseline, we separately evaluated the proportion achieving clinical cure in patients who tested positive for H ducreyi DNA and in patients who tested negative for H ducreyi DNA in their lesion at baseline.The primary analysis was restricted to participants with lesion samples that were positive by PCR for T pallidum ssp pertenue DNA detected at baseline. The imputation model included all baseline and outcome variables, and was implemented by use of the method of multiple chained equations.28To investigate the effects of missing data, we did a sensitivity analysis using multiply imputed data on the primary analysis population of participants with Assuming 95% efficacy of standard treatment, a non-inferiority margin of 10%, a type I error rate of 5%, and 10% loss to follow-up, we calculated that a total of 220 PCR-confirmed cases of yaws  would be required for the primary analysis. Based on PCR data collected in previous studies, we calculated that 524 individuals with clinically suspicious yaws lesions and a positive point-of-care serological test would be needed to achieve this sample size. Analyses were performed in Stata version 14.0 . This trial is registered with ClinicalTrials.gov, number NCT02344628.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Between June 12, 2015, and July 2, 2016, 895 children with clinically suspected yaws were screened for enrolment. Of these, 583 (65·1%) had a positive DPP point-of-care test and were enrolled . 400 68. BaselinT pallidum ssp pertenue alone in 161 participants  and for both T pallidum ssp pertenue and H ducreyi in 30 participants . These two groups constituted the population for the primary study analysis. The remaining 392 participants were included in secondary analyses; they comprised 150 (25·7%) participants with only H ducreyi-positive lesions by PCR (75 in each group), 228 (39·1%) participants with negative PCR results for all pathogens tested for (121 in the low-dose group and 107 in the standard-dose group), and 14 (2·4%) participants whose baseline PCR data were missing (six in the low-dose group and eight in the standard-dose group). No samples tested positive for M ulcerans.Baseline PCR was positive for In the primary analysis of participants with PCR-confirmed active yaws  the non-Clinical healing of lesions in both groups is shown in T pallidum ssp pertenue DNA in any lesion at follow-up. No mutations associated with azithromycin resistance in T pallidum were detected at either baseline or follow-up.No participant with clinical treatment failure had detectable T pallidum by PCR), the primary outcome was achieved in 132 (64·1%) of 206 patients assigned to the standard-dose group compared with 134 (67·0%) of 200 patients assigned to the low-dose group; this result met the non-inferiority criterion . In this secondary analysis, the proportion of participants achieving clinical cure and the proportion of patients achieving serological cure were similar in the low-dose group .vs 2·7%; eight in each group; There were no serious adverse events reported in response to treatment in either group. In the active surveillance data collected from participant reports at 4 weeks, the most commonly reported adverse event was gastrointestinal upset, with no significant difference in frequency between groups  participants had a 6-month RPR result available. Four (5%) participants were found to have definitive evidence of seroconversion (an RPR titre of 1:2 or higher) at 6 months (two from each group), of whom two had a T pallidum ssp pertenue PCR-positive lesion at baseline. A further seven (9%) participants had a conversion from a negative to undiluted positive RPR (four from the low dose group and three from the standard-dose group), which might represent false-positives, and the remaining 71 (87%) remained RPR-negative at 6 months (39 from the low-dose group and 32 from the standard-dose group).We did a post-hoc analysis of 93 individuals with a negative RPR at baseline who were excluded from the main analyses. This group included three participants in the standard-dose group whose lesions at baseline were In this randomised, controlled, non-inferiority trial, low-dose (20 mg/kg) azithromycin did not meet the prespecified non-inferiority margin compared with standard-dose (30 mg/kg) azithromycin in achieving clinical and serological cure in PCR-confirmed active yaws. The fact that we did not find non-inferiority of this dosage reflects wide confidence intervals around cure frequencies, which arose from the smaller than anticipated number of PCR-positive cases, and the lower than anticipated proportion of participants achieving serological cure. Despite this, low-dose azithromycin achieved a clinical cure rate of 100% , which met the non-inferiority criterion, and a point estimate for serological cure of 80%, which, despite not meeting the non-inferiority criterion, did not differ significantly from standard-dose treatment (84%). Additionally, our pre-planned secondary analyses of all individuals regardless of PCR results, and of participants who were PCR-negative, both suggested non-inferiority of low-dose treatment. These findings, considered together, imply that standard-dose and low-dose azithromycin are likely to be equally effective for patients with yaws. Unfortunately, we were unable to show this unequivocally in participants with active yaws in the current study.8 comparing benzathine benzylpenicillin to azithromycin for treatment of yaws, the proportion achieving serological cure at 6 months was lower in participants enrolled in Ghana than in those enrolled in Papua New Guinea, although this difference did not reach statistical significance. Two-thirds of our participants were enrolled in Ghana, which could partly explain the lower overall proportion of participants achieving serological cure at 6 months. Geographical variation in the outcome of randomised trials is well recognised, although it is unclear to us why serological cure rates might differ between these two settings. Strain differences, host immune responses, and random chance could all conceivably contribute. Our study was not powered to detect differences in outcomes between the two countries, and further studies are thus needed to explore the apparent differences in serological responses seen following antibiotic treatment.The overall proportion of participants achieving serological cure at 6 months was lower than anticipated. As in previous studiesT pallidum ssp pertenue PCR-positive lesions) and presumed latent yaws . PCR analyses allowed us to provide prospective data showing that both standard-dose and low-dose azithromycin were 100% effective for the clinical cure of skin ulcers caused by H ducreyi, which has emerged as a major cause of ulcerative lesions among children in tropical settings.25 The proportion of participants achieving clinical cure was also very high in lesions for which baseline PCR was negative for both T pallidum ssp pertenue and H ducreyi. This finding might reflect effective treatment of other ulcers caused by other azithromycin-susceptible pathogens, such as Streptococcus spp and Staphylococcus aureus, or healing of self-limiting skin lesions. Overall, the clinical effects of azithromycin seen in this study indicate that mass treatment with azithromycin is likely to provide additional benefit beyond its effect on yaws, which should be helpful for community acceptability. Our data also provide reassurance that the efficacy of low-dose azithromycin is not significantly different to standard-dose azithromycin for the serological cure of individuals with presumed latent yaws.29A strength of our work is the use of baseline PCR to stratify participants. This method allows us to explore clinical and serological cure rates in both active yaws  and who had no significant change in RPR titres at 6 months were actually serofast . Unfortunately, since there are no tests available that can distinguish serofast status31 from true latent infection, it is not possible to accurately determine the effect of this phenomenon on the proportion of our T pallidum ssp pertenue PCR-negative cases who achieved serological cure.Although a significant number of participants did not achieve the per-protocol definition of serological cure by 6 months, several factors related to interpretation of treponemal serology should be considered. First, amongst participants not achieving serological cure, only one patient had a four-fold increase in RPR titre, consistent with definitive serological failure, while three other patients had two-fold increases in RPR titre during follow-up. We cannot exclude the possibility that reinfection occurred during the period of follow-up, which might explain the rises in RPR titre in these patients. The absence of mutations conferring azithromycin resistance at baseline or emerging during follow-up in these patients is reassuring. All other participants not achieving the per-protocol definition of serological cure during the trial did achieve clinical cure but had either no change in titre or a two-fold RPR titre decrease from baseline to 6 months. It can take at least 12–24 months for the full amplitude of the RPR titre decrease to be expressed after successful treatment, particularly in latent yaws.T pallidum ssp pertenue will be crucial.In this RCT, low-dose azithromycin did not meet the non-inferiority criterion for serological cure among participants with PCR-confirmed active yaws, although non-inferiority was shown within the study population overall. In both study groups, the clinical cure rate was close to 100% and only one patient had definitive serological failure following treatment. Although further data are needed to unequivocally establish the non-inferiority of low-dose azithromycin, the data in this study, together with existing observational data, suggest that 20 mg/kg of azithromycin is an effective treatment for yaws. In co-endemic countries planning mass drug administration for trachoma, the current results provide reassurance that this will also have a beneficial effect on the prevalence of yaws. When azithromycin is coadministered for trachoma, yaws, or both diseases, close monitoring of the effects and for the emergence of drug resistance in Appendix 1Appendix 2


SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge.Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively.31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion.Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness. SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States.  In MarchAs has been previously described, our institution was one of the earliest donor sites for COVID-19 convalescent plasma in the US, and initially provided 25% of the total national donor pool for the American Red Cross. -10We describe our experience treating a series of COVID-19 patients with severe or life-threatening disease with convalescent plasma. Ventilatory and final patient outcomes are discussed, and the results compared to previously published data on convalescent plasma treatment.This study was approved by the University of Wisconsin Institutional Review Board. Cases met all criteria for enrollment under the Mayo Clinic Expanded Access Protocol (IND # 20-003312) and gave written, informed consent for CP transfusion and data collection. Enrollment criteria are described elsewhere.  Briefly,COVID-19 convalescent plasma was collected from a local donor recruitment and referral program in collaboration with the American Red Cross. Briefly, in response to guidance from the FDA dated April 3, 2020 We convened a local working group to establish a University of Wisconsin Hospital-based COVID-19 Convalescent Plasma program for both candidate recipients and potential COVID-19 recovered donors. Stakeholders were assigned to issues within their expertise including transfusion, the University’s Office of Clinical Trials, the Media Relations, and the local American Red Cross donor center. The Transfusion Medicine section developed an inventory and ordering process for convalescent plasma units within our electronic medical record system. The Office of Clinical Trials worked closely with American Red Cross and Food and Drug Administration to ensure compliance with rapidly evolving rules. Office of Clinical Trials staff also worked with potential donors identified by University of Wisconsin clinician referral or self-referral through local media coverage and via information provided to patients in the discharge instructions after all COVID-19 related hospital admissions. Potential donors were then screened and recruited to donate via a scripted telephone interview. The local American Red Cross established a process for receiving prospective donors and worked with national leadership to develop long-term protocols.Recipient data were abstracted from the medical record into a standardized case report form. Results were presented with descriptive statistics. Parametric and non-parametric tests were used as appropriate. All analyses were performed using commercially available statistical software .All appropriate regulatory, Institutional Review Board and patient care protocols were in place to begin transfusions by April 9, 2020. The first unit from our donor screening program was collected on April 10, 2020 with acceptable units available for patient transfusion on April 12, 2020.Between April 12 and June 2, 2020, there were 62 inpatient admissions for COVID-19 with severe or life-threatening disease. Of these, 31 met all inclusion criteria, gave consent, and received convalescent plasma. Among the 31 transfused patients, 15/31 (48%) met criteria for life-threatening disease, and 16/31 (52%) met criteria for severe disease at time of transfusion. Five patients were already in-house and were consented to receive plasma before units were available from our blood supplier. Four of these five patients had already progressed to or had presented with life-threatening disease at the time of transfusion. Characteristics of transfused patients are summarized in Inpatient respiratory support requirements over time for patients with severe disease are summarized in Inpatient respiratory support requirements over time for patients with life-threatening disease are summarized in Of the three patients with life-threatening disease who were not intubated at the time of transfusion, all three were in severe respiratory distress. One was transferred from a memory care facility and had a signed Do Not Intubate order, one had recently self-extubated during an episode of delirium and did not require re-intubation, and one adamantly refused intubation.We report a case series of 31 patients with either serious or life-threatening COVID-19 infection treated with COVID-19 convalescent plasma who demonstrated favorable clinical outcomes when compared to those reported in the literature to date. For both severe and life-threatened patients, respiratory support requirements began to decrease at about day 7. Once the ventilatory requirements began to decrease, they did so rapidly. Most patients were able to be discharged home on room air. The overall mortality was 13% (4/31). Among patients who were admitted with infection that met the criteria for severe disease and were transfused convalescent plasma prior to the development of respiratory failure the mortality to date is zero, and only one patient (6%) has had subsequent escalation of respiratory failure requiring mechanical ventilation. Among our patients with life-threatening disease we report an extubation rate of 67%. Overall, compared to outcomes reported in the literature to date, patients transfused convalescent plasma appear to have better outcomes in the face of both severe and life-threatening disease. ,13Our results are consistent with other early reports of outcomes in COVID-19 patients transfused with convalescent plasma. A recent cohort study by Liu and colleagues of 39 cases and 156 matched controls from Mount Sinai hospital in New York City reported a 12.8% mortality rate among patients with severe or worse disease who received convalescent plasma, and significantly better outcomes among patients transfused prior to mechanical ventilation.  TransfusWe observed a high rate clinical improvement among mechanically ventilated patients who received COVID-19 convalescent plasma. Although 4 (29%) of our patients with life-threatening disease died, 9 (64%) has improve respiratory by 14 days after transfusion. Improvement with convalescent plasma in patients already requiring mechanical ventilation is in line with one of the early reports of convalescent plasma treatment by Shen et al., who reported on improvement in multiple clinical parameters in five of five (100%) patients transfused convalescent plasma.  Li and cOne potential confounding factor in the improved outcomes we have seen could be the regional/geographical differences in outcomes as have been reported in the literature. Unlike the large patient surges experienced in Seattle and then in New York City, the healthcare system in Dane County/Madison, including at University Hospital, has not experienced a large or overwhelming surge of patients. In the initial reports from the Seattle area, a substantial number of patients (81%) were initially admitted to the intensive care unit, requiring intubation and mechanical ventilation, and by mid-March, 2020, they reported a mortality of 67% and the continued critical care needs of an additional 24% of patients.  SimilarlJi and colleagues described how infection prevalence compared to resource availability and healthcare burden are directly related to differences in mortality as seen in various areas of China. For instance, in the Wuhan province, the epicenter of the pandemic, mortality rates were reported to be greater than 3–4% where in other, even more populous areas, of China mortality was less than 1%. They go on to describe that mortality appears to be related to the incidence of disease per capita and the resources available in the local healthcare system to absorb and care for the number of cases in need.  This mayOur report has significant limitations. Because our institution did not see a large COVID-19 patient surge like those experienced elsewhere, we were unable to develop a well-matched control group for the purposes of comparison. Our patient population is also relatively homogenous and with good access to medical care. In addition, because most of our convalescent plasma came from donors in the earliest phases of collection, we did not have donor antibody titers available for analysis.Our experience to date at a large Midwest academic medical center demonstrates evidence of clinical benefit for patients treated with COVID-19 convalescent plasma in both the severe and life-threatening patient populations. Further, in both populations a de-escalation of oxygen support appears to occur at about 7 days after convalescent plasma transfusion, and the support decline is rapid after that. Although our data supports the promise of this therapy it also underscores the importance of ongoing and additional planned randomized clinical trials of convalescent plasma in the full spectrum of COVID-19 clinical presentations from salvage therapy in critically ill, mechanically ventilated patients to post-exposure prophylaxis/prevention in high risk individuals.


The sleepy OSA patients (AHI ≥ 15 events/h and ESS ≥ 10) who were offered CPAP, and the ones with no-OSA (AHI < 5 events/h) were included in the observational arm. A post-hoc analysis was done to compare untreated OSA  and nonadherent sleepy/non-sleepy OSA (n = 96) with the reference group without OSA (n = 81). The primary endpoint  during a median 4.7-year follow-up was evaluated in time-dependent Cox proportional hazards models adjusted for confounding factors. The incidence of MACCE did not differ significantly in intention-to-treat population. On-treatment analysis showed a significant risk reduction in those who used CPAP for ≥4 vs. <4 h/day or did not receive treatment . Compared with the reference group, nonadherent/untreated OSA was associated with an increased cardiovascular risk . We conclude that OSA is an independent risk factor for adverse cardiovascular outcomes in patients with ACS. CPAP treatment may reduce this risk, if the device is used at least 4 h/day.We aimed to address the impact of OSA and its treatment with continuous positive airway pressure (CPAP) on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with acute coronary syndrome (ACS). In this current analysis of the revascularized ACS subgroup ( Acute coronary syndrome (ACS) is a term used to describe ST-elevated myocardial infarction (STEMI), or non-STEMI or unstable angina in patients with coronary artery disease (CAD). Despite advances in pharmacological therapy and revascularization procedures, ACS continues to constitute a major health burden in Western countries . ObstrucContinuous positive airway pressure (CPAP) is the first choice of treatment for OSA, which reduces daytime sleepiness in symptomatic patients . NeverthWe have therefore hypothesized that (1) ACS patients with non-sleepy OSA randomized to CPAP would have less cardiovascular events than those not randomized to CPAP, and (2) that ACS patients with OSA that were not adherent to CPAP or assigned to no-CPAP would have an increased cardiovascular event rate compared to those without OSA.The methodology of the RICCADSA trial has been published previously , and is The Ethics Committee of the Medical Faculty of the University of Gothenburg approved the study protocol , and a written informed consent was provided from all participants. A blinded interim analysis was conducted in February 2010, and the protocol was amended for the primary endpoints of the main trial (see below). All data from hospital records and death certificates by the end of May 2013 were reviewed by an Independent Clinical Event Committee, blinded to patient identities and group allocation. The protocol and a random 10% selection of the database for baseline clinical data and follow-up procedures, including CPAP adherence and primary endpoints were monitored by a Data Monitoring Board. The trial was registered with the ClinicalTrials.gov (NCT 00519597) as well as with the national researchweb.org .Details of HSATs are provided in the online supplement. The 1:1 randomization of the participants with CAD and non-sleepy OSA in the main trial was scheduled with a block size of eight patients  stratified by sex and type of revascularization (PCI/CABG).® or S9®; ResMed, San Diego, CA, USA) by trained staff. Additional details of the follow-ups, including CPAP adherence, are given in the online supplement.Participants with non-sleepy OSA who were randomized to CPAP were fitted with an auto-adjusting device , 25th and 75th percentile (metric variables), and as counts and percent . For baseline differences between the groups, the Chi-squared test and t-test were applied. The primary endpoint was the first event of MACCE . Each event was evaluated separately and as part of the combined endpoint. For patients who experienced more than one event during the follow-up period, only the first event was included in the combined endpoint. All-cause mortality and acute hospital admission for cardiovascular reasons were among the secondary endpoints. Criteria for the cardiovascular diagnosis defined by the ICEC are available in the online supplement.2), gender, intervention at baseline (PCI or CABG), AHI at baseline, smoking status (current smoker/nonsmoker), diabetes (yes/no), former revascularizations (yes/no), and left ventricular ejection fraction (LVEF) were included in the propensity score. Between-group differences regarding nocturnal hypoxia severity indices such as oxygen desaturation index (ODI), minimum oxygen saturation (SpO2) and time spent below 90% SpO2 at baseline were conducted but not included in the propensity score due to collinearity with the AHI. An on-treatment analysis was performed using a time-dependent Cox model to estimate the impact of CPAP usage . With this approach, we accounted for the time-varying character of the intervention. Individual subject follow-up was split into multiple intervals according to the visit dates of the CPAP usage evaluation. Visits were planned after 1, 3, 6 and 12 months, and then annually until the end of the study. The time-dependent Cox model calculates the hazard ratios based on the individual usage intervals, with also considering the correlation of intervals belonging to the same patient.Associations between CPAP treatment and MACCEs were tested using Cox proportional hazards models. An ITT analysis was performed comparing the patients randomized to CPAP and to no-CPAP using Cox regression. Given the fact that randomization was performed in the original CAD cohort and not in the ACS subgroup, the approach of inverse probability of treatment weighting (IPTW) was applied in the ITT analyses. The IPTW is a propensity score method that mimics randomization. Covariables age (years), body-mass-index  and Stata version 14 .All Cox regression analyses were performed after a test for proportional hazards. All statistical tests were two-sided, and a As previously described in detail , there wAs shown in A total of 171 patients with ACS and non-sleepy OSA in the RCT arm were included in the current study. Patients allocated to CPAP did not differ significantly from those allocated to no-CPAP with regard to demographic and clinical characteristics including AHI and the nocturnal hypoxia indices .Median follow-up to the first MACCE or the end of study was 4.73 years (IQR 3.60–6.03 years). All ACS patients in the RCT arm were included in the final analysis for primary outcomes; 10 patients died , and none was lost to follow-up. The average CPAP use was 3.53 ± 3.31 h/day at 2 year-follow-up. Of OSA patients allocated to CPAP at baseline, 34 (39.5%) returned the device within 2 years. Of the non-sleepy OSA patients allocated to no-CPAP, 3 started CPAP at baseline, and 4 during the follow-up period due to reaching the nonfatal endpoints and/or developing daytime sleepiness. CPAP compliance data at follow-ups from participants who were still using the device as well as the entire group including the patients who stopped using and returned the device are shown in p = 0.51). Cumulative incidences of the first MACCEs are illustrated in In all, 37 patients reached the composite endpoint during follow-up, 19 (22.0%) in the CPAP group, and 18 (21.2%) in the no-CPAP group (not significant). The incidence of the primary endpoint did not differ significantly in non-sleepy OSA patients who did versus did not receive CPAP  whereas diabetes mellitus  and former revascularization  were significantly associated with increased risk  compared with CPAP usage <4 h/day or no-CPAP  and nonadherent (n = 96) OSA patients were included in the second post-hoc analysis to compare with 81 ACS patients without OSA as the reference group . . The median CPAP usage was 0  at 2 year-follow-up. In all, 60 patients reached the combined endpoint during follow-up: 48 (27.6%) in the untreated/nonadherent OSA group, and 12 (14.8%) in the no-OSA group. Incidence of the first MACCE was 6.78 per 100 person-years in untreated/nonadherent OSA patients compared 3.42 per 100 person-years in the reference group without OSA . .On multivariate analysis, diabetes mellitus tended to be a predictor of the MACCEs, and former revascularization was significantly associated with increased risk whereas CABG at baseline was protective . There wThis study showed that routine prescription of CPAP to adults with ACS and non-sleepy OSA had a neutral effect on the long-term cardiovascular event rate in the ITT population. A significant protective effect of CPAP was observed first after adjusting for baseline comorbidities and adherence to CPAP. Moreover, ACS patients with untreated/nonadherent OSA had an almost two-fold risk increase for MACCEs compared with the ACS patients without OSA at baseline. In addition, concomitant diabetes and previous CAD requiring revascularization seemed to be the most important conditions associated with the risk increase the current population.The null findings in this ACS subgroup in ITT analysis confirms our previous report on the entire revascularized CAD cohort , and areThere are multiple reasons why our results in the RCT population as well as in the post-hoc observational cohort are different from the findings in the ISAACC trial: First, the sleep studies in the ISAACC trial were conducted within 24–72 h of the hospital admission due to ACS; i.e., in a subacute setting  whereas Thus, the most crucial issue when evaluating the cardiovascular benefits of CPAP treatment in ACS patients with concomitant OSA without daytime sleepiness seems to be adherence to CPAP treatment. A recent meta-analysis focusing on the per protocol analysis of the RCTs, showed that adequate use of CPAP, defined as at least 4 h per day, was associated with clinically and statistically significant improvement in MACCEs . In liteFor the post-hoc observational arm, we enriched the sample of untreated OSA patients, who were allocated to no-CPAP, with nonadherent OSA patients, who returned or used CPAP less than 4 h/day, 70% CPAP days/period, corresponding 2.8 h/day/all days at 2 year-follow-up. The comparison of this untreated/nonadherent OSA group with the reference group (ACS patients without OSA) based on an AHI < 5 events/h clearly indicates that OSA is associated with increased risk for MACCEs in contrary to the findings in the ISAACC trial .The strengths of this study include its randomized controlled design for patients with ACS and non-sleepy OSA with none lost to follow-up for the primary composite endpoints. Although the inclusion rate for eligible patients for HSAT screening was only 53%, the inclusion design was consecutive, and there were no significant differences in baseline characteristics of the cases undergoing versus not undergoing HSAT .We should also acknowledge a number of limitations. First, the RICCADSA study was a single-center trial with two sites, which reduces generalizability of results across geographic regions. Second, the definition of “non-sleepy” OSA relied on an ESS score threshold of 10, which may not reflect an objective sleepiness in an ACS population. Nevertheless, this is a generally accepted tool for subjective daytime sleepiness, and the objective measurements such as Multiple Sleep Latency Test  are timeOSA is an independent risk factor for MACCEs in revascularized patients with ACS. However, routine CPAP prescription to non-sleepy OSA patients does not reduce this risk when compliance is not considered. Adequate use of CPAP, defined as at least 4 h per day, may reduce long-term adverse outcomes in ACS patients with OSA.


Our data support the correlation between SARS-CoV-2 load and disease severity, and suggest that IFNλ polymorphisms could affect the ability of the host to modulate viral infection without a clear impact on the outcome of COVID-19.The course of SARS-CoV-2 infection ranges from asymptomatic to a multiorgan disease. In this observational study, we investigated SARS-CoV-2 infected subjects with defined outcomes, evaluating the relationship between viral load and single nucleotide polymorphisms of genes codifying for IFNλs (interferon). The study enrolled 381 patients with laboratory-confirmed SARS-CoV-2 infection. For each patient, a standardized form was filled including sociodemographic variables and clinical outcomes. The host’s gene polymorphisms (IFNL3 rs1297860 C/T and INFL4 rs368234815 TT/ΔG) and RtReal-Time PCR cycle threshold (PCR Ct) value on SARS-CoV-2 were assessed on nasal, pharyngeal or nasopharyngeal swabs. Higher viral loads were found in patients aged > 74 years and homozygous mutant polymorphisms DG in IFNL4 . After adjusting for age and sex, a statistically significantly lower risk of hospitalization was observed in subjects with higher RtReal-Time PCR cycle threshold values (adj-OR = 0.95, 95% CI = 0.91, 0.99;  As of 1 September 2020, globally, more than 26 million cases of coronavirus disease 2019 (COVID-19) have been reported from 215 countries, territories, areas and 2 international surveys . AlthougHost factors could play a key role in determining clinical presentation and outcome of the infection. In fact, typical features of symptomatic patients infected by SARS-CoV-2 are disruption of the endothelial barrier, dysfunction of the alveolar capillary oxygen transmission and impairment of oxygen diffusion capacity .A possible contribution of human gene polymorphisms involved in the host antiviral responses to SARS-CoV-2 has been recently postulated, and there is growing evidence that some gene polymorphisms could affect susceptibility and severity of the COVID-19 course . Family In particular, there is growing evidence that some type III or lambda interferons (IFNLs) signaling are involved in the regulation of immunity and in the antiviral sustained response . The homAnother essential tool for managing and responding to the current COVID-19 pandemic is molecular testing. Clinical diagnosis of COVID-19 is confirmed by using the real-time reverse transcription polymerase chain reaction (rRT-PCR) to detect SARS-CoV-2 RNA . The useThis is an observational study carried out between 24 February 2020 and 8 April 2020 on 383 consecutive patients whose respiratory biological sample swabs had been sent to the referral Laboratory for COVID-19 Surveillance for Western Sicily located at University Hospital “P. Giaccone” of Palermo. All patients included were laboratory-confirmed SARS-CoV-2 cases that had a positive result of a reverse transcriptase real-time polymerase chain reaction  of nasal, pharyngeal or nasopharyngeal swabs according to the Centers for Disease Control and Prevention protocol . For eacEach patient was monitored for at least 21 days after recruitment, and the final day of follow-up was 8 April 2020. Due to the observational design , no follow-up biological samples were available. For two patients the rtReal-Time PCR cycle threshold value was not available and they were thus excluded.Before the swab sampling, an individual informed consent was obtained from each patient by the health care provider. An approval to conduct the study was required and obtained from the Ethical Committee of the A.O.U.P. “P. Giaccone” of Palermo, Italy. The research reported in this paper is in accordance with the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects.SNP (single nucleotide polymorphism) genotyping was carried out on the extracted whole nucleic acids from nasal or pharyngeal swabs  by the TaqMan genotyping allelic discrimination method  using custom genotyping assays . Complete genotyping was not possible for all patients due to the scarce amount of DNA available from swabs. The genotyping call was done by 2.3 Applied Biosystem Software . Genotyping was conducted in a blinded fashion relative to patient characteristics. Before testing for SNPs, samples were anonymized, and a unique randomly generated identification code was assigned to each record and to the correspondent swab. Researchers performing genetic analyses were unable to identify patients at all stages, and no permanent record linking these data to patient IDs was produced.The normality distribution of continuous variables was assessed by the Shapiro–Wilk test. Non-normal distributed continuous variables are presented as median and interquartile range (IQR), and categorical variables are expressed as the number of patients (percentage).The Mann–Whitney rank sum test or the ANOVA test were used to compare non-parametric continuous variables between subgroups. Chi-square, Fisher exact tests and Fisher–Freeman–Halton tests were used for categorical variables as appropriate.p ≤ 0.05. Analyses were performed using R Software analysis 3.6.1  [The multivariable logistic model was built to determine the association between RtReal-Time PCR cycle threshold values < 26  and homozygous mutant polymorphisms after adjustment for age. A multinomial regression model that was developed to test the relationship between clinical outcome  and independent variables  found statistically significantly associated to the outcomes at the univariate analysis. All statistical tests were two-tailed, and statistical significance was defined as Austria) .The general characteristics of the study patients are summarized in In A logistic regression analysis was computed on independent variables associated with RtReal-Time PCR cycle threshold values < 26. In this multivariable analysis, age > 74 years and IFNL4 DG homozygosity maintained their significance .In The variables found statistically significantly associated with clinical outcomes were included in a multinomial regression analysis reported in p = 0.028).In particular, after adjusting for age and sex, a significantly lower risk of hospitalization was found for subjects with higher RtReal-Time PCR cycle threshold values  and single nucleotide polymorphisms (SNPs) in genes codifying for IFNλs (IFNL3 and IFNL4) that are major components of the innate immune response system.The first intriguing finding of our study was that lower PCR Ct values and hence supposedly higher loads of SARS-Cov-2 were observed in older patients, in those with more severe outcomes and in the presence of DG homozygosity for INFL4. These associations should be considered with caution, since they have been found in two different multivariable models and, thus, a direct linkage between the three variables can be only inferred. However, a more in-depth reasoning could help to better clarify our hypotheses and these relations.In regard to age, our study confirms previous, well-substantiated evidence that older age is linked to a worse outcome ,20. It mA low PCR Ct value in our group of patients was also correlated to a higher risk of admission to the hospital or to an intensive care unit and therefore of death. A correlation with death has been already observed by Chu et al. in relation with SARS-CoV-2 viral load . In our As is already well documented ,26,27, wThis evidence is in keeping with the key role of IFNλs in the response to viral infection sustained by negative- and positive-sense RNA virus, double stranded RNA viruses and DNA viruses. As proof of the key role of type III IFNs in the regulation of immunity response, single nucleotide polymorphisms in IFNλ genes were strongly associated with outcomes of viral infection . BetweenAccording to this evidence, the use of IFNλs as an antiviral drug has been suggested in COVID-19 patients or in subjects at high infection risk, and current randomized clinical trials with peg-IFN L1 are ongoing .It is conceivable that subjects with rs1297860 TT and rs368234815 DG/DG haplotype show a lower ability in virus clearance , associated with the defective upregulation of inflammatory pathways .All of the previous findings should be considered with caution, since this study has several potential limitations. In particular, our sample size is relatively small to evaluate with appropriate strength, complex associations and interactions. However, a major limit of small sample sizes is the chance of type II error, thus, since we could have lost some associations, our results can be interpreted as exploratory and descriptive. Moreover, we used PCR Ct values, such as proxy of viral load, although this relationship is still not well standardized and quantified and, thus, could be affected by a low degree of precision and accuracy. Finally, we did not check for other potential confounding factors (such as comorbidities) that could be influencing the results. We also did not exclude the possibility that some hospitalizations were due to infection control reasons. For this reason, we have considered hospitalized subjects (those at higher misclassification risk) with caution by performing a multinomial analysis where home isolation was the reference. In this way, if results obtained for hospitalized subjects should also be biased, both home isolation and death/critical care would be poorly influenced by this bias.Despite possible limitations, we are confident that our findings contribute to the search for some pieces of this very complex puzzle and suggest an interesting link between SARS-CoV-2 load, estimated by RtReal-Time PCR cycle threshold value at presentation, severity of COVID-19 and specific IFNλ polymorphisms affecting the ability of the host to modulate viral infection in the early stages, thus acting as regulators of the ultimate outcome of COVID-19.


Even though 1 in 5 Americans experience some form of mental illness each year, 80% have been shown to discontinue psychotherapy prematurely. The traditional psychotherapy service delivery model, consisting of isolated clinical sessions, lacks the ability to keep patients engaged outside clinical sessions. Newer digital mental health platforms can address the clinical need for a robust tool that tracks mental well-being and improves engagement in patients with depressive symptoms.The primary goals of this feasibility study were to (1) assess compliance among providers and their patients with a digital mental health platform protocol, and (2) examine the usability and fidelity of a mobile app through structured participant feedback.A sample of 30 participants was recruited for a 5-week study from a community-based mental health clinic in Baltimore, Maryland, USA. Inclusion criteria were: aged 18 years or older, having access to a smartphone, and having at least mild-to-moderate depression and/or anxiety as measured by the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scales, respectively. Eligible participants were randomized into one of two study arms: (1) the intervention arm or (2) the waitlist control arm. Participants in the intervention arm were asked to download the Rose app and were prompted to complete clinical assessments (PHQ-9 and GAD-7) every other week, daily mood and anxiety Likert scales, and daily journal entries. The participants in the waitlist arm served as controls for the study and completed the clinical assessments only. Both arms engaged in weekly psychotherapy sessions, with participant in-app input informing the psychotherapy process of the intervention arm, while those in the waitlist control arm continued their standard care. Outcomes of interest included adherence to completion of in-app assessments and usability of the Rose mobile app assessed through the modified Mobile Application Rating Scale.Over the study period, a sample of 30 participants used the Rose app 2834 times to complete clinical assessments. On average, 70%  of participants completed mood and anxiety daily check-ins and journal entries 5 days per week. Nearly all participants  completed all PHQ-9 and GAD-7 in-app scales during the study. Subjective impressions showed that 73% (22/30) of participants found the mobile app to be engaging and in line with their needs, and approximately 70% (21/30) of participants reported the app functionality and quality of information to be excellent. Additionally, more than two-thirds of the participants felt that their knowledge and awareness of depression and anxiety management improved through using the app.Steady compliance and high app ratings showcase the utility of the Rose mobile mental health app in augmenting the psychotherapy process for patients with mood disorders and improving mental health knowledge. Future studies are needed to further examine the impact of Rose on treatment outcomes.ClinicalTrials.gov NCT04200170; https://clinicaltrials.gov/ct2/show/NCT04200170 Each year, 1 in 5 Americans (approximately 46.6 million people) experience some form of mental illness . The NatIn recent years, feedback-informed care (FIC) models have been used to improve patient compliance and psychotherapy outcomes ,10. FIC The widespread use and availability of smartphones have made successful adoption of mobile technology increasingly crucial in developing FIC models -14 and iThe primary goals of this feasibility study were to (1) assess the usage compliance with a mobile mental health platform among providers and their patients with at least mild-to-moderate depression and/or anxiety, and (2) examine the usability and fidelity of the mobile app through structured participant feedback. We hypothesized consistent usage adherence to the mobile platform over the study’s duration. A secondary exploratory aim evaluated the short-term impact of mobile app usage on mood and anxiety symptomatology.Participants were recruited from the patient population at Key Point Health Services, a sizeable outpatient community psychiatric clinic in Baltimore, Maryland, USA. Inclusion criteria consisted of age 18 years or older, regularly making on-going appointments with a psychotherapist at the clinic, having a score of >5 on the Patient Health Questionnaire-9 (PHQ-9) and/or >5 on Generalized Anxiety Disorders-7 (GAD-7), having access to a smartphone, and being fluent in English. Exclusion criteria included a current diagnosis of decompensated psychosis  and/or current suicidal or homicidal ideation. The cut-off of 5 on the PHQ-9 and GAD-7 represent mild depression and mild anxiety from clinical severity categorization ,17. EligEligible participants continued meeting with their therapists for weekly psychotherapy sessions. Therapists were asked to register for the Rose web-based clinical dashboard, which generated a unique therapist ID. Participants in the intervention arm were asked to download the Rose app to their mobile device and were given their therapist’s unique ID for linking within the app. Participants were informed that the health metrics would be shared with their therapist to help the clinician better plan upcoming sessions. Participants were prompted to complete a prepilot battery of assessments  upon first logging into the app. This battery was also pushed to the users at 2- and 4-week (postpilot) time points. Those in the intervention arm were also asked to continue using the Rose app daily during the 4-week period. The therapist was asked to use the Rose clinical dashboard to review data in conjunction with each weekly in-clinic session for four sessions. All in-clinic sessions were scheduled in the same clinical space where participants previously received care. Each clinical session was approximately 45 minutes long, and therapist documentation was done using their standard of care electronic medical record system.The participants in the waitlist control arm served as controls for the study. They completed the prepilot and postpilot assessments  only. These participants continued their weekly standard care with the psychotherapy process. Waitlist participants were offered entrance to the intervention arm at the end of the study period or earlier if participants in the intervention arm dropped out mid-study. During their time on the waitlist, participants could reach out to study personnel if they needed assistance with their psychiatric care.The study was reviewed and approved by the Advarra Commercial Institutional Review Board. For data security purposes, Rose utilizes cloud-based file-sharing and data storage services that are ISO 27001 certified and HIPAA  compliant. If at any point during the study, participants denoted suicidal ideation or other acute psychiatric concerns, they were automatically provided with emergency contact numbers and the study clinician (AJ) reached out directly. Additionally, if a high-risk participant was identified during in-person psychotherapy sessions, the therapist contacted the study clinician immediately with any concerns. If it was deemed that a participant required a higher level of care , they were removed from the study.Rose is a mobile health platform that consists of two primary components: (1) a patient-facing mobile app and (2) a clinician-facing web-based dashboard. Patients and clinicians are linked within the Rose system using a unique identifier that the clinician provides to the patient. The Rose app allows patients to track their mood and anxiety levels in real-time, complete validated assessments, and keep an in-app daily journal. Rose utilizes machine learning algorithms that identify mental health status and provide curated, individualized in-app daily insights for self-care. The Rose clinician-facing dashboard is designed for use in conjunction with in-person appointments. It is meant to augment in-person care by summarizing the data entered by the patient into the mobile app. Providers are given a walkthrough on using the dashboard and can reach the Rose team with any questions directly through the dashboard.The measures were as follows:Patient Health Questionnaire-9 (PHQ-9)  and GeneModified Mobile Application Rating Scale (mMARS)  19]. Th. Th19]. Mood & Anxiety Likert Scales . The RosIn-app Journaling. The in-app journaling feature allows the user to enter a free text description of how they are doing, like in the case of a diary. A built-in sentiment analysis analyzes the entered sentences.d=0.61 (large mean effect size of d=1.0). Based on the study’s five-psychotherapy session design (first session for on-boarding and four follow-up sessions), and paired-sample design (multiple measurements from the same person), a sample size of 30 has sufficient power (90%) to detect a moderately large effect size (d=0.8) [The power calculation for this study is based on a meta-analysis of internet-delivered treatments for adult depression and anxiety. It was found that internet interventions used in tandem with professional psychotherapy support showed an average between-group effect size of  (d=0.8) . AdditioThe primary analysis included checking distributional assumptions from the primary scores and assessing relationships among covariates. Continuous variables were described using mean, standard deviation, median, minimum and maximum, and 95% confidence interval for parameter estimation.t tests were conducted on continuous baseline variables , and chi-square analyses were performed on categorical variables .To determine whether any significant differences between groups existed at baseline, independent Descriptive in-app metrics were calculated for compliance of assessments with PHQ-9 and GAD-7 every two weeks and daily mood/anxiety Likert scales and journaling. In-app use was also explored for time-of-day frequency and weekly variations.Adherence over time. Adherence was defined as the completion of in-app assessments at predefined intervals. For example, daily adherence to mood assessment was seen if a participant completed at least one of the mood or anxiety Likert scales each day. Non-adherence was recorded as days with no data. Each assessment measure was reviewed individually for the duration of the study (4 weeks) for the percentage of adherent days and was stratified for each study week in which the app was being used. Logistic regression models were carried out to examine whether adherence to in-app assessments would be associated with the severity of depressive symptoms at baseline.Fidelity of app use. Fidelity defines the degree to which programs are implemented as intended by the program developer . In thisPre-post analysis (Wilcoxon matched-pairs signed-rank test) was used to evaluate the short-term impacts of mobile app usage in the intervention arm and the control arm within in-person psychotherapy sessions.P<.05. All subjects were included in intention-to-treat (ITT) analyses.All analyses were conducted using STATA 14 (StataCorp). All statistical tests were judged for significance based upon a two-tailed alpha level of P=.02), there were no significant demographic differences between arms.Looking at baseline mental health status, 42.22% of the sample was in the moderately-severe or severe range of depression, as measured by the PHQ-9. GAD-7 ratings showed 9.60% of the participants were in the moderately-severe or critical range for anxiety. There were no statistical differences in the distribution of participants randomized to each arm based on baseline mental health status.Participants in the intervention arm used the Rose mobile app over 4 weeks as part of care management. Looking at the use of PHQ-9 and GAD-7 in-app scales , particiUsing the mMARS scale we evaluated the perceived usability of the mobile app as rated by participants . OverallWe further asked participants about the perceived impact of the Rose app on their knowledge, attitudes, intentions to change, as well as the likelihood of actual change in depression and/or anxiety symptoms . More thWe looked for changes in depression and anxiety symptoms (measured through PHQ-9 and GAD-7) before and after the study in both the intervention and control arms .P=.01). On the GAD-7, there was an average 3-point improvement in participants over four weeks . Overall, 47% of patients with moderate-to-severe depression improved to mild depression and 56% of patients with moderate-to-severe anxiety improved to mild anxiety by the end of the study. Additionally, Kruskal-Wallis H test revealed statistically significant improvements in both PHQ-9 (P=.02) and GAD-7 (P=.001) scores over the course of the study in the intervention group.Participants in the intervention arm showed statistically significant improvements in measurements of both depression and anxiety symptoms. On the PHQ-9, there was an average 4-point improvement in participants over four weeks  for monitoring daily mental health and wellbeing outside of psychotherapy sessions and maintaining engagement in patients with depression and anxiety symptoms. Exploratory analyses examined changes in depressive and anxiety symptoms at baseline versus after study interventions. Improved PHQ-9 scores were observed in 76% (23/30) of intervention arm participants and 70% (21/30) showed improvements in their GAD-7 scores over the study period. Furthermore, patients rated the Rose mobile app as having high engagement and usability as well as content curation relevant to their needs.The study paralleled current psychotherapy care practices for moderate depression. These results showed using Rose is no worse than not using an app within psychotherapy sessions. Consistent compliance by patients between and during clinical psychotherapy sessions indicates that high levels of adherence can be achieved and retained. A larger multisite randomized controlled trial is being planned to look at the impact of the Rose digital health platform with an active  control.The economic impact of mental illness is marked, with the United States alone seeing $210 billion in annual medical expenditures tied to mental health disorders ,24. The Participants in this study were selected from a single study site and were not randomized by therapists. Thus, there may be a sampling bias that limits generalizability of the results. Furthermore, the sample consisted of 60%-90% women, which is not representative of the population of individuals with depression/anxiety in clinical settings or the community. While the pilot study had a waitlist control arm, it did not include an active comparison group . Furthermore, only 40% of the control arm completed the postpilot follow-up. This limited the pre-post analytical comparison. A follow-up randomized control trial is needed to evaluate inferences regarding the efficacy and contrast of effect sizes between the Rose digital health platform and other interventions.Steady compliance and high app ratings showcase the usability of Rose in practice and the utility of digital FIC models in improving patient compliance to therapy. Although exploratory, reduction in clinical depression and anxiety symptoms over the four-week study period highlights the potential utility of the Rose app for psychotherapy augmentation. Future studies are being developed to (1) further evaluate the clinical effectiveness of the Rose app through a multisite micro-randomized clinical trial, and (2) examine the impact of the Rose digital health platform on other diagnoses, including substance use and pain.