The most common documented IRAEs were pneumonitis , followed by rash  and thyroid dysfunction . FEV1 and DLCO were not found to be associated predictors of pneumonitis toxicity. The median PFS and OS were estimated to be >1.7 years and >2.7 years, respectively.The 2017 PACIFIC trial heralded the incorporation of routine adjuvant durvalumab following curative-intent chemoradiation for stage III non-small-cell lung cancer (NSCLC). However, carefully selected clinical trial populations can differ significantly from real-world populations, which can have implications on treatment toxicities and outcomes, making it difficult to accurately counsel patients. Consequently, we performed a real-world, retrospective analysis of outcomes and toxicities in 118 patients with stage III NSCLC treated with durvalumab after platinum-based chemoradiotherapy. The data were collected from patients who underwent treatment at a single, tertiary-level Canadian cancer centre from May 2018 to October 2020. The variables collected included patient demographics, treatment specifics, progression-free survival, overall survival, and immune-related adverse events (IRAE) from durvalumab. Descriptive statistics were used for toxicity analysis, and progression-free survival and overall survival estimates were calculated using the Kaplan–Meier method. The statistical analyses indicated a 64.4% ( Stage III non-small-cell lung cancer (NSCLC) represents a heterogeneous class of disease which continues to serve the oncology community a treatment quandary; often, such tumours are not resectable, yet the specifics of optimal multi-modality treatment remain elusive . In the However, carefully selected clinical trial populations can differ significantly from populations in routine clinical practice, which can have implications on treatment toxicities and outcomes . Real-woSince the publication and implementation of the PACIFIC trial protocol, several real-world studies have been performed across the globe. For instance, Sankar and colleagues demonstrated similar PFS in a real-world population, while the OS benefit was lower, likely related to differences in the patient population compared to the PACIFIC study . As seenIn this single-centre, retrospective study, we reviewed the safety and survival outcomes of consolidative durvalumab after platinum-based chemoradiation. We focused on key patient factors to assess any potential risk factors for toxicity, in particular, immune-related pneumonitis.(1)To compare the PACIFIC trial toxicity outcomes to the outcomes in a real-world, non-trial-based population.(2)To determine whether the efficacy outcomes of the PACIFIC trial are maintained in a real-world analysis.Primary objectives:(1)To determine whether there are risk factors for (severe) IRAEs from durvalumab.Secondary objectives:This retrospective study was reviewed and approved by Western University’s research ethics board . Data were collected from patients with stage III NSCLC who underwent treatment with consolidative durvalumab following curative-intent concurrent chemoradiation at a single tertiary-level Canadian cancer centre, with Health Canada approval in 2018 until October 2020; this included the provincial funding approval received in March 2020. Due to ethics constraints, events were captured up to June 2021. A total of 136 patient charts were identified through medical records for having been scheduled for durvalumab; of these, 118 patients were identified as fitting our criteria (below) and included in the analysis. The variables collected included patient demographics, treatment specifics, progression-free survival, overall survival, and toxicities from durvalumab. A complete list of variables collected is included in IRAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE v5) based on the clinical notation available in the patient charts. In this study, immune-related pneumonitis was defined as an event of pneumonitis occurring after at least 1 cycle of durvalumab, in an effort to try to avoid collecting data from patients with (purely) radiation-driven pneumonitis.The patient inclusion and exclusion criteria are detailed below.(1)Histologic/cytologic diagnosis of stage III non-small-cell lung cancer.Received two or more cycles of platinum-based chemotherapy, at least one of which was given concurrently with radiation.No disease progression observed during chemoradiation or between chemoradiation completion and start of immunotherapy.Received at least one dose of durvalumab.Treated locally at our tertiary-level centre.Patient inclusion criteria: (2)Identification of metastatic disease prior to start of treatment.Patient exclusion criteria: Patient criteria:Analysis was performed mainly using descriptive statistics. IRAE outcomes were assessed as binary outcomes with proportions presented, as well as their associated 95% confidence intervals. Efficacy outcomes  were assessed using survival curves estimated using the Kaplan–Meier product limit estimator. Cumulative probability of the outcomes at various time points and median survival were also estimated based on the Kaplan–Meier curves.Based on these findings, we calculated the odds ratios to assess potential risk factors for toxicities.From 2018 to 2020, 118 patients with a diagnosis of locally advanced non-small-cell lung cancer were treated with concurrent chemoradiation followed by consolidative durvalumab. The majority of these patients had an ECOG status of 0 or 1, as listed in The median time from end of chemoradiation (defined as last day of radiation) to durvalumab start was 40.5 days. In this patient population, the shortest amount of time from chemoradiation to durvalumab start was 7 days and the longest was 238 days. In total, 53 patients (44.9%) began treatment more than 42 days after the completion of chemoradiation. The median follow-up was 534 days (just under 1.5 years).At the time of analysis, 86 patients out of 118 were alive. The statuses of six patients were unknown as they were lost to follow-up. Of the 26 patients who died, 14 patients died due to disease recurrence. Death related to non-oncologic/toxicity causes was not recorded.Due to a lack of events, we were unable to calculate specific median progression-free survivals and overall survivals, but these were estimated to be >20 months and >32 months, respectively. The Kaplan–Meier curves, both overall and stratified by PD-L1 status, are shown in n = 76) of patients developed at least one IRAE of any grade, with 21% (n = 25) developing grade 3+ toxicities. Three patients (2.5%) died due to toxicity while on treatment, all from immune-related pneumonitis. A total of 50 (42.4%) patients stopped treatment prematurely due to severe IRAEs. Another 25 patients (21.2%) experienced a treatment delay due to an event but were subsequently rechallenged on durvalumab. The most common documented IRAEs occurring during treatment were pneumonitis , followed by rash and thyroid dysfunction . A full list of toxicities and frequencies can be found in In total, 64.4% (We noted our 40% pneumonitis rate (14.4% for grade 3/4) is numerically higher from the quoted 33.9% for all-grade and 3.4% for grade 3/4 rate of pneumonitis in the PACIFIC trial study. In an attempt to exclude clear radiation-induced pneumonitis as much as we were able to, although it should be understood that the delayed-onset nature of radiation pneumonitis can make it difficult to distinguish from durvalumab-induced pneumonitis, we only included cases of pneumonitis diagnosed after at least one dose of durvalumab.p = 0.91) and 1.00 , respectively, which suggests against any potential relationship. Other factors, such as total radiation dose, total radiation fractions, radiation planning treatment volume (PTV), radiation gross tumour volume, V30, V20, V5, and mean lung dose, were initially going to be analyzed; but due to the poor documentation of this information, there were not enough data points to look for any possible association with the risk of developing pneumonitis.Based on our findings, we were specifically interested in any potential risk factors for pneumonitis, as this appeared to be not only the most common toxicity, but also the most common grade 3+ toxicity and cause of all IRAE-related deaths. Consequently, we calculated the odds ratios for the association between pneumonitis and FEV1 and DLCO for 61 patients with available pulmonary function tests (PFTs). The odds ratio for FEV1 or DLCO was 1.00 . We did collect information such as treatment after progression/cessation of consolidative durvalumab as this might impact overall survival rate or EGFR status . We alsoPotential next steps could include further analyses investigating further risk factors or potential indicators for pneumonitis. Additionally, new evidence for neoadjuvant chemoimmunotherapy might pose a new focus of real-world study in the lung cancer/immunotherapy population ,15.In summary, this analysis confirmed the survival benefits of the PACIFIC trial in a real-world setting, although it did show high rates of pneumonitis. We were not able to identify risk factors for pneumonitis; specifically, differences in baseline lung function tests were not predictive for the development of immune-related pneumonitis.


Radiographs revealed that no component loosened, migrated, or subsided. The median operative time was 75.5  min. No implant-related complications were reported. The Global Icon stemless replacements have excellent clinical outcomes in this cohort at 12- and 24-month follow-up with no implant-related complications.The primary aim of this study was to assess the medium-term outcomes of the Global Icon stemless shoulder replacement in patients who have undergone primary total shoulder arthroplasty (TSA) for glenohumeral joint osteoarthritis. A retrospective review of patients who had undergone a TSA using the Global Icon stemless shoulder system was performed. The Western Ontario Osteoarthritis Shoulder (WOOS) Index and Oxford Shoulder Score (OSS) were evaluated pre-operatively and at 12 to 24 months post-operatively. Radiological outcomes, operation time, and post-operative complications were reported. Primary analysis for the WOOS Index and OSS focused on detecting within-group treatment effects at 24 months using a repeated measures ANOVA. Thirty patients were included in the study. Post-surgery, there was a significant improvement at 24 months on the OSS (ES = 0.932, CI: 41.7 to 47.7,  Glenohumeral joint osteoarthritis is a loss of the articular surface of the glenoid and the humeral head and typically results in pain and degradation of upper limb function . It affeAnatomic total shoulder arthroplasty (TSA) is a successful treatment option for glenohumeral osteoarthritis with an intact rotator cuff . There hThe biomechanical basis for the success of stemless implants has been confirmed ,7, and cThe Global Icon  stemless shoulder system is relatively new and has been approved in Europe and Canada since April 2017 and September 2017, respectively. To date, there has only been one study investigating the short-term outcomes of the stemless Global Icon. Smith et al.  reportedTherefore, the aim of this study is to present medium-term clinical outcomes of 30 total shoulder replacements (TSRs) implanted for glenohumeral osteoarthritis using the Global Icon stemless shoulder system, with a follow-up period of 24 months.We performed a single surgeon, retrospective review of a consecutive series of patients from a single institution ) undergoing primary TSA. Ethical approval for this study was obtained from Ramsay Health Care .Patients were included if they had undergone primary anatomic TSA using the Global Icon between January 2018 and February 2020 for glenohumeral joint osteoarthritis. Patients with pre-operative inflammatory joint disease, avascular necrosis, non-functioning rotator cuff, poor metaphyseal bone stock, acute trauma, and infection were excluded. Patients with no follow-up patient reported outcome measures (PROMs) were also excluded. Early indications to use stemless instead of stemmed component were deformity of humeral shape. The previously reported success of the stemless component [All patients were assessed medically for anaesthetic suitability. A pre-operative CT scan was performed with DICOM views sent for “Trumatch” computer planning and sizing. Three-dimensional models were not made as PSI was not utilized in this group. Contralateral imaging confirmed sizing in unusual pathologies. A pre-operative haematolological workup was performed but no blood was cross-matched as no patient was transfused by the senior author in primary arthroplasty.All surgeries were performed by 1 surgeon (GH) with the patient in the semi-supine position with a pneumatic arm holder under regional nerve block. A deltopectoral approach and subscapularis tenotomy was performed. A guided anatomic resection of the humeral head was made with the ring of the guide resting on the posterior and superior cuff insertions, while being aligned with the anatomic neck to achieve the correct inclination and retroversion. An Anchor Peg Glenoid  was implanted with cement in the peripheral holes only for immediate fixation (and none on the under surface of the component), and cancellous bone autograft reamings were applied circumferentially around the central interference peg for bony ongrowth, as previously published in short and longer term outcome studies using this implant ,16 Figu. The Glo®, Warsaw, IN, USA). A standardized rehabilitation protocol was utilized with shoulder pendulum exercises in the first 2 weeks after surgery. The sling was discarded at 4 weeks, and the patient then began progressive active assisted range of motion exercises at 2 weeks post-operatively and started strengthening exercises at 6 weeks post-operatively. Unlimited physical activities were allowed at 3 months.The subscapularis tenotomy was subsequently repaired end-to-end with a contracting strong, synthetic suture in an interrupted fashion (DynacordThe primary outcome measures included the Western Ontario Osteoarthritis Shoulder (WOOS) Index and the OSS. Patients were asked to complete these scores pre-operatively and 12 to 24 months post-operatively via a secure online platform. The WOOS Index is a self-administered tool with 19 items over the four domains of physical symptoms, sport/recreation/work, lifestyle function, and emotional function. The total score is expressed as a percentage with 100% representing a normal, healthy shoulder. The WOOS Index is valid, reliable, and responsive for measuring change in patients with shoulder osteoarthritis . The OSSRadiographs were evaluated for radiolucency, osteolysis, loosening, migration, fractures, glenohumeral subluxation, and subsidence by an independent fellowship-trained orthopaedic surgeon at routine follow-up. Radiological evaluation of the glenoid component for component loosening was graded as described in Lazarus et al. . AnalysiOperative time and the occurrence of any post-operative compilations (including revision surgery) were recorded. Operative time reflects the time from incision to wound closure . Implantt tests were performed to obtain a t statistic and effect size (Cohen’s d) for pairwise comparisons. An effect size of 0.2 to 0.5 would be considered a small effect, 0.2 to 0.5 a medium effect, and >0.8 a large effect [Analysis was performed using SPSS . Primary analysis for the WOOS Index and the OSS focused on detecting within-group treatment effects at the 24-month time point (with effect sizes and 95% CIs) using a repeated measures ANOVA. Missing data for PROMs were handled by using ANOVA with listwise deletion . Post-hoThe practice database retrieved 43 participants who had undergone a total shoulder replacement using the Global Icon stemless system. Thirteen participants had no follow-up PROMs, leaving a total of 30 participants included in the study . GlenoidOperations were performed by one consultant shoulder surgeon (GH). All components were implanted in conjunction with a glenoid anchorpeg component as previously published ,17 as pap < 0.001, p < 0.001, p < 0.001) (p < 0.001) and the WOSS Index , and baseline and 24 months for the OSS  and the WOOS Index . There was no significant difference between 12- and 24-month scores for the OSS and the WOOS Index, indicating that most improvements occurred in the first 12 months post-surgery.Post-surgery, there was a significant improvement at 24 months on the OSS  . Post-ho< 0.001)  revealedRadiological outcomes are outlined in No implant-related complications were recorded. One patient had a transient partial posterior cord plexopathy resolving within 6 weeks and thought to be related to the nerve block. One patient has symptoms from a possible supraspinatus cuff failure and is being monitored but has not been revised. There were no episodes of infection, instability, or unexplained pain. The median operative time was 75.5 min .This study demonstrates good medium-term results of the Global Icon stemless TSA.There were significant improvements on the OSS and the WOOS Index post-surgery at 12 and 24 months compared to pre-operative scores. The size of the treatment effect at 24 months was above 0.8 for both outcomes, indicating patients’ perceived effectiveness of treatment was great ,24. To dClinical studies investigating stemless systems alone have consistently demonstrated significant improvements in shoulder function with a low risk of implant-related complications ,10,11,12In studies directly comparing the stemmed vs. stemless component, the stemless component does not appear to perform inferiorly to its stemmed counterpart and may offer several advantages including reduced operating time and reduced blood loss. In a retrospective review, Berth et al.  found noComplication rates of stemless implants have been comparable to stemmed implants. In a systematic review, Upfill-Brown et al.  found a The stemless implant may have advantages over the stemmed system when it comes to pre-operative planning with three-dimensional (3D) templating software. Freehill and colleagues  evaluateOther potential advantages of the stemless implant have been reported in the literature, including a lack of disruption of the endosteal blood supply, improved accuracy in sizing the humeral head, preservation of bone stock for future revisions, reduced risk of intra- and post-operative periprosthetic humeral shaft fractures, elimination of broaching, replacement of the humeral head independently from the humeral axis in post-traumatic deformities, and reduced stress shielding ,25,34. IA strength of this study is that it is the first to investigate outcomes for the Global Icon with medium-term follow-up (24 months), showing a significant improvement in shoulder function comparable to other clinical outcomes in stemless and stemmed protheses. In addition, this study used a PROM that is sensitive and specific to measuring change in the glenohumeral joint osteoarthritis population (the WOOS Index), in contrast to many studies which do not ,26. Our Limitations of our study include the retrospective nature, small number of included patients, and lack of randomized control or comparison groups, although we have previously studied the outcomes of the same glenoid component in published short- and medium-term outcome studies ,16. In aThis study demonstrates significant improvements in shoulder function after treatment of shoulder osteoarthritis with the Global Icon stemless system. Our study on the Global Icon system is at least comparable if not favourable when compared to other published studies on stemless implants, which demonstrate excellent medium-term outcomes and a low complication risk.


High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). In this study of 408 patients enrolled in a prospective early-stage TNBC neoadjuvant chemotherapy trial, we aimed to identify clinicopathologic features that could be combined with sTILs to better predict pCR. Applying a training set and a testing set, we found that integrating high Ki-67 (cutoff > 35%) and high sTIL (cutoff ≥ 20%) in a model of computed response scores could predict a pCR rate of 65%. This model may refine the selection of early-stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies.High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for the entire cohort was 41%. Recursive partitioning analysis identified ≥20% as the optimal cutoff for sTILs to denote 35% (143/408) of patients as having high sTILs, with a pCR rate of 59%, and 65% (265/408) of patients as having low sTILs, with a pCR rate of 31%. High Ki-67 (cutoff > 35%) was identified as the only predictor of pCR in addition to sTILs in the training set. This finding was verified in the testing set, where the highest computed response score encompassing both high sTILa and high Ki-67 predicted a pCR rate of 65%. Integrating Ki67 and sTIL may refine the selection of early stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies. The tumor immune microenvironment plays a fundamental role in the response to neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC) ,2,3,4. TTaken together, these data support the growing interest in utilizing sTILs to select TNBC patients for de-escalation strategies in appropriate clinical settings. In this study, we aimed to identify clinical and pathologic characteristics that are associated with improved pCR rates in early-stage TNBC treated with neoadjuvant anthracycline-based chemotherapy. We hypothesized that integrating high sTILs with additional clinical and pathologic features associated with pCR could strengthen the predictive power and enhance our ability to identify patients for whom de-escalation could be considered in the context of a clinical trial. A Robust TNBC Evaluation fraMework to Improve Survival; NCT02276443), which was approved by the Institutional Review Board of the University of Texas MD Anderson Cancer Center. Written informed consent was obtained from the enrolled patients. In this trial, tumors from patients diagnosed with early-stage TNBC prior to receiving NACT were profiled, and a unique algorithm of diagnostic imaging and biomarkers was used to select the optimized targeted therapy trial for patients with chemotherapy-insensitive disease. The trial design was previously described [The patients included in this study were enrolled in the ARTEMIS trial  negativity was defined according to the American Society of Clinical Oncology/College of American Pathologists HER2 testing guidelines ,18,19,20Immunohistochemical (IHC) staining was performed on unstained 4 μm thick tissue sections from a representative paraffin block of the pretreatment tumor in each case. The slides were incubated at 60 °C for 25 min. IHC staining for PD-L1 was performed using the FDA-approved PD-L1 IHC 22C3 pharmDx kit  on a Dako AutostainerLink 48, according to the manufacturer’s instructions. IHC staining for the androgen receptor (AR) and Ki-67 was performed using the polymeric biotin-free horseradish peroxidase method with a Leica Microsystems Bond III autostainer . Ki-67 was performed if the results were not collected from the diagnostic pathology reports. For AR, following heat-induced epitope retrieval with citrate buffer for 25 min at 100 °C, the slides were incubated with mouse monoclonal antibody to AR . For Ki-67, following heat-induced epitope retrieval with Tris-EDTA buffer for 20 min at 100 °C, the slides were incubated with mouse monoclonal antibody to Ki-67 . The Refine Polymer Detection kit was used to detect bound antibody, with 3,3-diaminobenzidine serving as the chromogen (Leica Microsystems). The slides were counterstained with Mayer’s hematoxylin. The results were evaluated with known positive and negative tissue controls. For PD-L1, the Combined Positive Score (CPS) was calculated as the number of PD-L1-stained cells  divided by the total number of viable invasive tumor cells, multiplied by 100. For AR, the percentage and intensity of any nuclear staining of the tumor cells were recorded. For Ki-67, the percentage of nuclear staining of any intensity in the tumor cells was recorded .n = 204). The remaining patients formed the testing set (n = 204). A comparison of the two sets for the low-sTIL and high-sTIL patients is shown in p-values of 0.05 or less were considered significant. Training and testing sets were created through randomization, stratified based on sTIL status and the date of enrollment. Briefly, patients were first placed in the order of the date of enrollment in the following sTIL groups: <5%, 10%, 20%, 30%, 40–50%, 60–90%. The higher-sTIL categories were grouped together because each had a small number (<20) of patients. Next, every other patient in each sTIL group was selected into a training set. The training sets from all the sTIL groups were then incorporated into the final training set (Patient characteristics of the 408 patients with early-stage TNBC included in this study are shown in p = 0.0004) and Ki-67 > 35% (p = 0.001) emerged as being independently and significantly associated with an increased likelihood of pCR in the training set (n = 204). When applied to the testing set (n = 204), these variables remained significantly associated with pCR . Based on their similar coefficients in the logistic regression model, each variable was given an equivalent weight in the computed response score (CRS) generated using the testing set (n = 65), the pCR rate was 65% (95% CI 52–76%). Of the 408 patients included in this study, 166 patients experienced a pCR (41%). Among the clinicopathologic variables, sTIL ≥ 20% .Next, recognizing that the predictors of response may differ between tumors with low sTILs and those with high sTILs, we separated the entire cohort into low- versus high-sTIL patient populations to investigate which variables may be associated with pCR. As shown in In this study, we assessed clinical and pathologic predictors of pCR in patients with early stage TNBC treated with NACT in a prospective trial. Historically, the reported rates of pCR in patients with early stage TNBC treated with anthracycline-based NACT have ranged between 35 and 50% ,25,26,27The patients in this study were enrolled and treated with anthracycline-based chemotherapy prior to the 2021 FDA approval of neoadjuvant and adjuvant pembrolizumab following results from the landmark trial KEYNOTE-522; however, the implications remain relevant . The comAnother limitation of this study is that nearly all the patients received combination anthracycline and taxane chemotherapy; therefore, we were unable to assess whether specific chemotherapy regimens were associated with different patterns of immune response, other clinicopathologic factors and the ultimate pathologic outcomes. Biomarker evaluation including sTIL, AR, Ki-67 and PD-L1 was performed on core biopsy materials as a representation of the entire tumor; therefore, limited sampling is an intrinsic limitation of this neoadjuvant study. While Ki-67 was identified as a strong predictor in the high-sTIL group, thus confirming our results using the training and testing sets, our study did not identify any clinically meaningful factors that could predict pCR in the low-sTIL group. This finding is intriguing, considering that 31% of patients in the low-sTIL group achieved pCR. Further work is needed using alternative analytic methods  to identify predictors of resistance and/or response in this population. The early detection of treatment response during NACT may also facilitate the proper triaging of patients, including low-sTIL patients, for further therapy.In conclusion, we demonstrated that integrating Ki-67 with sTILs provides independent and additional information beyond baseline sTILs in the prediction of pCR in patients with early-stage TNBC. The incorporation of Ki67 (>35%) and sTILs (≥20%) may refine the selection of this group of patients for neoadjuvant clinical trials evaluating de-escalation strategies upon further validation.


The current coronavirus disease 2019 (COVID-19) pneumonia pandemic, caused by the newly discovered coronavirus is a serious public health emergency and a highly infectious disease. Evidence to date suggests that there are groups of people who are at a higher risk of getting severe COVID-19 disease such as pregnant women and their fetuses. We reported 4 cases of pregnant women with COVID-19 admitted in the national containment center, Tunisia . The age range of the patients was 27-35 years and the range of gestational weeks at admission was 16 weeks to 32 weeks. None of the patients had underlying diseases. All four cases were totally asymptomatic and presented no complications. Two of them gave birth one by vaginal and the other by cesarean delivery, neonates presented no symptoms and no adverse outcomes. The current report does not present significant differences in the disease prognosis in the pregnant women´s group compared with the general women´s population. Careful observation, data collection and consecutive research are necessary. The first cases were reported in Wuhan, China, in December 2019, followed by a large outbreak across the country [Coronavirus is challenging the healthcare systems worldwide . The risPatient information: a 29-year-old woman returned from Algeria on July 3, 2020  testing) was performed, it returned positive on July 7 and thus was transferred to COVID-19 Monastir Center, a national containment center, dedicated for confirmed cases.Clinical findings: the patient did not develop any symptoms or complications during containment and the pregnancy was very smooth.Follow-up and outcome: after two consecutive nasopharyngeal swabs tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (on July 24 and 25), the case was home discharged, 2 weeks after the first positive RT-PCR. The patient gave birth on August 6, 2020, via a spontaneous vaginal delivery, the neonate presented no symptoms and no adverse outcomes.Patient perspective: the patient adhered perfectly to the follow-up during the containment and throughout the pregnancy. The patient was happy to have an uncomplicated pregnancy and a healthy newborn.Declaration of patient consent: the authors certify that they have obtained all appropriate patient consent.Patient information: a 27-year-old Tunisian woman, returned from Ivory Coast on July 9, 2020 . The patient was followed up after being home discharged. The last contact was on October 26. She had a smooth pregnancy according to regular checkups and her latest ultrasounds.Patient perspective: globally, the patient showed satisfaction with the healthcare in the containment center. Currently, her pregnancy is well monitored.Declaration of patient consent: the authors certify that they have obtained all appropriate patient consent.Patient information: a 35-year-old Tunisian woman, returned from Algeria on July 20, 2020 . The patient left the containment center. She was contacted on October 26, she was 27 weeks pregnant. The case had a smooth pregnancy without any complications.Patient perspective: the patient was satisfied with regular checkups in the national containment center and happy to have an uncomplicated pregnancy.Declaration of patient consent: the authors certify that they have obtained all appropriate patient consent.We reported data from four pregnant women with laboratory-confirmed COVID-19 pneumonia. Mothers´age were between 27 to 35 years and the gestational age when infection ranged from 16 to 32 weeks. The clinical characteristics of these four pregnant patients were similar to those of non-pregnant adults with COVID-19 infection. None of the four patients developed severe COVID-19 symptoms.et al. study found that clinical, laboratory and radiological data were comparable to those observed in the general population [According to the latest studies, pregnant women can be completely asymptomatic as they can present severe forms indicating even hospitalization ,5. Indeepulation . Howeverpulation . Pregnanpulation . Pregnanpulation .In the past two decades, severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemics were responsible for almost one-third of deaths between infected pregnant women . In the A total of 24 studies, including 324 infected pregnant women with COVID-19, revealed that the most frequent COVID-19 onset symptoms were fever and cough. However, less common symptoms were myalgia, malaise, sore throat, diarrhea, and dyspnea. Lymphopenia and higher concentrations of alanine transaminase (ALT) or aspartate transaminase (AST) could also be detected [Concerning neonatal and maternal outcomes, no complications occurred. Although, a systematic review demonstrated that the incidence of preterm births, low birth weight, C-section, and neonatal intensive care unit (NICU) admission was higher than the general population . Case 1 The current report does not present significant differences in the progression of the disease in the pregnant women´s group compared with the general women´s population. Following the new recommendations and update knowledge is crucial to ensure the highest quality of health care services among pregnant women. High quality studies are needed to establish the impact of COVID-19 on pregnant women.


Effects of This post-hoc analysis used data from the TB APPRISE trial, a multicentre, double-blind, placebo-controlled trial, which randomised women to 28-week IPT starting in pregnancy (pregnancy-IPT) or postpartum week 12 (postpartum-IPT) in eight countries with high tuberculosis prevalence. Participants were enrolled between August 2014 and April 2016. Based on modified intent-to-treat analyses, we analysed only live-born babies who had at least one follow-up after birth and compared time to infant growth faltering between arms to 12 weeks and 48 weeks postpartum in overall and sex-stratified multivariable Cox proportional hazards regression. Factors adjusted in the final models include sex of infant, mother's baseline BMI, age in years, ART regimen, viral load, CD4 count, education, and household food insecurity.Among 898 HIV-exposed uninfected (HEU) infants, 447 (49.8%) were females. Infants in pregnancy-IPT had a 1.47-fold higher risk of becoming underweight by 12 weeks  than infants in the postpartum-IPT; increased risk persisted to 48 weeks postpartum . Maternal IPT timing was not associated with stunting or wasting. In sex-stratified analyses, male infants in the pregnancy-IPT arm experienced an increased risk of low birth weight (LBW) , preterm birth  and becoming underweight by 12 weeks  and 48 weeks . Maternal IPT timing did not influence growth in female infants.Maternal IPT during pregnancy was associated with an increased risk of LBW, preterm birth, and becoming underweight among HEU infants, particularly male infants. These data add to prior TB APPRISE data, suggesting that IPT during pregnancy impacts infant growth, which could inform management, and warrants further examination of mechanisms.10.13039/100000002National Institutes of Health (NIH)  through the 10.13039/100000060National Institute of Allergy and Infectious Diseases, with cofunding from the 10.13039/100009633Eunice Kennedy Shriver National Institute of Child Health and Human Development  and the 10.13039/100000025National Institute of Mental Health.The TB APPRISE study Supported by the  Pregnancy isoniazid preventive therapy (IPT) has not been associated with adverse pregnancy outcomes in observational studies on pregnant women. A rigorously assessed multicenter randomized control trial in women living with HIV on antiretroviral therapy revealed that pregnancy-IPT was associated with an increased incidence of composite adverse pregnancy outcomes , preterm delivery, and infant congenital anomalies). However, in subsequent secondary analyses of pregnancy cohorts and in a large-scale study of programmatic data in South Africa, antenatal IPT did not appear to be associated with adverse pregnancy outcomes. On the basis of these data, the World Health Organization (WHO) continues to recommend IPT for pregnant women living with HIV, both for their own and their infant's health. In reviewing these studies, we noticed that the long-term and sex-specific effects of pregnancy-IPT on HIV-exposed-uninfected infants were unknown.This post-hoc analysis of the TB APPRISE trial studied the effects of pregnancy-IPT beyond the previously reported composite pregnancy and birth outcomes to include longer term infant growth outcomes and employed sex-stratified analyses. The data shows that maternal IPT during pregnancy was associated with a significantly increased risk of low birth weight and risk of becoming underweight among HEU infants. Male infants exposed to pregnancy-IPT had a significant risk of low birth weight, preterm birth, and longer-term risk of being underweight that persisted over the first year of life.These data add to prior TB APPRISE findings of increased risk of composite adverse pregnancy and birth outcomes associated with IPT during pregnancy, suggesting IPT during pregnancy also impacts the birth size and subsequent infant growth, specifically among male infants. Given that WHO recommended IPT and ART during pregnancy based on data from nonpregnant adults and the absence of harm from observational studies, these data could inform monitoring and management and warrants further examination of potential mechanisms.,Prevention of tuberculosis (TB) among women living with HIV (WLWH) is a high priority in TB endemic areas.,Observational studies on pregnant women, primarily secondary analyses, did not reveal associations of pregnancy IPT with adverse pregnancy outcomes., and growth compromise.Exposure to HIV and ART in-utero may increase the risk of preterm birth, LBW and low birth length, small for gestational age (SGA), stillbirth,12th week postpartum. The postpartum-IPT arm initiated a placebo immediately after trial entry during pregnancy until the 12th week postpartum and then switched to isoniazid daily until the 40th week postpartum. All participants received vitamin B6 and a prenatal multivitamin from week 0 to week 40 postpartum. The randomisation was stratified by the gestational age at trial entry (≥14 weeks to <24 weeks or ≥24 weeks to ≤34 weeks) and was balanced at each site.This post-hoc analysis utilised data from the P1078 TB APPRISE trial – a randomised, double-blind, placebo-controlled, multicentre, non-inferiority study designed to evaluate the effect of pregnancy-IPT vs postpartum-IPT on maternal complications and composite adverse birth outcomes. The trial, as reported in detail previously,As detailed in the parent paper,3, >7.5 g/dL haemoglobin, and >50,000 platelets count/mm3 were eligible. Participants were required to have liver enzymes  at or below 1.25 times the upper limit of the normal range within 30 days prior to study entry. Women with active TB, recent TB exposure, TB treatment for more than 30 days in the previous year, or peripheral neuropathy of grade 1 or higher were excluded. The original study included 956 participants, 477 randomised to pregnancy-IPT and 479 to postpartum-IPT arm. Participants were enrolled between August 2014 and April 2016.Pregnant WLWH, 14–34 weeks of gestation, weighing >35 kg, with >750 absolute neutrophil count cells/mmThis analysis was restricted to HEU infants born to mothers participating in the RCT. Exclusion criteria for this analysis included lack of infant information , HIV infection of the infant, and twin births.Mother-infant pairs were followed up to 48 weeks postpartum. Weight and length of infants were measured at birth, 4th, 8th, 12th, 24th, 36th, 44th, and 48th weeks postpartum to the nearest 0.1 kg and 0.1 cm. The scales were calibrated regularly as per the manufacturer's instructions. Shoes and outer layers of clothing were removed before weight measurements were taken. Infants' lengths were measured with horizontal boards. The data collectors were trained and experienced in weight and length measurement. There was a two-week extension period for mothers who did not attend their last visit. Missing values at the scheduled last visit were replaced by measurements within two weeks after the end of the study.Low birth weight (LBW) was defined as less than 2.5 kg regardless of gestational age. Birth before completion of 37 weeks of pregnancy was regarded as preterm. Small for gestational age (SGA) was defined by weight less than the 10th percentile for gestational age using INTERGROWTH growth standards.Weight-for-age z-score [WAZ], weight-for-length z-score [WLZ], and length-for-age z-score [LAZ]) were defined using WHO child growth standards.3), education, and household food insecurity. Household food insecurity was considered positive if the respondents answered yes to at least one of the following questions: did you experience a lack of resources to get food, have you gone to bed hungry in the last 30 days, and have you passed the entire day and night hungry?Cofactors of growth faltering assessed in the analyses included: Infant sex and maternal characteristics at enrolment, including body mass index (BMI), age, ART regimen, viral non-suppression , CD4 count (cells/mm2 tests (Fisher's exact tests if assumptions were not met) for categorical variables.Means and standard deviations (SDs) were used to describe normally distributed continuous variables, medians and interquartile ranges (IQRs) to describe skewed distributions, and frequencies and percentages to describe categorical variables. Baseline maternal and infant characteristics were compared between pregnancy-IPT and postpartum-IPT randomisation groups using two-sided t-tests (Mann–Whitney U tests if assumptions were not met) for continuous variables and Pearson χIn the primary study, randomisation was carried out on pregnant women. The randomisation groups were compared in modified intent-to-treat analyses adjusted for predetermined potential confounding variables.For the measurement of adverse birth outcomes, the effects of pregnancy-IPT on LBW and preterm birth were examined in the primary trial publication; however, sex-stratified analyses of these outcomes were not conducted. We examined the effects of pregnancy-IPT on birth outcomes  using generalised linear models with a Poisson family and a log link (to estimate relative risks) in overall and sex-stratified analyses. Multivariable generalised linear models were fitted to control potential confounders.For the measurement of growth faltering during infancy, mothers in the postpartum-IPT arm initiated IPT at 12 weeks after delivery, therefore data were censored at 12-weeks postpartum to examine the effect of pregnancy-IPT compared to no IPT during pregnancy and postpartum. In addition, to compare the longer-term effects of pregnancy-IPT on growth faltering, randomised arms were compared up to 48 weeks after birth. Growth faltering was compared between randomised groups using Cox proportional hazards regression models and generalised estimated equations (GEE).th week and after were censored.We used Kaplan–Meier survival analysis to compare, unadjusted, time to the first event of growth faltering  to 12 weeks postpartum and 48 weeks postpartum in overall and sex-stratified analyses. Univariate and multivariable Cox proportional hazards regression models and models including interaction terms between randomisation arm and infants' sex were fit to compare the risk of experiencing the first episode of growth faltering between the randomised groups and any effect modification by infant sex. For these analyses, time zero was the randomisation date, and no failure  was assumed prior to birth. Since participants were randomly assigned to either a treatment or a control group during pregnancy, whatever difference occurred between the two arms, such as gestational age at birth or low birth weight, was assumed to be attributable to the intervention. Infants lost to follow-up or who died prior to failure were censored at their last visit date. Growth data from visits following growth faltering were censored. We used multivariate Cox proportional hazards regression models to identify cofactors , education, and household food insecurity and infant sex) of growth faltering. As fewer than 5% of at-risk participants remained in the study after 60 post-randomisation weeks, the values at 60In multivariable models, we didn't adjust birth characteristics because adjusting for low birth weight, preterm birth, and/or SGA would underestimate the effect of the intervention on the outcome as they are in the causal pathway between pregnancy IPT exposure and long-term growth.Moreover, univariate and multivariable generalised estimated equations (GEE) were fit with a Poisson family and a log link (to estimate relative risk) and exchangeable correlation structure to compare risks of growth faltering  at any time up until 12 weeks postpartum and up to 48 weeks, as well as testing for interaction by infants' sex and analyses stratified by sex. Infants who experienced growth faltering anytime were not censored in this analysis. The multivariate GEE model was used to identify cofactors of growth faltering in HEU infants.We also fitted multivariable linear regression to examine the long-term impact of IPT on growth  at 48 weeks of infant age.We used R version 4.1.0 for analyses.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BAR, ASC, and GM had access to the dataset. ASC, SML, GJS, AG, and GM were responsible for the final decision on the submission of this manuscript for publication.In this study, 898 infants were included: 448 in the pregnancy-IPT and 450 in the postpartum-IPT arm .Fig. 1FiThe median age of mothers at enrolment was 29 years (IQR 24–33), and median BMI was 26.2 (IQR 23.3–29.7). All mothers were on ART and the majority received either efavirenz-tenofovir-lamivudine ) or efavirenz-tenofovir-emtricitabine ). Almost half (49.2%) of mothers had a CD4 count above 500 cells/mm3, and 37.6% (316/850) of mothers had a viral load of >40 HIV RNA copies/ml. Almost half (447/898) of the infants were female – 228 in the pregnancy-IPT arm and 219 in the postpartum-IPT arm. Baseline maternal and infant demographic and clinical characteristics were similar between randomised arms .Table 1BAs reported in the primary analysis, six mothers (0.4%) and one infant (0.1%) developed TB, and 241 mothers (32.4%) and 41 (5.8%) infants tested positive on a QuantiFERON-TB Gold In-Tube (QGIT) test. There was no significant difference in TB disease or infection incidence in mothers or infants between arms.There was no unadjusted mean difference in WAZ , LAZ , and WLZ  at 48 weeks of infants age between pregnancy-IPT and postpartum-IPT. Similarly, there was no adjusted mean difference in WAZ , LAZ , and WLZ  at 48 weeks of infants age between pregnancy-IPT and postpartum-IPT.Overall, 10.7% of infants were premature, 11.5% were LBW, and 19.2% were SGA at birth. Adjusted for relevant cofactors, infants in the pregnancy-IPT arm had a 1.60-fold higher risk of LBW  than infants in the postpartum-IPT arm . There wIn sex-stratified analyses adjusted for all cofactors, male infants in the pregnancy-IPT arm had a 2.04-fold higher risk of LBW  and 1.81-fold increased risk of preterm birth  than those in the postpartum-IPT arm. Pregnancy-IPT was not associated with LBW or preterm delivery among female infants or SGA among male and female infants .The overall risk of being underweight during the 48-week follow-up period was 22.8 per 100 person-years , risk of stunting was 40.1 per 100 person-years , and risk of wasting was 32.8 per 100 person-years .In univariate analysis, male infants in the pregnancy-IPT had a significantly higher cumulative probability of being underweight , p = 0.041) than male infants in the postpartum-IPT arm a. Fig. 2In multivariable Cox regression models, pregnancy-IPT was associated with infant underweight in analyses to 12 weeks and 48 weeks postpartum. Infants in the pregnancy-IPT arm experienced a 1.47-fold higher risk of becoming underweight in the first 12 weeks  and a 1.34-fold higher risk of becoming underweight in the first 48 weeks  than infants in the postpartum-IPT arm. Maternal IPT timing was not associated with stunting  or wasting  .Table 3RInfant sex significantly modified the effect of pregnancy-IPT on underweight in analyses to 12 weeks  and 48 weeks . Male infants in the pregnancy-IPT arm experienced a 2.02-fold increased risk of becoming underweight in the first 12 weeks  and a 1.82-fold increased risk of becoming underweight in the first 48 weeks  than male infants in the postpartum-IPT arm .There was also a statistically significant differential effect of pregnancy-IPT on wasting in male and female infants by 12 weeks , but not by 48 weeks . Male infants in the pregnancy-IPT arm experienced a 1.61-fold higher risk of becoming wasted in the first 12 weeks , and a 1.43-fold higher risk (nonsignificant) of becoming wasted in the first 48 weeks  than male infants in the postpartum-IPT arm .Among female infants, pregnancy-IPT was not associated with growth faltering – underweight , stunting , and wasting .We also fitted GEE multivariable models to estimate the repeated prevalence of growth faltering during infancy which yielded similar results to Cox regression analyses .2 increase in maternal BMI, infant risk of being underweight decreased by 7% , and wasting risk decreased by 8%   .Table 4CFor every additional year of maternal age, the risk of wasting in infants increased by 4% , while the risk of stunting decreased by 2% . Infants born to mothers who used NVP-regimens experienced 1.6-fold increased risk of being underweight  and 1.34 increased risk of stunting  compared to EFV, TDF, 3TC/FTC regimens. Infants born from mothers who have secondary education have a 21% lower risk of stunting  but a 45% higher risk of wasting  .Multivariable GEE models used to assess cofactors of growth faltering yielded similar results as Cox proportional hazard regression models above .In this post-hoc analysis of a multi-site RCT evaluating maternal IPT in pregnancy versus postpartum, timing of maternal IPT influenced growth outcomes among HEU infants with a significantly higher risk of underweight among infants born to mothers in the pregnancy-IPT arm. There was an effect modification of associations of IPT with growth by infant sex, with significantly increased underweight and wasting in males born to mothers in the pregnancy-IPT versus postpartum-IPT arms. Our findings suggest that the timing of maternal IPT may influence birth size as well as postnatal growth in infants and provide valuable data for policymakers and clinicians considering the optimal timing of IPT in pregnant WLWH.,Our data suggest growth-altering effects of in utero IPT exposure. Infants born to mothers randomised to pregnancy-IPT had a 1.60-fold higher risk of LBW and of becoming underweight during the first year of life than infants born to mothers randomised to postpartum-IPT. During pregnancy, IPT causes embryocidal effects on rats and rabbits, delays neurodevelopment in zebrafish, and affects postnatal growth, development, and cognitive ability in rats.,,,,,,We found that associations between pregnancy-IPT and growth were modified by infant sex. Male infants in the pregnancy-IPT arm had a significantly higher risk of preterm birth, LBW, and longer-term growth faltering than male infants in the postpartum-IPT arm. In contrast, birth outcomes and growth in female infants were not affected by pregnancy-IPT. In utero growth trajectories differ by sex; male foetuses typically grow faster and may not alter their growth trajectory when facing adverse challenges.Pregnancy-IPT was not associated with overall or sex-stratified SGA. The fact that male infants in pregnancy-IPT had a 1.81 higher risk of preterm birth while there was no difference in SGA risk than male infants in postpartum-IPT suggests that the mechanism for LBW in male infants may be through preterm birth.In addition to our primary goal of defining the impact of pregnancy IPT exposure on infant growth, we assessed other cofactors of growth in HEU infants. We found expected associations between maternal BMI and being underweight. Nutritional status during pregnancy affects the Foetus's nutrition, potentially altering its growth. We also found that stunting risk decreased by 2% for every additional year of maternal age. This was consistent with a study using data from 18 countries' Demographic Health Surveys, which found that infants of young mothers had lower heights than infants born to older mothers.This study has multiple strengths, including randomised allocation of IPT timing, excellent retention, and sufficient sample size to investigate growth outcomes. The study also has limitations. This post-hoc analysis was designed after the primary RCT was completed. After 12 weeks of age, infants in the deferred arm received postpartum IPT, so there is not a no-IPT comparator after this time point. However, in analyses that excluded the time period with exposure to postpartum IPT, growth effects of pregnancy-IPT remained similar. Because of the lack of information about infants' growth during pregnancy, we assumed no failure  prior to birth, and birth was assumed as time-one, which could be a limitation. Infants with compromised growth before delivery would have been censored before birth if we had this prior birth information. As a result, it is possible that some infants might have switched categories before birth as a result - from compromised growth to normal growth and vice versa. However, we strongly believe that the design of our study has addressed/minimised the impact of this on the results of our study. Given that randomisation was applied, any difference between the two arms is attributed to IPT exposure during pregnancy. Similarly, the double-blind placebo-controlled randomised controlled trial design has addressed/minimised potential bias and measurement errors. Randomization has addressed selection bias. To reduce measurement error, data collectors were trained in how to measure height and weight in infants. As it was a double-blinded and placebo-controlled design, even if measurement error occurred, there would have been non-differential misclassification, which would attenuate the effect of the exposure on the outcome. Therefore, the design allows us to ensure that our findings are not biased or influenced by measurement errors . And, randomisation was balanced by study site to account for heterogeneity.Breastfeeding is crucial for infant development and growth. We did not include breastfeeding-related variables in our models for the following reasons: 1) to avoid adjusting a potential mediator: Preterm birth and low birth weight are hypothesised pathways to long-term growth effects, and both affect breastfeeding negatively, which make breastfeeding part of the potential causal pathway. As a result, adjusting breastfeeding variables would attenuate intervention effect. 2) Differential censorship: Randomisation date during pregnancy was time zero, and breastfeeding is a time-varying variable that can only be collected after birth. The association between breastfeeding and growth would exclude infants with restricted growth at birth due to censoring in the survival analysis design. 3) Left truncation bias: If adverse birth outcomes affect breastfeeding practice and a large number of infants with adverse birth outcomes are censored at birth (time 1), including breastfeeding in our models to assess its association with growth over each follow-up period would introduce bias. We would be able to fit breastfeeding variables only to infants who survived time one (infants without adverse birth outcomes). For these reasons adding breastfeeding variables to our models would be problematic." As a result of these reasons, and the fact that only a few infants had concurrent infections at each follow-up (on average less than 4 infants had pneumonia), we did not include infection status in the analysis.Other important factors that affect the growth of infants during pregnancy are the drinking and smoking experiences of mothers. Due to the very small number of mothers smoking at enrolment (<2%), we did not include maternal smoking experience as a cofactor in the model. Mothers' drinking experience at enrolment or after was not collected. Nonetheless, the results of the study regarding the effects of IPT on growth would not have been affected by these variables since randomisation would distribute them evenly between the randomisation arms.In conclusion, in this post-hoc analysis, maternal IPT during pregnancy was associated with a significantly increased risk of LBW and risk of becoming underweight among HEU infants. Male infants exposed to pregnancy-IPT had a significant risk of LBW, preterm birth, and longer-term risk of being underweight that persisted over the first year of life. These data add to prior TB APPRISE findings of increased risk of composite adverse birth outcomes associated with IPT during pregnancy, suggesting IPT during pregnancy also impacts birth size and infant growth specifically among male infants. These data could inform monitoring and management and warrants further examination of potential mechanisms.ACH participated in the investigation of the parent study and reviewed and edited this manuscript.AG designed and analysed the parent study. Reviewed and edited this manuscript.ASC∗ participated in all activities of this post-hoc analysis: data management, analysis, writing and editing the manuscript.AW participated in the investigation of the parent study and reviewed and edited this manuscript.BAR∗ participated in all activities of this post-hoc analysis: data management, analysis, writing and editing the manuscript.BTM participated in the investigation of the parent study and reviewed and edited this manuscript.DAE participated in all activities of this post-hoc analysis: data management, analysis, writing and editing the manuscript.DW participated in the investigation and validation of the parent study and reviewed and edited this manuscript.EJ participated in the investigation and validation of the parent study and reviewed and edited this manuscript.GM participated in the investigation of the parent study and reviewed and edited this manuscript.GM∗ designed/analysed parent study, data curation, and methodology and reviewed & edited the manuscript.GT participated in the investigation of the parent study and reviewed and edited this manuscript.GJS participated in all activities of this post-hoc analysis: data management analysis, writing and editing the manuscript.HC participated in the investigation of the parent study and reviewed and edited this manuscript.LA participated in the investigation of the parent study and reviewed and edited this manuscript.LSC participated in the investigation of the parent study and reviewed and edited this manuscriptMSR participated in the investigation and validation of the parent study and reviewed and edited this manuscript.NC participated in the investigation of the parent study and reviewed and edited this manuscript.PJP participated in the investigation of the parent study and reviewed and edited this manuscript.SB participated in protocol development and study implementation, and operational support.SML participated in all activities of this post-hoc analysis: data management, analysis, writing and editing manuscript.TN participated in the investigation and validation of the parent study and reviewed and edited this manuscript.TM participated in the investigation and validation of the parent study and reviewed and edited this manuscript.∗ASC, BAR, and GM have accessed and verified the underlying data.sdac.data@fstrf.org) with the agreement of the IMPAACT Network.Due to ethical restrictions in the informed consent documents and in the approved human subjects protection plan of the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, the study's data cannot be made publicly available; public availability could compromise participant privacy. However, data are available to all interested researchers upon request to the IMPAACT Statistical and Data Management Center's data access committee (email address: AW declares grants from GSK, Merck, and Janssen; payment for expert testimony from GSK and Merck; and participation on a data safety monitoring board for GSK, Merck, and Seqirus. All other authors declare no competing interests.


Liver transplantation (LT) represents the primary curative option for HCC. Despite the extension of transplantation criteria and conversion with down-staging loco-regional treatments, transplantation is not always possible. The introduction of new standards of care in advanced HCC including a combination of immune checkpoint inhibitor-based therapies led to an improvement in response rates and could represent a promising strategy for down-staging the tumor burden. In this review, we identify reports and series, comprising a total of 43 patients who received immune checkpoint inhibitors as bridging or down-staging therapies prior to LT. Overall, treated patients registered an objective response rate of 21%, and 14 patients were reduced within the Milan criteria. Graft rejection was reported in seven patients, resulting in the death of four patients; in the remaining cases, LT was performed safely after immunotherapy. Further investigations are required to define the duration of immune checkpoint inhibitors, their minimum washout period and the LT long-term safety of this strategy. Some randomized clinical trials including immunotherapy combinations, loco-regional treatment and/or tyrosine kinase inhibitors are ongoing and will likely determine the appropriateness of immune checkpoint inhibitors’ administration before LT. Hepatocellular carcinoma (HCC) is the most prevalent form of liver malignancy  and the The utilization of systemic therapies to reduce tumor burden in patients with BCLC-B HCC not initially amenable to curative treatment might represent a new tool in the box of pre-LT therapies; still, its opportunity is very debated. Immune checkpoint inhibitors (ICIs) have recently become a new therapeutic option for advanced HCC. The new challenge is combining ICIs with LT as a modality for down-staging or bridging.In this review, we present the available data on ICIs as a down-staging therapy for HCC before LT and its rationale. We compare the described outcomes with those from traditional LRTs and display the perspective of novel approaches  being tested in ongoing clinical trials.LRTs, including TACE, TARE, radiofrequency ablation (RFA) and radiotherapy, are commonly used in clinical practice to lower tumor burden before LT, to reduce tumor growth, prevent dropouts from waiting lists and increase survival after LT ,15. MoreOptimal LRT choice depends primarily on their application goals. In case of bridging, RFA and TACE are recommended when the waiting time exceeds 6 months ,18.RFA represents a valid alternative to surgery in BCLC-0/A HCC. Data from the European Liver Transplant Registry showed that RFA had the highest 5-year OS (80.9%) after LT compared to chemoembolization (67.6%) and no bridging or no down-staging LRTs (65.8%) . AlthougTACE is a minimally invasive technique with a permanent curative effect and easy implementation which is recognized as the standard treatment for intermediate-stage HCC ,22. The The updated AASLD guidelines suggest TARE as an alternative conversion strategy to TACE, especially in cases of portal vein thrombosis or tumor burden, and TARE can achieve a regression rate of up to 25–50% ,28. TherThe opportunity to explore systemic therapy as a down-staging strategy derives from the significant advances made in the pharmacological landscape of HCC. Since sorafenib’s approval in 2008, many promising drugs, including other tyrosine kinase inhibitors (TKIs) and ICIs, have improved response rates. In detail, if sorafenib granted an ORR of 2–3% , lenvatiICIs have revolutionized the management of HCC after TKIs; however, single-agent ICIs, such as nivolumab, pembrolizumab and tislelizumab, reported an ORR of less than 20% due to primary resistance mechanisms against these strategies ,33,34,35From these promising activity results, ICI-based regimens have been postulated as even more advantageous options in terms of down-staging than LRT. Moreover, in addition to their greater ORR rates and their role in tumor immunity, ICIs seem to be important for transplantation immunity.Data about the combination of TACE and sorafenib are conflicting: in 2020, the TACTICS trial, TACE plus sorafenib, showed PFS and OS benefit as compared with TACE alone. Although the ORR is not reported, the combination showed better survival as compared to TACE alone, especially in patients outside the Milan and up-to-seven criteria; subsequent treatment was received in 58.8% of patients in the TACE plus sorafenib arm, but no LT was performed . While uThe SORAMIC trial examined the association of TARE and sorafenib in 424 advanced HCC patients, resulting in no survival benefit from the combination. In subgroup analysis, patients with a tumor burden of the up-to-seven criteria could benefit from the combined use of TARE and sorafenib .Regarding newer strategies than sorafenib, there is little knowledge about the association between TACE and lenvatinib. Recently, Ding et al. showed a favorable time to progress and ORR of TACE plus lenvatinib over the same LRT plus sorafenib, which reached a remarkable 53%, especially in patients with PVTT . The LAURecently, combination strategies have been evolving toward LRT and immunotherapy’s association.The studies reported below are rather heterogeneous, as not all provide the association between ICIs and LRT in terms of sequential strategy, but some propose the administration of ICIs as a post-LRT maintenance.In 2022, Sangro et al. presented data regarding the phase II trial NASIR-HCC, enrolling patients with unresectable HCC to receive TARE followed by nivolumab, with a promising ORR of 38.1% in all comers and 38.7% in patients with BCLC-B2 or higher . A recenRegarding the association of TACE plus ICIs, the IMMUTACE trial showed promising response rates from the combination of TACE plus nivolumab in intermediate-stage HCC (ORR 71.4% and 16.3% of complete response) , but no While to date there are no data on down-staging following LRT and ICI treatment, immunotherapy before LT will be discussed extensively in the following paragraphs.Of particular interest is the triplet multimodality therapy based on combining LRT (mainly TACE) with both TKIs and ICIs to pursue down-staging and conversion in HCC patients with no extrahepatic spread.The rationale for combining these strategies lies in the following factors: (1) anti-PD-1 antibodies block inhibitory signals given by the interaction of PD-1 with its ligand, activating an immune response against tumors; (2) TACE induces devascularization of HCC and releases tumor-specific antigens ,51; and The first piece of evidence derived from retrospective trials enrolling unresectable and/or TACE refractory HCC  is the fLooking prospectively to these results, they could lead the way to an LT approach in highly selected patients according to the obtained response to trimodal treatment.ICIs have revolutionized the algorithm of several malignancies: initially, ipilimumab was approved for metastatic melanoma by the US Food and Drug Administration (FDA) , and subStudies involving ICIs did not enroll patients with solid organ transplantation (SOT) and data regarding the safety and efficacy in this patient subset are still missing .Furthermore, SOT patients have a twofold higher risk of tumor compared with the general population , with a Graft rejection incidence has been investigated through different case reports and preclinical evidence in ICI-receiving patients. The blockade of PD-1/PD-L1 or CTLA-4 pathways mediates acute graft rejection. The main histological features of graft rejection include T-cell infiltration and inflammation of the bile duct and endothelial systems . The PD-From this perspective, testing the graft expression of PD-L1 could be helpful in the clinical management of this not-so-infrequent subgroup of patients; in fact, the absence of PD-L1 expression in organ donors appears safe for graft tolerance before ICI therapy.The PD-1 pathway appears to play a more critical role during graft immune tolerance than the CTLA-4 pathway ,77,78. SImmunosuppressant protocols represent a key aspect in SOT and they are subjected to periodic updates. Calcineurin inhibitors (CNIs), including tacrolimus and cyclosporine, changed allograft survival; on the other hand, these drugs also have the strongest evidence of increased tumor risk . In a prConversely, rapamycin and sirolimus, Mammalian Target Of Rapamycin (mTOR) inhibitors, have been reported to prevent tumor growth and progression in animal models . mTOR inp = 0.03). There were no differences in the median OS between patients receiving different immunosuppressive regimens at ICI initiation [Another weakness in the knowledge of ICIs’ role in SOT is the limited robustness of the available literature: the majority of data emerge only from case reports or small series involving different clinical scenarios. Abdel-Wahab et al. published an interesting mono-institutional experience from MD Anderson Cancer Centre in 2019. They retrospectively collected data from 39 patients who received ICIs after SOT. In their cohort, the majority of patients had advanced melanoma (62%) and received anti-PD-1 agents (37.7%). The most frequently transplanted organs were the kidney (59%), liver (28%) and heart (13%). The median time between initiation of ICIs and SOT was 9 years (range 0.92–32 years), and 51% of patients had pre-emptive modification of the baseline immunosuppressive regimen before ICI initiation. Overall, graft rejection after ICIs occurred in 16 patients (41%) and the median time to graft rejection was 21 days (95% CI 19.3–22.8 days). Graft loss occurred in 40% of cases  treated with anti-PD-1 and 36% (5 of the 14 patients) treated with anti-CTLA-4. Rejection occurred more frequently in patients receiving single-agent prednisone (≤10 mg/day) at the beginning of ICIs than those receiving single-agent CNIs . No differences were observed in the time between SOT and initiation of ICIs in patients with or without allograft rejection. The most common mechanisms of rejection identified via liver biopsies were the following: (1) acute rejection (75%) and (2) complex acute and chronic rejection (25%). Five patients who started ICIs at a median of 16 years (range 5–25 years) after SOT had a T-cell-mediated rejection; in the other five patients, who started ICIs at a median of 5 years (range 1.9–19 years) after SOT, a combination of cellular- and antibody-mediated rejection was reported. Four patients showed positive PD-1/PD-L1 expression at immunofluorescence analysis conducted on transplantation liver biopsies. Eighteen patients died (46%) because of allograft rejection or its complications. Median OS was 5 months (95% CI 1–9 months) for patients who had allograft rejection, compared with 12 months (95% CI 8–16 months) for those who had no rejection  cases received anti-PD-1. Eighteen patients (41%) had an acute rejection of the kidney allograft. The median time from ICI initiation to acute rejection diagnosis was 24  days. Also, in this analysis, cellular rejection (33%) and mixed cellular and antibody-mediated rejection (17%) are confirmed the most common mechanisms of allograft rejection. Eventually, allograft failure occurred in 83% (15/18) of patients and eight patients died subsequently. Approximately half of the patients were treated with a CNI, mycophenolate mofetil and a low-dose steroid. Interestingly, 11 patients were tapered down to steroids alone for graft preservation at the time of checkpoint inhibitor initiation. At the latest follow-up (length not reported), 18 patients were alive. Fifteen patients maintained response to treatment  despite half of them having allograft failure .DeLeon et al. reported the efficacy and safety of anti-PD-1 therapy in LT patients in a retrospective study. Seven patients with a previous LT received ICIs: five for HCC and two for melanoma. Rejection occurred in two of seven patients (28.6%) as an early event with a median time of 24 days. Regarding tumor response to ICI treatment, one patient showed complete response (CR) while three patients experienced progressive disease (PD). Three patients discontinued therapy before rescheduling assessments. Two of five patients with available tissue had tumor PD-L1 expression in the allograft and both developed rejection .Rammohan et al. presented an interesting clinical case in 2018: a 57-year-old man with multifocal HCC who underwent living donor LT after multiple cycles of TACE and RFA. Following a diagnosis of metastatic disease, his immunosuppression was modified by adding mTOR inhibitors (tacrolimus dose decreased to maintain a blood level of 2–3 ng/mL), and he received sorafenib for one year. For progressive disease, he started pembrolizumab along with sorafenib. After 3 months, a CT scan showed an excellent response to the combination with a complete radiological response. After ten months of starting therapy, he remained well on pembrolizumab and sorafenib with no radiological evidence of disease .To date, given the high rejection rate and fatal complications, post-transplant immunotherapy is contraindicated and is not a standard strategy.The use of ICIs as bridging or down-staging therapies before LT has been described in 17 case series. Literature data are generated from descriptive case studies and add up to 43 patients from different institutions. Despite limitations posed by this numerosity, we hereafter attempt to aggregate these data for the sake of their interpretation . Male geDespite the high response rate with ICIs, LRT was applied to stabilize lesions or to consolidate a response in five patients ,90,91,92In terms of safety, 7% (3/43) of patients had mild rejection which was successfully treated by modifying their immunosuppressant scheme. Eight patients (out of 43) suffered graft rejection between 20 h and 14 days after LT and four of them died as a result of this complication. Nordness et al. described a patient who, after 2 years of nivolumab, received the final dose 8 days prior to LT and developed a transplant rejection. Chen et al. reported a case of acute graft rejection in a patient who received pre-transplant treatment with toripalimab. Specific to this case, on the 33rd hour after LT, liver function deteriorated, and the patient received continuous renal replacement therapy and plasma exchange treatment. However, the patient developed multiple organ failure. In the other cases, a worsening of liver function has also been described. In the single case of Nordness et al., high doses of methylprednisolone and rabbit antithymocytic globulin (rATG) were given without improvement in liver function tests. Dave et al. administered rATG to three patients, but only one of these had biopsy-proven rejection. Interestingly, Chen et al. reported that PD-L1 expression in preimplant donor liver tissue was negative but turned positive in postimplant tissue. This confirms that ICIs could lead to failure of the transplant attempt to reach “immune escape” by expressing PD-L1, which results in a lethal acute rejection response ,100,101.Among eight patients who experienced graft rejection, three patients underwent re-transplant ,98,102. In conclusion, both mild and severe acute rejections were reported. A total of 8 of the 43 patients developed severe acute rejection. The most frequently used drugs were high-dose steroids and rATG. Dehghan et al. and Schnickel et al. described two different patients who developed acute rejection with high levels of donor-specific antibodies (DSAs). Compared to transplantation of other solid organs, the liver is quite immune-tolerant and most LT centers still do not account for human leukocyte antigen (HLA) matching in their allocation algorithms. DSAs are recipient-formed antibodies that can bind to HLA in the donor organ, causing damage to the graft. Preformed DSAs exist prior to transplant when the recipient has been exposed to a variety of non-self HLAs, whereas de novo DSAs form after transplantation in response to the new donor organ’s HLAs. Most preformed DSAs clear spontaneously early after transplant. In patients with persistent DSAs (preformed or de novo), there is a higher risk for overall rejection ,104. TheOverall, the death rate from rejection was 7% (3/43). Follow-up data and long-term outcomes are only partially available for 33 patients. Although there were different periods of follow-up (range: 7–38 months), no allograft rejection occurred in most of the patients. Schnickel et al. reported that one patient died 2 days after his last follow-up visit from a cardiac arrest with a functioning graft and normal liver tests. Chen et al. reported two patients who developed HCC recurrence: one progressed in the liver, bone and lungs after 7 months and the other experienced recurrence in the lungs after 3 months. Based on the data available from studies on ICIs before LT, the recurrence rate of HCC was 5% (2/43).Despite advances in immunomodulatory therapies, acute rejection remains a significant complication after SOT. Diagnosis of rejection typically involves invasive biopsy sampling for histopathological analysis and non-invasive biomarkers for early detection are still an unmet need.Cell-free DNA has emerged as a useful biomarker in multiple clinical settings. In oncology, the isolation of circulating free DNA allows for the studying of tumor molecular profiling in different malignancies. This gave rise to the notion of a “liquid biopsy” for diagnostic and management purposes. In SOT, genetic differences become fundamental. Except for an identical twin donor–recipient pair, it is possible to detect circulating free donor DNA (cf-dDNA) via minimally invasive blood sampling. This biomarker is found in all recipients. Based on the levels of cf-dDNA (low or high), graft integrity or graft injury/rejection can be detected, respectively ,106. TheAfter LT, the immune microenvironment is subjected to changes that can be detected by flow cytometry. Recently, T-cell monitoring has helped to determine the effect of various T-cell subsets on transplant outcomes: Tregs have a critical role in establishing tolerance in LT recipients and both Foxp3 + CD25 high and CD4 + CD25 + CD127 low/- T cells have been identified as regulatory subtypes in humans, which might improve graft survival ,109.Han et al. demonstrated that active Treg concentrations on day 7 post-LT were considerably lower in subjects with biopsy-proven acute rejection than non-rejectors, together with a lower expression of Bcl-2, an anti-apoptotic molecule linked to the survival of Tregs. Multivariate Cox regression analysis confirmed Tregs on D7 as an independent risk factor .Another proinflammatory player in graft rejection is Th17; it has been demonstrated that a balance between Th17 and Treg cell frequencies in recipients is essential to establish allograft. In the rejection group, the Th17/Treg ratio was significantly greater than in the stable one. Moreover, the percentages of Th17 and Treg cells in the peripheral blood of stable LT recipients at six months post-LT was significantly reduced, whilst the Th17/Treg ratio was comparable to the pre-transplant period . This sePD-1 plays an important role in the graft’s survival. During LT, immunological responses are inhibited and escape human surveillance due to the overexpression of immune checkpoint molecules; it has been demonstrated that PD-1 expression in CD8+ T cells was found to be significantly lower in acute rejection, suggesting that its downregulation could have a central role in this process .Serological markers of allograft rejection are under study. A pilot study revealed a strong link between IL-6 levels and graft loss . MoreoveAll the abovementioned experiences constitute preliminary evidence of the crucial role of immune function monitoring during LT follow-up. Nonetheless, the reproducibility and efficacy of these postulated biomarkers need to be validated in large prospective trials.As a consequence of small sample size and selective bias of the available literature, determining the actual likelihood of lethal rejection for patients receiving ICIs as down-staging or bridging for LT still remains a special issue. For instance, no guidelines exist on ICI discontinuation timing, despite being an important factor to be considered.A short interval between ICI infusion and transplant seems to increase the risk of acute rejection, although there are conflicting data in the literature; for example, Dave et al. reported graft losses in two patients who received ICI therapy < 90 days before LT, while Tabrizan et al. documented successful transplantation 1 and 2 days after the last nivolumab infusion. The minimal washout time is often set loosely based on the reported serum half-life for ICIs . HoweverSimilarly, there is no agreement with respect to the duration of neoadjuvant immunotherapy as bridging for LT. In other solid tumor settings, patients received up to six months of neoadjuvant ICIs before surgery ,118. In Given the sustained occupancy of ICI pharmacological targets and the role of PD-1 in graft survival, it will be important to evaluate the interplay of ICIs in the immune microenvironment after LT. Currently, there is a partial understanding of the immune activation’s effects triggered by ICIs and immune modulation with immunosuppressive drugs. Achieving a balance between the two extremes is not easy and further comprehensive investigations are required.Although rejection is an undesirable outcome in this setting, other immune-related adverse events (irAEs) can also occur. The incidence and onset of irAEs vary based on several factors: (a) the class and dose of the ICI administered, (b) the type of cancer and (c) patients’ related characteristics. In general, those receiving anti–PD-1 or PD-L1 monotherapy were exposed to a lower incidence of any-grade irAEs than anti–CTLA-4 agents, with combinations increasing the incidence, severity and onset of irAEs . IrAEs hThe use of LRT reduces the chance of dropping out of the LT waiting list. Response to LRT—either used as bridging for Milan criteria or as down-staging for expanded criteria patients—has thus been proposed as a surrogate of favorable tumor biology . Only 17There is no guideline or consensus on combining LRT with ICIs. Despite improvement in the response to newer systemic therapies, it is possible to integrate LRT to reduce viable tumors to meet the transplant criteria.The recurrence rate of HCC ranges from 10% to 20%, with 50% of the patients classified as beyond the Milan criteria at the explant pathology evaluation  and the There is too little knowledge of the long-term security of ICIs and LT. The expression of PD-L1 in the graft protects against chronic rejection . AlthougFurther investigations into down-staging strategies for LT are ongoing and comprise the combination of (1) ICI doublets (anti-PD-1 + anti-CTLA4); (2) ICI + anti-angiogenic (both anti-VEFG and TKI); and (3) LRT  + ICI and/or TKI.At present, there are eight ongoing prospective trials investigating the impact of pre-liver transplant immunotherapy . The PLEThe different strategies’ specific rationales rely on the abovementioned mechanisms.According to the evidence examined in this study, the role of ICIs to bridge or down-stage HCC for LT is not well established. Nowadays, no biomarkers, tissue or liquid biopsies are available to help in selecting patients for immunotherapy and, subsequently, for transplant. The best approach to optimize patients’ administration with locally advanced diseases with excellent responses to systemic therapy and who meet transplant criteria is the evaluation of a dedicated multidisciplinary team (MDT). An MDT assessment pre-LT is essential to evaluate tumor burden, vascular involvement, liver function and physical status. Evaluation of response to ICIs and a combination of LRTs should be assessed by the MDT. Currently, there is no way to understand when to direct patients toward transplant after ICIs. Factors that may influence the MDT’s choice include time with stable disease on ICIs or the length of the overall treatment.


The utilisation of massed therapy for treating posttraumatic stress disorder (PTSD) is gaining strength, especially prolonged exposure. However, it is unknown whether massed prolonged exposure (MPE) is non-inferior to standard prolonged exposure (SPE) protocols in the long term. The current study aimed to assess whether MPE was non-inferior to SPE at 12 months post-treatment, and to ascertain changes in secondary measure outcomes.A multi-site non-inferiority randomised controlled trial (RCT) compared SPE with MPE in 12 clinics. The primary outcome was PTSD symptom severity (CAPS-5) at 12 months post-treatment commencement. Secondary outcome measures included symptoms of depression, anxiety, anger, disability, and quality of life at 12 weeks and 12 months post-treatment commencement. Outcome assessors were blinded to treatment allocation. The intention-to-treat sample included 138 Australian military members and veterans and data were analysed for 134 participants .Reductions in PTSD severity were maintained at 12 months and MPE remained non-inferior to SPE. Both treatment groups experienced a reduction in depression, anxiety, anger, and improvements in quality of life at 12 weeks and 12 months post-treatment commencement. Treatment effects for self-reported disability in the SPE group at 12 weeks were not maintained, with neither group registering significant effects at 12 months.The emergence of massed protocols for PTSD is an important advancement. The current study provides RCT evidence for the longevity of MPE treatment gains at 12 months post-treatment commencement and demonstrated non-inferiority to SPE. Promisingly, both treatments also significantly reduced the severity of comorbid symptoms commonly occurring alongside PTSD. Although there exists well-established evidence-based treatments for posttraumatic stress disorder (PTSD)  including a clinical interview and a self-report booklet. Immediately following T1 assessment, eligible participants were randomly allocated in a 1:1 ratio to SPE or MPE therapy. Randomisation occurred using two components – randomisation to SPE or MPE, and then randomisation to a therapist to deliver the intervention. Assessors (blinded to condition) conducted follow-up assessments at 4 weeks post-treatment commencement (T2), 12 weeks post-treatment commencement (T3), and 12 months post-treatment commencement (T4).The Australian Defence Human Research Ethics Committee and Department of Veterans' Affairs Human Research Ethics Committee approved the protocol (now known as the Departments of Defence and Veterans' Affairs Human Research Ethics Committee), see Dell et al. . The autInclusion criteria were: aged 18–80 years, current or former Australian Defence Force member, PTSD diagnosis as determined by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and a Criterion A trauma that occurred while serving. Exclusion criteria included current: clinician-rated psychosis, mania, high risk of harm to self or others, and severe alcohol or substance-use disorder as determined by the Mini International Neuropsychiatric Interview (MINI), and receiving other trauma-focused psychological therapy and unwilling/unable to pause. Given the prominence of risk within this population, risk to self and others was assessed at several points through the trial, including the initial intake call, T1 baseline assessment, and where needed during therapy. High risk was defined as active thoughts to harm self or others and the potential for immediate harm, or recent risk with the potential to be exacerbated by trauma-focused therapy. Risk to self or others was rated as no foreseeable, low, medium, or high, and previous suicidality did not preclude individuals from participation in therapy. Individuals taking psychotropic medication were required to be on a stable dose (no titration) for at least 4 weeks prior to commencing and without intention to change for the duration of treatment. All participants provided informed written consent to participate in the trial.in vivo homework activities. Telehealth treatment  involved the same format and duration of therapy, however took place using online video platforms. Treatment completers were defined by attendance at a minimum of seven sessions, consistent with previous prolonged exposure research  was measured by the clinician-rated measure for PTSD, the CAPS-5  self-report questionnaire    . The LMM procedure accommodates both correlated data and unequal variances, and includes both between groups and repeated measures (within-groups) effects at the same time. Participants' scores are deemed to be the result of both fixed effects (e.g. treatment group) and random (e.g. subject) effects, and LMM utilises maximum-likelihood and restricted maximum-likelihood methods to yield optimum estimators (with minimum variance) for balanced and unbalanced designs. Separate LMMs were conducted for each outcome measure. For all measures except for the AQoL-6D, a negative score indicates a reduction in symptoms. For the AQoL-6D a positive score indicates an improvement in quality of life. While not included in the original protocol , T3 , and T4  was performed using SPSS with variables in the imputation model chosen if they correlated strongly with CAPS-5 diagnoses being imputed. Imputations were conducted separately for each treatment group to produce 10 imputed datasets. The pooled estimates of the frequencies of CAPS-5 diagnoses were then subjected to χPTSD diagnostic status was determined by dichotomising individual symptoms as ‘present’ or ‘absent’, following the DSM-5 diagnostic algorithm. A symptom was considered present only if the corresponding item severity score was rated 2 (moderate/threshold) or higher. In the CAPS-5, items 9 and 11–20 have the additional requirement of a trauma-relatedness rating of definite or probable, otherwise a symptom is considered absent. The DSM-5 diagnostic rule requires the presence of at least one Criterion B symptom, one Criterion C symptom, two Criterion D symptoms, and two Criterion E symptoms. In addition, Criteria F and G must be met. Criterion F requires that the disturbance has lasted at least 1 month. Criterion G requires that the disturbance causes either clinically significant distress or functional impairment, as indicated by a rating of 2 (moderate) or higher on items 23–25. This calculation of diagnosis is consistent with Voorendonk, De Jongh, Rozendaal, and Van Minnen .Power and sample size were based on the upper endpoint of the 95% confidence interval (CI) for the difference in mean change scores from baseline to 12 weeks between MPE and SPE (adjusted for baseline) being less than the margin of 7 CAPS-5 points, the outcomes of which have been reported elsewhere  or SPE (n = 71).One hundred and sixty-two individuals were assessed for eligibility at T1, and 138 current and ex-serving Australian Defence Force (ADF) members with PTSD were randomised to therapy in the RESTORE trial. Of the 138 who were found to be eligible and randomised to therapy, four were later found to be ineligible and were excluded  and SPE ] to 12 months post-treatment [MPE  and SPE ], treatment gains were maintained in both groups, with a 95% CI of −6.82 to +3.92. The upper endpoint of the 95% CI (+3.92) was below +7, indicating non-inferiority. The baseline (T1), and 4 weeks (T2), 12 weeks (T3), and 12 months (T4) post-commencement of therapy scores for the PTSD outcome measure is presented in v. T4), large effect sizes were observed for change scores within both groups on the CAPS-5  = 0.002, p = 0.963.The proportions of participants with a diagnosis of PTSD on the CAPS-5 was compared across time separately for the MPE and SPE groups using McNemar's test of related samples. There were statistically significant reductions in the proportions of participants with a PTSD diagnosis in the MPE and SPE groups from baseline (T1) to 12 months (T4). Neither group changed significantly from T3 to T4. At T4, 53.2% of the MPE group and 54.1% of the SPE group had no PTSD diagnosis; χThe change scores for all secondary measures are presented in v. T4) for any of the outcome measures.Neither group reported a significant deterioration in comorbid mental health issues. With the exception of disability scores for the MPE group, both groups improved significantly over time on all measures on at least one occasion. Small-to-moderate effects were found for change in anger, with moderate-to-large effects found for change in anxiety and depression scores. Finally, for both groups, there were no significant changes from 12 weeks to 12 months (T3 The current study aimed to assess whether the longevity of treatment gains for MPE therapy was non-inferior to SPE therapy, and to ascertain whether MPE was non-inferior to SPE in the impact on secondary outcome measures. As hypothesised, MPE and SPE maintained a reduction in PTSD severity at 12 months, consistent with outcomes reported at 12 weeks (Dell et al., The emergence of MPE in recent years has been a promising advancement in the field, however until now, the long-term gains of a massed protocol have not been examined in a large-scale high-quality RCT. The effect size for PTSD symptom changes from baseline to 12 months was large and MPE was non-inferior to SPE. Further, the percentage of individuals who lost their diagnosis was sustained from T3 (Dell et al., It is widely acknowledged that patients experiencing PTSD frequently have comorbid mental health issues, particularly military and veteran patients. While significant reductions in depression, anxiety, and anger have been reported following SPE therapy (Aderka et al., Alongside the reductions in PTSD and other comorbid mental health conditions, improvements in quality of life were observed for both groups at 12 weeks and maintained at 12 months. This finding is consistent with recent SPE research (Schnurr et al., The outcomes of this study should be considered with limitations in mind. First, measures of comorbid mental health conditions were all self-reported and may not accurately reflect the rates present in the population. Second, the extent to which these findings can be applied to populations other than military and veterans is yet to be determined, and with the sample being predominantly male, there is the question of applicability of the results to females. Third, the substantial observed loss to follow-up requires us to exert some caution in interpretation of the results. Lastly, while the current findings contribute to increasing evidence for MPE's clinical utility, it is worth acknowledging that prolonged exposure may be suitable for certain clinical presentations, while another evidence-based treatment may be most suitable for others. It is imperative characteristics relevant to optimal treatment response continue to be explored. Similarly, MPE may not be suitable for all therapists given the intensity of treatment delivery and requirement to allow for five sessions with one individual per week.This study demonstrated that MPE was non-inferior to SPE in the reduction and maintenance of PTSD symptomatology and loss of diagnosis up to 12 months following therapy. Comparable reductions in depression, anxiety, and anger symptoms were also evident across the two treatments. The PTSD treatment field is cognisant of the front-line treatments for the disorder, however in a practical clinical setting, these treatments need to be offered in a modality that will suit patients and the demands of their life, particularly given that patients who are provided their preferred treatment are more likely to adhere and report greater reductions in self-reported mental health issues (Zoellner, Roy-Byrne, Mavissakalian, & Feeny,