The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally, reflecting an increase in human papillomavirus (HPV)-related lesions. Indigenous populations are disproportionately affected by OPSCCs. Currently, testing for oral HPV is not recommended as a screening tool to permit early detection of OPSCCs due to the high population prevalence of HPV infection. Periodontitis may be a marker of oral HPV infection, but previous research evaluating this association has been inconclusive. Here we report a large population-based study examining the association between high-risk oral HPV infection and periodontitis among Indigenous South Australians.We utilised a large convenience sample of Indigenous South Australians aged 18+ years recruited between February 2018 and February 2020. Of the original cohort (n = 1011), 748 (73.9%) participants participated in the 12 month follow-up. Detailed information on sociodemographic characteristics, health-related behaviours, and sexual history were collected at enrolment. Saliva samples were collected at 12 months and tested for the presence of oral HPV DNA using the optimized general primer (GP) + PCR system. The primary outcomes were the prevalence of any high-risk oral HPV DNA, and separately, HPV 16 and/or 18. Periodontitis was assessed at follow-up by using validated self-reported periodontitis screening questions. Logistic regression analyses were undertaken to assess the association between self-reported periodontitis and oral HPV infection with adjustment for potential sociodemographic and behavioural confounders, with estimates presented as odds ratios (OR) and 95% confidence interval (CI).Data on 673 participants (89.9% of the follow-up cohort) were available. Participants ranged in age from 18 to 80  and 31.5% were male. Overall, 115 (17.1%) participants had self-reported periodontitis, 40 (5.9%) had any high-risk oral HPV and 14 (2.1%) had HPV 16 and/or 18. Any high-risk HPV was detected among seven (17.5%) participants and HPV 16 and/or 18 was detected in three (21.4%) who self-reported periodontitis. In the regression analyses no significant association was found between self-reported periodontitis and high-risk oral HPV  or HPV 16 and/or 18 .This study did not find any association between self-reported periodontitis and high-risk oral HPV among Indigenous South Australians. Further targeted studies with standardized clinical measures of periodontal disease are needed to clarify the link between high-risk oral HPV and periodontal disease. If confirmed this would add further weight to the importance of recommendations about the utility of periodontitis screening to identify individuals at risk of carrying high-risk oral HPV, who may benefit from more intensive screening and ongoing monitoring. The global prevalence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is between 23.0–31.0% , in the Currently, screening for OPSCCs is done visually via an examination of the oral cavity to detect cancerous lesions. While screening has been shown to improve clinical outcomes only in those who are at risk of oral cancer , 8, manyNearly two decades ago, the presence of high-risk HPV in healthy and diseased periodontium was reported . Recent In Australia, 3.3% of the population are Indigenous, which includes Aboriginal and Torres Strait Islander peoples with unique languages, histories, and cultural traditions. Like many other health conditions, Indigenous Australians experience a disproportionate burden of poor oral health. Both incidence and mortality from OPSCCs are considerably higher in this group than in the Australian non-Indigenous population . SimilarThere has been limited examination of the possible link between high-risk oral HPV and periodontitis among Indigenous Australians, despite the high burden of oral health conditions and OPSCCs in this population. If a link between oral HPV infection and periodontitis is confirmed, then this population may have great potential to benefit from improved screening for periodontitis and high-risk HPV infection. The aim of this study was to assess the association between periodontitis and high-risk oral HPV among Indigenous South Australians. We hypothesized that individuals with periodontitis would have higher prevalence of high-risk oral HPV compared to those with no periodontitis.We used a large convenience sample of Indigenous South Australians aged 18+ years recruited between February 2018 and February 2020 as part of a broader study investigating oral HPV and OPSCCs among Indigenous Australians , 17. IndAn Indigenous research officer explained the study aims and objectives to the participants and after obtaining written consent, participants were asked to share information related to their sociodemographic characteristics, health-related behaviours including tobacco and alcohol use, sexual history, self-reported oral and general health, HPV vaccination and answer questions about self-reported periodontitis. Each participant was requested to provide a saliva sample, through spitting and dribbling in a commercially available kit  from which microbial DNA for genotyping was extracted.Sociodemographic information collected at baseline included age, gender, geographic location, highest level of education completed and sexual history. Information on health-related behaviours including tobacco consumption, alcohol intake, and self-reported periodontitis were derived from the 12-month follow-up.Age was dichotomised into individuals aged up to 40 years and 41 or older. Geographical location was categorised as metropolitan or non-metropolitan. The highest completed education level was dichotomised as up to and including high school or tertiary level. Smokers were categorised as a current regular smoker or non-smoker. Alcohol consumption included ex/current alcohol use or never consumes alcohol. Oral sex history was categorised as yes or no.Saliva samples were collected using a commercially available kit , and analysed for HPV status using the optimized general primer (GP)+PCR system, which detects most mucosal HPV types and all high-risk HPV types. All HPV DNA positive samples were sequenced to confirm viral DNA sequences. Detail on the laboratory processes has been published elsewhere . For theAt 12 month follow-up, self-reported periodontitis was assessed using eight periodontitis screening questions which have previously been validated among non-Indigenous Australians as part of the Australian National Survey of Adult Oral Health (2004–2006) administered via questionnaire . The eigThere were two main outcomes: first, the presence of any high-risk oral HPV (Yes/No); and second, the presence of two specific subtypes, HPV 16 and/or 18 (Yes/No). Individuals were classified as having any high-risk HPV if they had a saliva sample positive for any one of the following HPV subtypes: 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and/or 70 in line with IARC classifications . For oraDescriptive analyses were undertaken to ascertain frequencies of all eight questions on self-reported periodontitis as well as the frequency of any high-risk oral HPV, and separately, any HPV 16 and/or 18 subtypes. Bivariate analyses were initially conducted to explore relationships between oral HPV status and sociodemographic status, health-related behaviours, sexual history characteristics and periodontitis. Logistic regression models were undertaken to examine the association between self-reported periodontitis and separately, high-risk oral HPV and HPV 16 and/or 18. Estimates are reported as an odds ratio (OR) with 95% confidence interval (CI). Models were adjusted for potential confounders reported in the literature –22 alongThis study was granted ethics approval from the University of Adelaide Human Research Ethics Committee and the Aboriginal Health Council of South Australia’s Human Research Ethics Committee (H-2016-246). Interviewers (Indigenous and non-Indigenous) with extensive experience of working with Indigenous Australians conducted the surveys at each time point. Participant information sheets were shared with the participants in plain English language before commencing the survey. Participants provided written informed consent.Data on oral HPV status and periodontitis status were available for 673 participants (89.9% of the follow-up cohort) at the follow-up. Regarding sociodemographic characteristics, just over half were aged 40 years or younger (50.5%), more than two thirds were females (68.5%), living in non-metropolitan location (65.9%), and had attained a high school-level education (66.6%). Three quarters of participants were smokers (74.7%) and 91.2% had currently or previously consumed alcohol. Sixty five percent of participants reported a history of oral sex . OverallIn the bivariate analyses, being ≤40 years and living in metropolitan location were both significantly associated with the presence of any high-risk oral HPV . Regarding HPV 16 and/or 18, there was a significant association between age and the presence of HPV 16 and/or 18 .In the unadjusted models, there was no significant increase in odds of either any high-risk oral HPV or HPV 16 and/or 18 among individuals with self-reported periodontitis  Tables . Both adTo the best of our knowledge, this is the first study to evaluate the association between high-risk oral HPV and periodontitis among Indigenous South Australians. Overall 6.0% of participants had any high-risk oral HPV (IARC classification) and HPV 16 and/or 18 subtypes were detected among 2.1%. Our estimates of any type of high-risk oral HPV are lower than estimates reported among non-Indigenous Australians  and otheOur study did not find any significant association between self-reported periodontitis and the presence of any high-risk oral HPV or the specific HPV 16 and/or 18 subtypes. This is in contrast to a previous study among Hispanic individuals which found a significant correlation between oral HPV and periodontitis; however, that study focused on any type of HPV and did not report high-risk subtypes alone . A furthThe conflicting results of the published literature are likely due to methodological differences in the detection and definition of periodontitis, as some studies have used radiographic assessment, whereas others are based on a clinical assessment or self-reporting . FurtherThere are a number of possible mechanisms which could relate periodontitis with oral HPV persistence. Periodontitis is the result of an inflammatory response of the pathogens that leads to pocketing, alveolar bone loss, and subsequent tooth loss , 32. It The clear biological plausibility underpins the need for future targeted studies using validated clinical data on periodontitis to clarify the relationship between periodontitis and high-risk oral HPV. This information is essential as it would allow screening and ongoing monitoring of individuals with periodontitis to reduce the persistence of oral HPV which in turn may reduce the risk of HPV-positive OSCCs, particularly in high-risk groups such as Indigenous Australians. Moreover, the detection of high-risk oral HPV in Indigenous adults in our study reinforces the continued need for dental counselling on the importance of good oral hygiene and also the importance of HPV vaccination among Indigenous peoples, given the known efficacy of vaccination against oral HPV infection .It is also recommended that dentists should advise patients about the risk of HPV and promote public awareness of oral health and HPV-related risks of cancer. As the current diagnosis of OSCCs relies on patient presentation and oral physical examination plus biopsy, most OSCCs are diagnosed at a late stage, reflected in less than optimal survival rates. As a result, new approaches to screening are required to permit early detection and management. Implementation of screening for OPSCCs as part of routine dental care should be considered. This is particularly pertinent for Indigenous peoples, who experience both a higher incidence rate and lower survival rate from OSCCs than non-Indigenous Australians.There are several limitations that should be considered when interpreting the findings of this study. First, participants were not representative of the entire Australian Indigenous population, therefore, findings may not be generalizable. Second, the cross-sectional nature of data collection limits examination of temporality, and possible causal relationships. Third, a self-reported questionnaire was used to collect information from sociodemographic variables and also for assessing periodontitis and could be subject to recall bias. Fourth, clinical assessment of periodontitis was not possible due to restrictions on travel and clinical consultations during the COVID-19 pandemic. Therefore, a non-validated self-reported tool was the best available assessment. Strict criteria were used to define periodontitis, through the inclusion of questions that have been shown to have high sensitivity and specificity for detecting periodontitis among non-Indigenous Australians. As a result, it is possible that our criteria only identified participants with moderate to severe periodontitis, which may explain our null findings. Nevertheless, clinical and radiographical assessments of periodontitis are costly, time-consuming, and often not feasible in large population-based studies. Further exploration and validation of self-reported measures of periodontal disease is an important area of future research to permit lower-cost population assessment of periodontitis. Finally, the types of HPV found in the mouth are almost entirely sexually transmitted. Several sexual behaviours could affect the transmission of HPV in the mouth for example number of sexual partners, unprotected sex, and age at first sex . HoweverThis study did not find any association between self-reported periodontitis and high-risk oral HPV among Indigenous South Australians. Further studies using the clinical diagnosis of periodontitis are needed to evaluate the role of periodontitis in the acquisition and persistence of high-risk oral HPV, as this may help in identifying individuals at high-risk of oncogenic HPV and thus OPSCC.S1 Checklist(DOC)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.


The development of immune checkpoint inhibitors (ICIs) has greatly improved survival of patients with advanced malignancies. ICIs can cause immune-related adverse effects (irAEs) involving any organ. Neurological irAEs are infrequent and have mostly been reported in patients with melanoma. We describe the case of a 57-year-old male with right eye uveal melanoma, gene expression profile (class 2), and PRAME  positivity, who received plaque brachytherapy with Iodine-125 for 4 days with subsequent adjuvant ICIs (immune checkpoint inhibitors), nivolumab and ipilimumab. 18 weeks after discontinuation of immunotherapy, the patient presented with acute onset of left-sided headaches, pain with eye movements, and vision loss. The patient was tested positive for serum anti-aquaporin-4 antibody (AQP4-Ab) and was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). Subsequently, he was treated with 5 days of intravenous methylprednisolone followed by an oral prednisone taper over 10 weeks, with improvement in symptoms. We report a unique case of neuromyelitis optica spectrum disorder (NMOSD) following treatment with ICIs. To our best knowledge, this is the third reported case in English literature of NMOSD following ICI therapy and the first reported case of NMOSD caused by ICI treatment in uveal melanoma. The development of immune checkpoint inhibitors (ICIs) has greatly improved survival of patients with advanced malignancies such as melanomas and non-small-cell lung cancers over the last decade –11. The The patient was a 57-year-old man with the diagnosis of right-eye uveal melanoma since 2017. His uveal melanoma had a high-risk gene expression profile (Class 2) and was positive for the cancer-testis antigen PRAME which stands for “preferentially expressed antigen in melanoma”. Primary treatment consisted of plaque brachytherapy with Iodine-125 for 4 days with subsequent adjuvant ICI, nivolumab 240 mg intravenously every 2 weeks, and ipilimumab 1 mg/kg intravenously every 6 weeks, on a clinical trial. ICIs were discontinued after 18 weeks due to development of side effects including pneumonitis, uveitis, and hypophysitis. He required high-dose steroids, mechanical ventilation, and physiologic hormone replacement of thyroid and cortisone. Three months later, the patient presented with acute onset of left-sided headaches, pain with eye movements, and vision loss. Neuro-ophthalmology examination revealed visual acuity of 20/30 in the right eye (OD) and 20/40 in the left eye (OS) with left relative afferent pupillary defect (RAPD). Color vision (Hardy–Rand–Rittler) was 5/14 OD and 4/14 OS. Intraocular pressures were within normal limits in both eyes. Slit-lamp examination was unremarkable. Extraocular motility was full, but with left-eye discomfort with eye movements. Dilated fundus exam showed circumferential optic disc edema with peripapillary hemorrhage OS and a normal disc in the OD. Humphrey visual field (HVF) 24-2 showed an inferior altitudinal defect in the left eye Figure 2Based on diagnostic criteria, the patient was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) and was treated with 5 days of 1,000 mg intravenous methylprednisolone followed by an oral prednisone taper over 10 weeks, with improvement in symptoms. He remained on physiologic hydrocortisone for adrenal insufficiency from hypophysitis. The patient was referred to a neurologist for further management of NMOSD. After extensive discussion regarding eculizumab vs. rituximab between medical oncology, neuro-ophthalmology, and neurology, the mutual decision was made to move forward with rituximab for treatment of this patient’s NMOSD at a dose of 1,000 mg intravenously every 6 months. Interestingly, the patient was found to have low IgG levels, and he was started on intravenous immune globulin (IVIG) along with rituximab. The etiology of low IgG levels is unknown and could be related to the ICI treatment. The timeline of his diagnoses and treatment is illustrated in Our patient developed anti-AQP4 antibody-positive NMO 3 months after receiving adjuvant treatment with the ICIs nivolumab and ipilimumab for a total of 18 weeks. NMOSD is a central nervous system (CNS) inflammatory disease spectrum that is associated with serum AQP4 immunoglobulin G (IgG) antibodies . The mecOur patient presented with an anti-AQP4 antibody positive NMO after 18 weeks of adjuvant nivolumab plus ipilimumab. To our knowledge, this is the third known case in English literature of NMOSD caused by ICI treatment. The first case was a 75-year-old male with squamous cell carcinoma of the lung who developed transverse myelitis and was anti-AQP4 positive after 1 month of nivolumab treatment . The secThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.KK and SP contributed equally to this work and share first authorship. All authors contributed to the article and approved the submitted version.Author SP received institutional clinical trial or research support from Bristol Myers Squibb, Foghorn Therapeutics, InxMed, Novartis, Provectus Biopharmaceuticals, Reata, TriSalus Life Sciences, is on the advisory board for Cardinal Health, Castle Biosciences, and TriSalus Life Sciences, and has provided consulting services for Advance Knowledge in Healthcare and Immunocore.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Previous research has confirmed that symptoms of postnatal depression (PND) can be ameliorated through internet-delivered psychological interventions. Advantages of internet-delivered treatment include anonymity, convenience, and catering to women who are unable to access face-to-face (FTF) treatments. To date, no research has examined the efficacy of such interventions compared directly with FTF treatments in women clinically diagnosed with PND.MumMoodBooster [MMB]) with FTF-CBT in a randomized controlled trial (RCT).This study aims to compare the efficacy of one of the first web-based cognitive behavioral therapy (CBT) interventions  for PND  diagnosis of major or minor depression were randomized to MMB , FTF-CBT , or a treatment-as-usual (TAU) control condition . Diagnostic status was determined at baseline and at 21-week follow-up using the Structured Clinical Interview for the DSM-IV. Severity of anxiety and depressive symptoms was evaluated using the Depression Anxiety Stress Scales and the revised Beck Depression Inventory at baseline, 12-week follow-up (after treatment), and 21-week follow-up.In this study, 116 postnatal women with a Of the 116 participants, 107 (92.2%) had a diagnosis of major depression at baseline. Rates of remission from a major or minor depressive episode at 21 weeks in both the FTF-CBT and MMB groups were superior to that of the TAU group  and they were not significantly different from each other. Although remission rates differed between TAU and FTF-CBT, growth models showed that, in terms of symptom reduction across time, the FTF-CBT treatment was not significantly better than TAU. By comparison, MMB was statistically superior to both TAU and FTF-CBT in reducing symptoms of depression, anxiety, and stress from baseline to the 21-week follow-up (large and moderate effect sizes). Thus, after 21 weeks, the average symptom scores for depression and anxiety of women receiving MMB were approximately half those of women in both the TAU and FTF-CBT groups.In this RCT, MMB was at least as effective as FTF-CBT in achieving remission from a diagnosed PND episode. MMB was superior to TAU and FTF-CBT in encouraging and maintaining reduction of symptom severity over the 21-week follow-up for depressed postnatal women. These findings replicate results of prior studies on MMB that showed clinically significant improvements in depressive symptoms, and they provide direct empirical support that internet-delivered treatment for depressed postnatal women is a viable alternative to FTF treatment. The generalizability of the results needs to be examined in future research, as RCTs of internet-based versus FTF treatments necessarily involve a subset of people who are willing to undertake either modality of treatment.Australia and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000881730; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364683&isReview=true A substantial proportion of new mothers suffer from postnatal depression (PND). A meta-analysis by Gavin et al  estimateA considerable body of research supports the effectiveness of cognitive behavioral therapy (CBT) interventions for depression in clinical settings ,8. Approsafety net for individuals who may need additional help should their situation worsen. Alliance with a trustworthy coach is central to this model, and a number of studies have shown that a strong web-based working alliance can be achieved in guided internet-delivered treatments for posttraumatic stress disorder and depression [Reviews of the available evidence -19 have pression ,23. The pression -19.The balance of existing evidence ,24-26 subad mother, feelings of failure, poor understanding of depression or the available help, concern about medication being passed through breastmilk [PND is undertreated: fewer than half of perinatal women seek help even when identified as depressed . Barriereastmilk , and difeastmilk . Interneeastmilk . Similartechnician or coach support). The emerging picture suggests that internet interventions may help overcome several important barriers to seeking treatment in perinatal populations, and they have the potential to offer a scalable alternative for the delivery of psychological treatments.Spurred by these possibilities, a number of such internet interventions have been developed to address maternal perinatal depression. Beginning with our own work , the delMeta-analyses suggest that internet interventions have achieved medium-sized effects in reducing perinatal depressive symptoms, usually in comparison with TAU or waitlist control conditions -52. To dThis study aims to evaluate remission from clinical depression and reduction of depressive and anxiety symptom severity among a sample of postnatal women with diagnosed depression. We aim to evaluate the relative efficacy for women randomly assigned to (1) MMB, a guided version of an internet intervention for PND; (2) a validated FTF-CBT program for PND; and (3) TAU. The secondary aim of this randomized controlled trial (RCT) is to compare the 2 active conditions with respect to symptom trajectory, stress, and process measures of treatment engagement, competence in the mothering role, marital functioning, acceptability, and satisfaction.Our a priori hypothesis was that women allocated to either of the 2 active conditions (MMB and FTF-CBT) would have significantly higher remission rates, greater reductions in depression and anxiety symptoms, and greater improvement in secondary outcomes compared with the TAU condition but that MMB and FTF-CBT would not differ significantly from each other.This study was a parallel 3-group RCT involving 116 participants and consistent with the CONSORT standards ,54. The Screening and recruitment were conducted via maternal and child health centers in rural and metropolitan Victoria, Australia, and by localized advertising on the internet, in newspapers, and on the radio. The project was conducted between August 2014 and November 2017.Inclusion criteria were determined in 2 phases. Phase 1 criteria included the following: Edinburgh Postnatal Depression Scale  scores oDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, posttraumatic stress disorder, risk of suicide, and under current treatment for depression (medication or psychotherapy). Women who received a diagnosis of major or minor depressive episodes and who met all other eligibility criteria were invited to participate. Women who gave written consent and completed the baseline assessment were then randomized to a study condition.Women found eligible in the screening phase 1 were subsequently assessed in phase 2 by a clinical psychologist or a provisional psychologist in a phone-administered SCID-IV . ProspecWomen were randomized in a 1:1:1 ratio to 1 of the 3 conditions: internet-based CBT with telephone support , individual FTF-CBT , or TAU . An automated permuted block  allocation schedule was pregenerated by a computer by an independent technician. Allocation concealment was ensured by a central, computer-automated administration. Upon completion of baseline questionnaires, the system assigned the participants to 1 of the 3 conditions. Their allocation was subsequently revealed to them in a phone call. Given the nature of the treatment conditions, allocation could not be concealed from participants beyond the point of allocation.MMB is designed to deliver content that is similar to FTF depression treatment, with tailored, interactive activities used to address individual issues and engage women. Support from a telephone coach is intended to encourage women to use and complete the program. The initial steps of the program provide explicit direction, whereas the latter steps encourage participants to assume increasingly greater responsibility for managing their own plan for change.You and Your Partner provides content relevant to partners of women with PND. In addition, MMB enables participants to choose whether to invite their partner to use a free-standing partner support website with a separate user log-in. The MMB library also includes articles on relaxation, problem solving, and getting support for parenting . As deser et al ,43,60,61Weekly low-intensity telephone coaching support (30 minutes maximum per week) was provided. Rather than providing therapy per se, coaches were instructed to reinforce participant progress, encourage program use (practice of strategies and completion of tasks), and introduce the themes of upcoming sessions. In an initial welcome call, the assigned MMB coach explained the MMB core structure, additional library articles, and partner website. Coaches were able to access a secure administrative website to review each participant’s program use to help tailor their support. Coaching call fidelity was facilitated by the use of a manualized script and a session-by-session checklist. Coaching calls were provided over a period of 9 weeks, which enabled participants to work through the 6 sessions at <1 session per week and allowed for the rescheduling of up to 3 missed coach calls.Getting Ahead of Postnatal Depression program [relax on the run), getting support, and dealing with partner issues. The program included 1 additional session that involved both participants and their partners [Women in the FTF-CBT condition were scheduled to receive weekly individualized CBT therapy from an experienced psychologist who followed a detailed, scripted manual for delivery of the  program ,62. This program ,63,64, aAfter screening was completed on the web, the research protocol was explained to potential recruits and following a SCID-IV interview, if randomized to FTF-CBT, participants visited their general practitioner (GP) with a referral letter from the study to arrange treatment with a suitable local psychology provider located by the research team. Psychologists kept session-by-session checklists of items covered in the FTF-CBT program. A report was also sent to the GPs of participants in the other 2 conditions; however, their GPs were not actively encouraged to connect their patients with a local psychology provider.Women in the TAU condition were referred back to their GP supplemented with a written summary of their diagnostic assessment. Support and referral to other services could then occur as necessary as typically occurs in Australia when specialized programs are not available.Measures were collected primarily using web-based questionnaires, although phone calls were also used, as described in the following section . All parDSM-IV diagnosis of major depression or minor depression [Trained diagnostic interviewers blinded to treatment allocation conducted the SCID-IV  by phonepression . To measpression ,67, a wepression -70 and hpression . The 9-ipression  was usedpression ,72 (inclpression ), (2) hapression , (3) haspression , and (4)pression . Participression ,78. The pression .Participants completed the 30-item Automatic Thoughts Questionnaire (ATQ) . The ATQParticipants completed the 25-item Behavioral Activation for Depression Scale , which mDrawing upon Bandura’s theoretical work, Wittkowski et al  describeWomen’s relationships with their partners were assessed using the 7-item Dyadic Adjustment Scale . The genParticipants in the MMB and FTF-CBT conditions were asked to rate their satisfaction with their assigned treatment as well as a set of select treatment components using a 4-point scale . MMB participants were also asked to rate the helpfulness of phone coach calls using a 4-point scale .Participants were asked to complete a checklist of other support services and treatments they used during the study interval.MMB use  was tracked continuously and unobtrusively via database flags and analysis of server activity logs .Coaches in the MMB condition and psychologists in the FTF-CBT condition recorded data on participant session completion on session-by-session compliance checklists itemizing the elements of each session plan covered. A subset of coaching calls and FTF-CBT therapy sessions were audio recorded (with permission) to facilitate fidelity checks.All measures were collected at baseline, 12-week posttest, and 21-week follow-up, except for the SCID-IV diagnostic assessment, which was not conducted at 12 weeks. In addition, the PHQ-9 was also monitored during safety calls at weeks 3, 5, 9, and 16 after enrollment. The follow-up time point of 21 weeks was selected to reflect 3 months of posttreatment completion (with MMB and FTF-CBT treatment taking 9 weeks to complete).Symptom severity and safety of participants in each of the RCT conditions were monitored in calls for all conditions using the PHQ-9. A written risk management protocol, based on the successful approach of Simon et al , was iniDepression remission was assessed using the evidence-based definition of Frank et al , which rCategorical outcomes  were analyzed using contingency tables and logistic regression; survival analysis (Cox regression and Kaplan–Meier product limit) was used to predict time-to-remission of the index depressive episode using the results from follow-up interviews. Continuous outcomes  were analyzed using random-effects regression models, accommodating time-independent and time-dependent covariates, fixed and random factors, and incomplete data.Random-effects growth models were estimated from baseline (the intercept) to the 21-week follow-up using the PROC MIXED procedure in SAS 9.2 (SAS Institute). The growth models were estimated with full information maximum likelihood and an unstructured variance/covariance matrix, and the intercepts and slopes were allowed to vary. First, unconditional means models were run for each outcome and the estimated and observed data plotted. Next, linear conditional growth models were run with time coded in weeks since the pretest assessment. All primary analyses to address major hypotheses adhered to intention-to-treat principles, and 3 a priori comparisons were examined: MMB versus TAU, FTF-CBT versus TAU, and MMB versus FTF-CBT . The condition×time interaction is a test of the efficacy of the program for each a priori comparison. The effect size for the condition×time interaction was computed as a d-statistic equivalent .Descriptive statistics and plots were used to screen all outcomes for normality and outliers. No serious violation of normality was found, with the exception of anxiety at 12 and 21 weeks, which showed a preponderance of zeros. During modeling, anxiety scores were examined in their normal metric and also log transformed to better approximate normality. A participant was flagged as an outlier on anxiety and stress at the 12-week assessment. During modeling, the outlier was evaluated for its impact on change over time.clinical depression . With 80% power at α=.05, the required n=15.7×(8.09/6.5)2=24.3, which rounds up to 25. Taking into account a prudent noncompliance rate of 30%, the adjusted sample size, n* = 25 / (1 − 0.3)2 = 51, which rounds up to 55. Thus, an estimated n=70 per condition yielded sufficient power to detect a small between-group effect size and a minimum clinically important difference in the primary measure of symptom severity. This sample size was not achieved within the funding period; however, post hoc analysis of power with the sample size achieved confirmed sufficient power to address the minimum clinically important difference for the primary outcomes. We had sufficient power (>80%) to detect significant group differences (P<.05) in our primary outcomes. We used a simulation approach with 1000 replications using the likelihood ratio test [An a priori consideration of power suggested that for the survival analysis predicting time-to-remission from the index episode, with a 2-tailed α of .05, n=70 per condition would yield 80% power to detect a small effect size (hazard ratio 2.0). For the measure of depressive symptoms (BDI-II), data from previous work by Milgrom et al  providedtio test  and implAt baseline and during the routinely scheduled safety monitoring calls , all participants completed the 9-item PHQ-9 over the telephone. These data were used to calculate the trajectory of depressive symptom changes over time.A total of 116 participants were randomized during the study period. A range of primiparous and multiparous, high-income and low-income women were included (see participant baseline characteristics in P=.57), any of the demographic characteristics in P>.22), or baseline measures of the primary or secondary outcomes .Failure to complete scheduled assessments (attrition from the study) was 12.9% (15/116) at the 12-week assessment and 20.7% (24/116) at the 21-week assessment . AnalysiOf the women allocated to the MMB intervention, 85% (33/39) completed ≥3 MMB sessions, and 72% (28/39) viewed all 6 MMB sessions. The MMB program was not visited by 3% (1/39) of participants. Of the women who visited MMB at least once, the mean number of sessions viewed was 5.6 (SD 1.7), and the mean number of visits was 15.6 (SD 8.7). The mean total time spent using MMB averaged 230 (range 2-440) minutes. The mean number of library articles accessed was 3.5 out of a possible 8, and the mean number of activities accessed was 15 out of 63. Approximately 39% (15/39) of participant partners accessed the partner support website.Of the women offered FTF-CBT, 62% (24/39) completed ≥3 sessions, 51% (20/39) finished ≥6 sessions, and 46% (18/39) completed all 10 sessions. Approximately 31% (12/39) of women did not attend any FTF sessions. The mean number of FTF-CBT sessions attended for all 39 women was 5.5 (SD 4.5).DSM-IV diagnosis of either major or minor depression; 92.2% (107/116) of the sample had a major depression diagnosis. χ21=0.1, P=.81). At baseline, all women in all 3 groups had a Parameter estimates from the growth models for each a priori comparison are provided in t value and P value indicate that the intercept is significantly different from 0 (P<.001). The condition parameter (−2.154) indicates that the MMB condition had an estimated baseline score that was 2.15 points lower than the TAU group. The t value and P value indicate that the lower baseline depressive score for the MMB condition was not statistically significant (P=.24). The time parameter (−0.614) indicates that the TAU group had an estimated linear decrease in depressive symptom score of 0.61 points for each week through the 21-week follow-up assessment. The t value and P value indicate that the weekly linear decrease for the TAU group is significantly different from 0 (P<.001). The condition×time interaction term (−0.3029) indicates that the MMB group decreased an additional 0.30 points each week through the 21-week follow-up. The t value and P value indicate that the greater decrease over time for the MMB group relative to the TAU group was statistically significant (P=.01). In d) for all the condition×time interaction terms is presented in d=−0.83) and medium-sized reductions in anxiety (d=−0.42) and perceived stress (d=−0.73). Compared with the FTF-CBT condition, MMB participants reported large reductions in both depressive symptoms (d=−0.98) and perceived stress (d=−0.89). The TAU and FTF-CBT conditions did not differ significantly in any of the outcome measures.The effect size (Of the 79.3% (92/116) of participants who responded to this questionnaire, approximately 19% (6/32) of participants in the TAU group and 6% (2/31) of participants in the FTF-CBT group reported using depression medication. None of the MMB participants reported using medication. Approximately 3% (1/31) of women in the FTF-CBT group, 7% (2/29) of women in the MMB group, and 6% (2/32) of women in the TAU group reported having taken part in group therapy. Approximately 23% (7/31), 21% (6/29), and 13% (4/32) of women in the FTF-CBT, MMB, and TAU conditions, respectively, reported using self-help books, and 2 women each in the MMB and TAU groups reported having used acupuncture or hypnotherapy.P=.02).Participants in the 2 active conditions (FTF-CBT and MMB) rated the helpfulness of their treatment on a rating scale of 0 to 3. Compared with those in the MMB group , participant ratings in the FTF-CBT group  were significantly higher  out of a possible 3 points. MMB participants further rated their satisfaction (from 0 to 3) with the following features of the internet program: mood tracking , pleasant activities , strategies to reduce negative thinking , strategies to increase positive thinking , partner support program , library articles , and videos .Existing research confirms that PND can be successfully treated by internet-delivered psychological interventions . HoweverIn a sample of postpartum women, 92.2% (107/116) of whom had a major depression diagnosis and were in the moderate-to-severe range for depression symptoms on the BDI-II, we found that the MMB internet-delivered treatment program performed at least as well as FTF-CBT on remission from a diagnosed depressive episode at 21 weeks. Moreover, MMB was also significantly more effective than FTF-CBT in reducing depression symptom severity and perceived stress over time. Compared with TAU, MMB was significantly more effective in reducing depression, anxiety, and perceived stress. At follow-up, depression and anxiety symptom scores for MMB participants were approximately 50% lower than those observed in the FTF-CBT and TAU conditions.These results are broadly consistent with the literature that delivery of psychological treatments via the internet can be as effective as traditional FTF approaches for treating depression and anxiety -28,88,89The use of coaches as an adjunct to the MMB program may have contributed to the relatively low attrition in this condition and enhanced the effectiveness of the MMB program. This is consistent with our previous trials of MMB ,91 and wThis study has a number of strengths. First, this RCT produced very similar effect sizes for reductions in depression and anxiety symptoms and the rate of session attendance and program adherence compared with those we observed in our 2 previous trials of MMB ,43. In oImportantly, this research provides the first direct comparison of internet-delivered psychological treatment for perinatal depression with evidence-based FTF treatment. This was achieved in a sample of women clinically diagnosed with depressive disorders rather than in a sample of women with a mix of subclinical symptoms assessed using screening tools as in many existing studies.other supports found in the TAU group, the participants assigned to the MMB condition reported greater reductions in depression and anxiety symptom scores.Furthermore, the rate at which participants accessed other treatments outside of those provided in the trial was low and appeared similar in the 2 active treatment groups. However, despite the higher use of Our use of a 3-arm RCT that included TAU and intention-to-treat analyses gives us further confidence in interpreting these results. As such, this study extends the literature showing promising results from trials of internet-based treatments for PND ,51.The FTF-CBT intervention was primarily provided by practicing psychologists in the community, making the comparison as close an approximation as possible to a real-world treatment option. In Australia, FTF-CBT is 1 of the 2 main treatments that postnatal women with depression are likely to be offered (the other being antidepressant medication).As our results showed that MMB was at least comparable with traditional FTF-CBT in efficacy, its more widespread implementation could potentially increase the reach of treatment to benefit women with PND not currently accessing traditional services because of geographic or social isolation or through a preference for anonymous, nonclinical settings.The study has a number of limitations that should be noted, some of which are common to most RCTs. Our observed 21-week outcomes may have reflected some cases in which relapse occurred after treatment completion, perhaps in both of the active treatments as well as some spontaneous recovery over time in the TAU group. Participants in this study agreed to be assigned to any of the 3 possible experimental conditions; therefore, they may be a particular subset of the population and not representative of postnatal women with depression as a whole. It is possible that our study results may not generalize to women who would have preferred to use only the internet intervention (MMB) or alternatively only attend the clinic-based FTF-CBT treatment. Furthermore, given the nature of the intervention, the participants could not be blinded beyond the point of treatment allocation. Finally, the limited sample size was not sufficiently powered to examine subgroup differences or the moderating effects of baseline participant characteristics.Emerging evidence suggests that the COVID-19 pandemic is seeing substantial increases in perinatal mental health difficulties ,95 concublended or guided approach that combines clinical therapy or counseling with internet program content show promise [Various options for deploying digital delivery as part of a  promise -101, wit promise . Systema promise , and bas promise ,104,105,Evaluation is also warranted for the stepped-care model or adaptive treatment strategies for moderate depression and anxiety symptoms that offer a standalone internet intervention as an initial treatment option ,107. FutThe current trial replicated key findings of prior MMB studies, providing further evidence that internet-delivered treatment for postnatal women with depression is a viable treatment option. These findings are broadly consistent with the notion that speed of access, anonymity, and convenience may be specific advantages of internet-delivered treatment for women who prefer not to engage in traditional treatment modalities. Notably, this study also provides empirical evidence that participants assigned to the MMB condition report greater treatment gains compared with those assigned to the TAU and FTF-CBT conditions.


Letter to the Editor—We describe a case of delayed COVID-19 diagnosis due to unrecognized community transmission in Atlanta, Georgia, in mid-February 2020. This case resulted in transmission of COVID-19 to 3 of the 4 healthcare workers present during a diagnostic bronchoscopy procedure where only procedural masks were worn.1On February 28, 2020 the Centers for Disease Control and Prevention (CDC) announced guidelines recommending COVID-19 testing for persons with compatible symptoms and either recent travel to COVID-19 affected regions, contact with known COVID-19 cases, or “fever with severe acute lower respiratory illness ”  for the evaluation of persistent fevers, which began around February 21, 2020. His only other symptom was very mild dyspnea on exertion. He denied any travel outside of the Atlanta area over the past several years. A family member at home had a febrile illness and was recovering at home. He also had a coworker with a febrile illness, but neither contact had any recent travel history. The patient worked in a nearby restaurant frequented by CDC and Emory University employees during lunch breaks, and he resided in Atlanta, Georgia.On March 2, 2020, Georgia officials announced the first 2 cases of coronavirus disease 2019 (COVID-19) in the state, among a Fulton County man who had recently returned from Italy, and his teenaged son.His initial evaluation in the ED showed normal vital signs and flu and respiratory syncytial virus rapid tests were negative. He was admitted to the medical floor for further evaluation, where droplet and contact precautions were continued for the remainder of hospitalization. Subsequent evaluation revealed a negative HIV test and negative respiratory viral panel. A computerized tomography scan of the chest revealed “peripheral ground-glass with associated consolidation worse in bilateral lower lobes.” Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) testing was considered and discussed among the hospital medicine, infectious disease, and pulmonary consultation services; however, the patient did not meet the recommended CDC criteria for novel coronavirus testing at that time because he had no relevant travel history, contact with known cases, or severe illness. No commercial or other testing options were available at the time.On the third day of his hospitalization, he underwent diagnostic bronchoscopy, and staff wore procedural masks. The patient was discharged later that day because he was feeling well and his fever had resolved. He was instructed to remain isolated at home for at least 1 week. Bronchoalveolar lavage fluid was sent for bacterial, fungal, and AFB cultures, which were negative. BAL fluid cellular differential was notable for having 94% macrophages. Cytology was negative for microorganisms, and a Biofire FilmArray Respiratory panel was negative. On March 11, as more SARS-CoV-2 testing capacity became available, his remaining bronchial fluid was mailed to Associated Regional and University Pathologists (ARUP), and it tested positive for SARS-CoV2 virus on reverse transcriptase PCR testing on March 14.The patient was notified of his test results by telephone, and he reported feeling well with no reoccurrence of fevers or other new symptoms. Within the following week, 3 of the 4 healthcare workers present during the bronchoscopy tested positive for SARS-CoV-2.3 The precise source of this patient’s COVID-19 remains unknown, but it may have been acquired from either his coworker or a family contact. Due to both restrictive CDC testing criteria and a lack of available SARS-CoV-2 testing outside of public health laboratories, this patient was not diagnosed when rapid public health actions, including contact tracing and isolation, could have limited community spread of this disease. This case also illustrates the risk of SARS-CoV-2 transmission to healthcare workers during bronchoscopy when COVID-19 is not recognized and procedural masks are used instead of N95 or other high-level respirators.This case provides evidence of community transmission of SARS-CoV-2 in Atlanta, Georgia, likely between February 10 and February 19, 2020, based on our current knowledge of the incubation period for SARS-CoV-2.


The laboratory biomarkers, procalcitonin (PCT) and D-dimer, were significantly higher in the weaning failure group, as were the biomarkers of endothelial injury, such as angiopoietin-2 (Ang-2) and Ang-2/Ang-1, and tumor necrosis factor-α (TNF-α). Patients’ qSOFA scores, SpO2/FiO2, and PCT, D-dimer, Ang-2, Ang-2/Ang-1, endocan (4-day and 7-day increases), and TNF-α levels predicted weaning failure; 7-day endocan levels were the best predictor of weaning failure with an AUC of 0.81 . We identified clinical and laboratory parameters, including plasma biomarkers of endothelial injury, that may be considered as biomarkers for predicting failure of liberation from oxygen therapy in patients with severe COVID-19.This study aimed to investigate whether clinical and laboratory biomarkers can identify patients with COVID-19 who are less likely to be liberated from oxygen therapy. This was a retrospective study comparing 18 patients in the weaning failure group with 38 patients in the weaning success group. Weaning failure was defined as death or discharge with an oxygen device before day 28 after hospital admission or requiring oxygen support as of day 28. The median quick Sequential Organ Failure Assessment (qSOFA) score was significantly higher and the median SpO Coronavirus disease 2019 (COVID-19) has now spread to over 220 countries worldwide, approaching 224 million cumulative cases and reaching 4,627,540 deaths as of 14 September 2021 .Early identification of laboratory predictors of progression to severe COVID-19 has been extensively studied, as valid predictors may help guide risk stratification and clinical management, allocate limited medical resources, and target patients for interventional studies. Recent meta-analyses of numerous studies worldwide have found significant associations between hematologic, biochemical, coagulation, and inflammatory biomarkers and COVID-19 severity ,5. In adPatients with severe COVID-19 may not be functionally independent at hospital discharge due to old age, comorbidities, and/or prolonged mechanical ventilation (MV). In a recent study investigating the functional status of COVID-19 survivors receiving MV, half of the patients were discharged with supplemental oxygen . The earThis study aimed to analyze clinical and laboratory parameters in patients with severe COVID-19 to discriminate patients who were less likely to be liberated from oxygen therapy. Baseline values and changes during the 7-day study period were assessed to account for dynamic changes of biomarkers in terms of predicting outcomes.In this retrospective single-center study, we enrolled confirmed COVID-19 pneumonia cases in an 835-bed university-affiliated tertiary hospital in Seoul, Republic of Korea. Patients were hospitalized between June 2020 and March 2021. We excluded patients who did not receive oxygen or who had substantial missing data. For the present study, we measured plasma biomarkers of endothelial/epithelial injury and inflammation using prospectively collected blood samples for the investigation of clinical characteristics and viral shedding among patients with COVID-19. Written informed consent was obtained from the patient or their next of kin. The study was approved by the Chung-Ang University Hospital Institutional Review Board (2092-001-432) and was conducted in accordance with the principles of the Declaration of Helsinki.The study patients were divided into two groups according to oxygen therapy status at day 28 after hospital admission. The weaning failure group comprised patients who died or required any form of oxygen support at day 28. Patients who were discharged to long-term care  with MV or low-flow oxygen therapy before 28 days were included in the weaning failure group. The weaning success group comprised patients who were alive and required no oxygen therapy at day 28. Baseline data, clinical outcomes, and changes in laboratory parameters were compared between the two groups.The confirmation of COVID-19 was based on the positive detection of the viral genome in upper respiratory tract specimens using the reverse transcription polymerase chain reaction (RT-PCR) assay , bacteri® Assay Human Premixed Multi-Analyte Kit . The assay was performed according to the manufacturer’s instructions. In brief, 50 μL of the sample and microparticle solution were added to each well of the 96-well microplates. After incubation and washing, a biotin-antibody solution was added. Microplates were incubated and washed again; a streptavidin–phycoerythrin solution was added, followed by another washing procedure. After resuspending the microparticles of each well with a washing buffer, multiple signals generated from each well were read and converted to concentrations using the MAGPIX® Multiplexing System  with Bio-Plex Manager MP/Bio-Plex Manager 6.1 software . Measurements of biochemical parameters were performed using standard laboratory techniques.Simultaneous measurements of biomarkers of endothelial/epithelial injury and inflammation were conducted within plasma samples using the LuminexU test (for continuous variables) and through the chi-squared test or Fischer’s exact test . To assess dynamic changes in biomarker levels during the study period, the areas under the curve (AUCs) were calculated for clinical variables and laboratory parameters with repeated measurements , as previously described [U test. Receiver operating characteristic curve analysis was used to determine the ability of different biomarkers to predict weaning failure. Identification of an optimal cut-off value for each variable of interest was based on Youden’s index [p-values < 0.05 were considered statistically significant. Data analyses were performed using IBM SPSS software  and MedCalc for Windows .Continuous variables were reported as medians and interquartile ranges (IQRs), and categorical variables were reported as numbers and percentages. We compared differences in demographics, clinical variables, and laboratory parameters between the weaning failure and success groups through the Mann-Whitney escribed . The AUC’s index . Kaplan-We initially screened 77 consecutive patients with COVID-19 pneumonia who were admitted to our hospital between June 2020 and March 2021. Twenty patients who did not receive oxygen therapy as well as a patient who had missing baseline laboratory data were excluded from the analysis. A total of 56 patients with severe COVID-19 were included in this study (18 patients in the weaning failure group and 38 patients in the weaning success group).p = 0.01). ARDS  and MV  were more prevalent in the weaning failure group. The median qSOFA score was also significantly higher in the weaning failure group , whereas the median pulse oximetric saturation to fraction of inspired oxygen ratio (SpO2/FiO2) was significantly lower . Further, the median respiratory rate was significantly higher  in the weaning failure group. We did not detect a statistical difference in initial chest radiography or viral load between the groups.Patients’ baseline characteristics and clinical outcomes are described in Compared with the weaning success group, the weaning failure group had longer hospital stays, higher hospital mortality, and higher proportions of hospital-acquired infections . In the Routine laboratory data are shown in p = 0.001) and neutrophil lymphocyte ratio (NLR)  changes were significantly different between the groups , and TNF-α (p < 0.001) was the best predictor when compared with SpO2/FiO2, SOFA score, PCT, and D-dimer  in the prediction model were biomarkers of endothelial injury. As mentioned above, the activation of inflammatory cascades and vasculitis are the central mechanisms underlying severe COVID-19. Thus, measures of endothelial injury may be useful in monitoring patients with COVID-19 not likely to wean from oxygen therapy. Angiotensin-converting enzyme 2 (ACE2) regulates the renin-angiotensin system by converting Ang-2 into Ang-(1–7) and Ang-1 into Ang-(1–9) . SARS-CoThe main strengths of the present study include prospectively collected blood samples and serial analyses of biomarkers. We evaluated dynamic changes in clinical variables and laboratory biomarkers in the weaning failure and success groups during the progression of COVID-19 with the aim of examining differences in the pathophysiology of severe COVID-19 and how these are associated with outcomes. Through longitudinal dissection of various parameters, we found that inflammatory changes (from baseline) may be better predictors of weaning failure than baseline parameters. This study also has some limitations. First, due to its retrospective single-center design, some potential selection bias and confounding variables were not considered. Second, the study cohort sample size and number of patients with weaning failure were relatively low, such that comprehensive statistical analyses  could not be conducted and a comparison of different combinations of biomarkers with varying cut-off levels to predict weaning failure was not feasible in our study. Several potential biomarkers (baseline lymphocytes and IL-6) appeared to be associated with weaning failure, although they failed to reach statistical significance, possibly due to limited sample size. Third, due to the retrospective nature of the study, follow-up data were not available from each patient for several parameters, such as ferritin, PCT, D-dimer, and Ct value. Thus, the predictive values of these parameters during disease monitoring are unclear. Fourth, the high costs of some of the biomarkers evaluated in the current study may be a factor limiting widespread use in clinical practice.In conclusion, abnormal levels of nine clinical and laboratory biomarkers provided moderate discrimination for the prediction of failure to liberate from oxygen therapy at day 28 following hospital admission in patients with severe COVID-19. Four of the nine biomarkers represent endothelial injury, which is a critical determinant of ARDS and organ failure, leading to decreased pulmonary function and prolonged oxygen support. These biomarkers may thus be useful indicators in the early rehabilitation of high-risk patients and may potentially be implemented in selecting patients for discharge to long-term care facilities or long-term in-home care . Our findings should be validated within highly powered studies. If confirmed, our findings will inform medical guidelines and medical decision-making.


Routine HIV testing accompanied with pre-exposure prophylaxis (PrEP) requires innovative support in a real-world setting.This study aimed to determine the usage of HIV self-testing (HIVST) kits and their secondary distribution to partners among men who have sex with men (MSM) in China, who use PrEP, in an observational study between 2018 and 2019.In 4 major cities in China, we prospectively followed-up MSM from the China Real-world oral PrEP demonstration study, which provides daily or on-demand PrEP for 12 months, to assess the usage and secondary distribution of HIVST on quarterly follow-ups. Half of the PrEP users were randomized to receive 2 HIVSTs per month in addition to quarterly facility-based HIV testing. We evaluated the feasibility of providing HIVST to PrEP users.We recruited 939 MSM and randomized 471 to receive HIVST, among whom 235 (49.9%) were daily and 236 (50.1%) were on-demand PrEP users. At baseline, the median age was 29 years, 390 (82.0%) men had at least college-level education, and 119 (25.3%) had never undergone facility-based HIV testing before. Three months after PrEP initiation, 341 (74.5%) men had used the HIVST provided to them and found it very easy to use. Among them, 180 of 341 (52.8%) men had distributed the HIVST kits it to other MSM, and 132 (51.6%) among the 256 men who returned HIVST results reported that used it with their sexual partners at the onset of intercourse. Participants on daily PrEP were more likely to use HIVST  and distribute HIVST kits  than those using on-demand PrEP.MSM who used PrEP had a high rate of usage and secondary distribution of HIVST kits, especially among those on daily PrEP, which suggested high feasibility and necessity for HIVST after PrEP initiation. Assuming that fourth-generation HIVST kits are available, HIVST may be able to replace facility-based HIV testing to a certain extent.Chinese Clinical Trial Registry ChiCTR1800020374; https://www.chictr.org.cn/showprojen.aspx?proj=32481RR2-10.1136/bmjopen-2019-036231 Oral pre-exposure prophylaxis (PrEP) can reduce HIV infections among adherent men who have sex with men (MSM) -3. WhileHowever, the implementation of PrEP has increased the rate of missing facility-based testing. Almost 30% of PrEP users did not show up for their first quarterly clinical visits , and appIn order to improve and expand PrEP uptake, nonclinical PrEP approaches are being piloted, such as central dispensing at pharmacies , communiHIVST can also promote partner testing through secondary distribution of test kits ; that isHIVST technology has advanced in recent years. Third-generation HIVST technology has a testing period of 3 weeks, with high sensitivity and specificity . PrEP reWe aimed to assess the usage and secondary distribution of internet-based HIVST kits and their correlates among MSM using PrEP, prospectively. This information can provide evidence regarding the utility of HIVST in the era of PrEP and support a better paired and targeted HIV-testing strategy among PrEP users in the future.We conducted a randomized control trial of HIV self-testing among MSM who are PrEP users . Participants were recruited from among MSM in the ongoing PrEP pragmatic trial , which provides regimens of daily and on-demand PrEP, in 4 major Chinese cities  from December 2018 to September 2019. CROPrEP provides all participants standard care of PrEP, including quarterly facility-based HIV testing. Given the well-documented protective effect of PrEP, the sample size of the CROPrEP study at each site was not determined through power calculations. The sample size at each site was increased maximally by fully considering the human resources and capability of each study site .We randomized half of the enrolled PrEP recipients to provide them 2 HIV self-tests per month, in addition to the standard care. The study team has generated a service account on one of the most popular social media in China (WeChat) to provide web-based services on the application of extra testing kits, instructions on self-testing, real-time consultation with the staff, uploading of test outcomes, and follow-up questionnaires. All HIVST kits distributed or secondarily distributed were marked with a serial number. Participants who received HIVST were also encouraged to share them with their male sexual partners. All participants were prospectively followed up quarterly. This study adhered to the STROBE  checklist .The study sites are general hospitals equipped with HIV voluntary counseling and testing clinics and HIV treatment clinics with physicians specialized in infectious diseases in 4 major cities in China: The Youan Hospital of Capital Medical University, Beijing; The First Affiliated Hospital of China Medical University, Shenyang; The Chongqing Public Health Medical Center of Southwest University, Chongqing; and The Third People’s Hospital, Shenzhen.Participants were eligible to participate in this study if they (1) were designated male at birth; (2) have sex with male partners; (3) are aged 18-65 years; (4) report having ≥1 of the following risk factors in the last 6 months: (a) had condomless receptive anal sex with a male partner, (b) had more than 2 male sexual partners, (c) had self-reported sexually transmitted infections (STIs) such as syphilis, gonorrhea, chlamydia, chancroid, or lymphogranuloma venereum, or (d) have ever used postexposure prophylaxis medication, but have not received postexposure prophylaxis medication in the previous month; (5) have a nonreactive outcome on a fourth-generation HIV enzyme-linked immunosorbent assay test at baseline screening and undetectable HIV-1 RNA; (6) have no evidence of severe liver or kidney dysfunction on a comprehensive evaluation ; and (7) indicate willingness to participate and sign an informed consent form. Individuals were excluded if they (1) are deemed ineligible on eligibility evaluation for the CROPrEP trial, (2) refuse to accept or use the HIVST kits (with reasons recorded), or (3) refuse to sign the informed consent form.To prevent loss to follow-up bias, the clinicians and study staff provided one-on-one personalized compliance support, counseling, and cohort maintenance during the follow-up period. Furthermore, community-based organizations and the weekly internet-based retention strategies were used to strengthen group- and individual-level supervision of retention and cohort management. This internet-based strategy included interactive peer counseling focusing on study retention; a short message providing routine follow-up visit reminders, along with a live chat.Information on demographic characteristics , HIV-related risk behavior in the past 3 months , and testing history for HIV and STIs in the past were collected at baseline through self-administrated questionnaires distributed on each participants’ smartphone. The aforementioned information was obtained in accordance with a systematic review that analyzed studies on HIV testing behaviors among MSM in China . ParticiP<.20 on univariable analysis were included in the multivariable model to avoid the omission of clinically relevant variables, which had an underestimated effect in univariable analysis [P<.05 was considered the cut-off for a significant difference. We plotted Kaplan–Meier survival curves for predictors for HIVST usage and their secondary distribution during multivariable Cox regression analysis with P<.05 indicating significance.Statistical analysis was conducted using SPSS . Demographics, the PrEP regimen, and HIV-related risk behavior in the past 3 months among all participants were expressed as numbers and percentages. Follow-up time was determined as the number of days from the date of enrollment to the date of quarterly follow-up. Univariable and multivariable Cox regression analyses were performed to assess the predictors of self-reported usage of HIVST and secondary distribution of HIVST at the first quarterly follow-up. Variables with analysis ,26. VariThe study protocol was approved by the ethics review board of the First Affiliated Hospital of China Medical University IRB-2018-273), Shenyang. Written informed consent was obtained from each participant before collecting study information or blood samples. Participants voluntarily participated in the study and had the right to refuse to answer any question. Participants had the right to withdraw from the study without penalty. The protocols for the CROPrEP trial  and this3, ShenyaA total of 939 MSM were recruited from the CROPrEP trial, with 470 daily PrEP users and 469 on-demand PrEP users. In total, 471 men were randomized to receive 2 HIV self-tests per month, in addition to the standard care, which included 235 (49.0%) daily PrEP users and 236 (50.1%) on-demand PrEP users.The median age of these 471 participants at baseline was 29 years (quantile 25-35 years); among them, 390 (82.0%) had an education level of undergraduate and above, 241 (51.2%) had a monthly income of less than US $857, and 266 (56.5%) were single. Regarding HIV-related risk behavior in the past 3 months, 165 (35.0%) individuals had had anal intercourse every week and 234 (49.7%) had had anal intercourse every month, 312 (66.2%) of them had condomless anal intercourse with male sexual partners, 226 (48.0%) used Poppers in the previous 3 months, and 103 (22.5%) had participated in group sex. In total, 39 (8.3%) of them self-reported having STI-related symptoms in the previous 12 months. Further, 375 (79.6%) participants self-reported having used HIVST in the past, and 352 (74.7%) reported having undergone facility-based HIV testing in the past .Among these 471 men, 458 men were retained at the first quarterly follow-up, resulting in a retention rate of 97.2%. At the first quarterly of PrEP initiation, a total of 341 (74.5%) participants self-reported that they had used the HIVST in the past 3 months, among whom 256 (75.1%) returned HIVST testing outcomes by uploading photographs of the used HIVST kits marked with a serial number. In total, 260 (76.2%) men self-reported that they had recommended HIVST to their male sexual partners or gay friends, and 180 (52.8%) participants self-reported that they had shared their HIVST kits with the male sexual partners or gay friends. Among the 256 participants who had returned HIVST outcomes, the most frequent place of using HIVST was at home . In total, 132 (51.6%) men reported that HIVST was used immediately before or after sexual intercourse with their male sexual partners .P=.03), having an education level of senior high or below , having STI-related symptoms in the previous 12 months , having ever used HIVST in the past . Participants with the following variables were less likely to use HIVST: having had anal intercourse every day in the past 3 months , having had condomless anal intercourse in the past 3 months   .P<.20 on univariable regression analysis were included in the multivariable regression model, and participants with the following variables were more likely to use HIVST during follow-ups: being on daily PrEP , having an education level of senior high or below , and having used HIVST in the past . Furthermore, participants who self-reported having used Poppers in the past 3 months  were less likely to use HIVST , being currently married , having ever used HIVST in the past   .P<.20 on univariable regression were included in the multivariable regression model, and participants with following variables were more likely to secondarily distribute HIVST during follow-ups: being on daily PrEP , being currently married , and having used HIVST in the past   .We prospectively identified a high rate of usage and secondary distribution of the internet-based HIVST among MSM who are using PrEP in a multicenter pragmatic trial in China, especially among the daily PrEP users. This result warrants the internet-based HIVST as a crucial part of the HIV testing strategy paired with PrEP among the MSM population. Furthermore, the high rate of secondary distribution of HIVST kits and self-testing among sexual partners among PrEP users assures a promising future for peer-initiated expanded HIV testing and maximization of the HIV prevention among the MSM community.Approximately 80% of PrEP users have used HIVST within 3 months after PrEP initiation and found it easy to use, reflecting HIV testing behavior among PrEP recipients. Every 4 of 5 of these PrEP users had used HIVST before the initiation of PrEP, which is much higher than the level among the general MSM population in China (20%-40%) ,29. SincNotably, there was a high rate of secondary distribution of HIVST and testing of sexual partners among those who had used HIVST after PrEP initiation. Half of the HIVST was used to test together with their sexual partners immediately before or after intercourse. This is significant because of the limited success and high cost of accessing MSM at clinics or provider-initiated expanded HIV testing strategies ,32. AccoFactors promoting the usage and secondary distribution of HIVST among PrEP users were also identified. Men on daily PrEP were more likely to use and secondarily distribute HIVST after PrEP initiation than those on the on-demand regimen. Since most of the HIVST was used immediately before or after sexual intercourse, this correlation can be explained by the fact that MSM on daily PrEP displayed more frequent HIV-related risk behavior and a higher number of sexual partners ,36. AccoAn inhibitor of the use of HIVST among PrEP users is the use of Poppers, which is one of the most popular recreational drugs among MSM worldwide . AccordiThis study has several limitations. First, there is no fourth-generation HIVST kit available currently in China. These are available in the United Kingdom and in other countries and would potentially allow this model to replace some of the facility-based testing. Second, this study was conducted before the COVID-19 pandemic, which might underestimate the usage of HIVST among PrEP users. Third, this study only assessed the usage and secondary distribution within the first 3 months after PrEP initiation, which requires a longer follow-up period to illustrate its long-term usage. Finally, this study only included participants from 4 major cities in China, which did not represent the general MSM population in China.Within a pragmatic setting, MSM who are using PrEP had a high rate of usage and secondary distribution of HIVST kits, especially among those on daily PrEP. Offering multiple HIVST to PrEP users to replace some of the facility-based HIV testing and to facilitate expanded HIV testing is feasible and necessary, especially during the COVID-19 pandemic.


No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas. Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4–6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of β-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51–1.00;  Colorectal cancer (CRC) is the second most commonly diagnosed malignancy and one of the main causes of cancer death in both men and women . CRC is APs are present in approximately one-half to two-thirds of patients diagnosed with colorectal polyps. APs are precancerous lesions associated with a higher risk of CRC, particularly the advanced ones  with or without multiplicity >3 adenomas) . The ade adenomasAPC, k-RAS, and P53), cytokine, and reactive oxygen species (ROS) production due to the fact that inflammation can lead to mutations and the progression of adenoma to carcinoma  methods ,38,39. Tv/v). The samples were vortexed and then centrifuged, and the supernatant was transferred to HPLC vials for injection onto the LC-ESI-MS/MS system, which consisted of a Waters Alliance 2695 separations module and a Waters 2487 UV detector, connected to a Micromass Quattro Platinum  tandem quadrupole mass spectrometer with an electrospray interface. The full details of the analysis conditions and instrument settings have been reported previously - ion transition 271→145 m/z. Data were acquired using MassLynx software (version 4.0). The concentrations of curcumin and its metabolites in plasma samples were determined using individual calibration lines constructed by the addition of different amounts of each analyte to the control sample matrix (ranging from 20 to 1000 fmol detected in the column) [The samples were analyzed in negative ESI mode with selected reaction monitoring for the following [M-H]Formalin-fixed samples were embedded in paraffin, cut at 2 μm, stained with hematoxylin and eosin and used for IHC analysis. Primary antibodies for IHC included rabbit antibodies against Ki-67 , NF-κB-p65 , β-catenin , and p53 . Heat-induced antigen retrieval was performed with a citrate buffer at pH 6 for c-Jun, cleaved caspase-3, NF-κB p65, and β-catenin or with an EDTA buffer at pH 8 for Ki-67, DKK1, and INCENP. Rabbit primary antibody binding was detected with goat anti-rabbit polymer HRP . Color was developed with Diaminobenzidine substrate-chromogen , and tissues were counterstained with hematoxylin.Immunostaining was performed with an autostainer  according to the procedure reported previously . All serTwo independent investigators (MR and RB), blinded to the treatment arm, patients’ characteristics, and the time of tumor sampling, evaluated the immunostaining results. The semi-quantitative analysis was applied to score Ki-67 expression: for each sample, the percentage of positive dysplastic cells among the total number of tumor cells was evaluated. Moreover, all the positive cells for the tissue biomarkers assessed by IHC expressed an intensity from moderate (++) to severe (+++).t-tests or Kruskal–Wallis tests were adopted for continuous variables, while Fisher’s Exact or Chi-squared tests were used for categorical variables. The main analysis on the effect of treatment at polypectomy was conducted using several generalized mixed models on the log-transformed value of each marker. Each model was adjusted for the baseline value of the marker, age, and sex. Other possible covariates were inserted, if they involved a change greater than 5% on the GMR related to the effect of treatment. Hypothesis testing was carried out at the alpha = 0.05 level (two-sided) when comparing treatments. Statistical significance was declared, if the rounded p-value was be less than or equal to 0.05. The analysis was performed using STATA .Descriptive statistics were provided for all variables in the summary tables by treatment group according to the type of variable summarized. Continuous variables were summarized by using n (sample size), geometric mean, and coefficient of variation (CV) or arithmetic mean and standard deviation (SD) according to their distribution, median, and percentiles. Categorical variables were summarized by using frequency distributions and percentages. Univariate tests were performed to explore the distribution of each variable according to the treatment group and the time point.


Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disorder.Death typically occurs within 3–5 years after disease onset. The main cause of death in ALS is respiratory failure (RF). No effective treatment is available and no molecular biomarker related to respiratory outcome and to early ventilatory dysfunction was described so far. The club-cell protein (CC-16) is a biomarker associated with respiratory distress and lung inflammation.The aim of this work is to test if CC-16 and IL-6 could be new biomarkers of ALS for early signs of respiratory insufficiency and disease progression. Additionally, we intend to study morphological and viscoelastic changes of the erythrocytes’ membrane associating them with ALS patients’ clinical profile.Eighty-one ALS patients and 30 matched controls were included. Functional capacity and respiratory function  were evaluated. CC-16 and IL-6 were quantified by ELISA and multiplex technology, respectively. Morphological and viscoelastic properties of the erythrocytes were analysed by Atomic Force Microscopy (AFM).CC-16 levels were significantly raised in ALS patients. In 17% of them, CC-16 level was above the upper cut-off value. On these patients, the risk of non-invasive ventilation was greater in the following 6 months and they tend to have higher mortality in the following 30 months. IL-6 values were not different in ALS population as compared with controls.ALS patients have higher erythrocyte maximum height, area and volume, decreased erythrocyte membrane roughness and increased membrane stiffness than the control group. These results indicates abnormal erythrocyte structure and possible changes on membrane lipid composition on ALS patients.We propose that increased CC-16 levels could be a marker of lung inflammatory response, associated with ventilatory insufficiency and related to impending respiratory failure, which are not fully predicted by conventional respiratory tests. Moreover, abnormalities in erythrocyte morphology may enhance the risk of tissue hypoxia.Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disorder. Death typically occurs within 3–5 years after disease onset. Respiratory failure (RF) is the main cause of death. No effective treatment and no molecular biomarker related to respiratory outcome and to early ventilatory dysfunction are available. The club-cell protein (CC-16) is a biomarker associated with respiratory distress and lung inflammation.The aim of this work is to test if CC-16 and IL-6 could be new biomarkers of ALS for early signs of respiratory insufficiency and disease progression. Additionally, we intend to study morphological and viscoelastic changes of the erythrocytes’ membrane associating them with ALS patients’ clinical profile.Functional capacity and respiratory function  were evaluated in 81 ALS patients and 30 matched controls. CC-16 and IL-6 were quantified by ELISA and Multiplex-technology, respectively. Morphological and viscoelastic properties of the erythrocytes were analysed by Atomic Force Microscopy (AFM).A significant negative correlation was found between [IL-6] and PhrAMPL, but not with ALSFRS-R or disease duration. CC-16 levels were significantly raised in ALS patients. In 17% of them, CC-16 level was above the upper cut-off value. On these patients, the risk of non-invasive ventilation was greater in the following 6 months and they tend to have higher mortality. ALS patients have higher erythrocyte maximum height, area, volume, decreased erythrocyte membrane roughness and increased membrane stiffness.These results indicates that abnormal erythrocyte structure and possible changes on membrane lipid composition on ALS patients. Our results show that IL-6 levels are not dependent on the duration or severity of the disease, however, IL-6 may provide a marker of respiratory dysfunction in ALS. We propose that increased CC-16 levels could be a marker of lung inflammatory response, associated with ventilatory insufficiency and related to impending RF, which are not fully predicted by conventional respiratory tests. Moreover, abnormalities in erythrocyte morphology may enhance the risk of tissue hypoxia.