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Objectives: According to the conventional postoperative procedure after total ankle arthroplasty (TAA), mobilization and weight-bearing is currently started after completion of wound healing. Recently, early mobilization for dorsiflexion after TAA with modified antero-lateral approach was reported to be feasible and safe. To investigate the further possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early full weight-bearing and gait exercise after cemented TAA. Materials and Methods: This retrospective, observational study investigated 23 consecutive ankles (OA: 14 ankles, RA: 9 ankles) that had received cemented TAA with a modified antero-lateral approach. These ankles were divided into three groups 1. conventional postoperative protocol, 2. early dorsiflexion protocol, 3. early dorsiflexion+full weight-bearing protocol. Postoperative wound complications were observed and recorded. Number of days for hospitalization was also evaluated. Results: No postoperative complications related to wound healing were observed even after early full weight-bearing and gait exercise. Days for hospitalization was significantly shortened in early full weight-bearing and gait exercise group (group 3) from 35-38 days to 24 days. Conclusions: Within this small number of cases, early full weight-bearing and gait exercise from 7 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Combination of early dorsiflexion mobilization and weight-bearing/gait exercise contributed to shortening the hospitalization day. Innovations in postoperative procedures for rehabilitation after TAA can be expected. [ABSTRACT FROM AUTHOR]

There has been interest in the impact of the cultural background of analysand and analyst on psychoanalysis. Basch-Kakre (1984) argued that analyst may have more difficulty in treating analysand with different sociocultural background. There was a claim that the characteristics of Asians were not suitable for psychoanalysis. Akhtar (1999) argues that theories are likely to come from racial discourse. Psychoanalysis has been successful in non-western countries. After Confucius was born, Confucianism of Confucius and Confucians for 2500 years in China, Vietnam, Japan, and Korea developed with various religions and ideologies that were controversial with them and developed differently in each country. I think it is helpful to consider the effect of Confucianism on the psychoanalysis for understanding patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the factors associated with retinal pigment epithelium (RPE) tear development in the early phase after anti-vascular endothelial growth factor (VEGF) drug initiation in eyes with neovascular age-related macular degeneration (nAMD) and retinal pigment epithelial detachment (PED). Methods: Treatment-naive eyes with nAMD and PED for which anti-VEGF drug injections had been initiated and followed up for at least 3 months after the 1st anti-VEGF drug injection, were retrospectively investigated. Baseline characteristics of the PEDs, including type, height, and area, were evaluated using fundus photographs, fluorescein angiography, and optical coherence tomography images. The association between patient age, sex, medical history, PED characteristics, and the development of RPE tears within 3 months of starting anti-VEGF therapy was examined. Results: This study included 244 eyes (230 patients; mean age 75.0 years, 159 males and 71 females). RPE tears occurred in 13 eyes (5.3%) within 3 months of the start of anti-VEGF therapy. Multivariate analysis showed an association of the development of RPE tears with PED height (every 100 µm, odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.07–2.12, p = 0.019), PED area (every 10 mm2, OR: 3.02, CI: 1.22–7.46, p = 0.016), and the presence of fibrovascular PED (OR: 59.22, CI: 4.12–850.59, p = 0.002). Eyes with cleft (the hypo-reflective space beneath the fibrovascular PED) were more likely to develop an RPE tear (p = 0.01, χ-square test). Conclusions: Fibrovascular PED, large PED area, high PED height, and the cleft finding are independent risk factors for the development of RPE tears early after the administration of anti-VEGF drugs. [ABSTRACT FROM AUTHOR]

Background: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian‐Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade. Methods: This cross‐sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics. Results: Over the 10‐year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10‐year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination. Conclusions: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies. [ABSTRACT FROM AUTHOR]

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

This study examines the use of conceptual modeling to aid in selecting a power generation system concept in the maritime industry. The research objective is to understand how conceptual modeling can enhance decision‐making during the early phases of concept evaluation. The study was conducted at a world‐leading maritime technology company to address the need for more formal processes to support decision‐making in complex development projects. The study applied a conceptual modeling approach in an industry case to facilitate decision‐making in the early phases of a development project. The study shows that conceptual modeling is effective in supporting early‐phase decision‐making in the development project. Conceptual models effectively manage complexity, enhance understanding, and enable effective communication among team members. By combining conceptual modeling with a Pugh matrix, informed decision‐making is facilitated, aligning with stakeholders' objectives. Overall, conceptual modeling provides a structured representation of the problem domain, guiding early‐phase decision‐making. [ABSTRACT FROM AUTHOR]

How the weight-bearing asymmetry pattern and related maximum lateral weight-bearing capacity, physical functions, balance, and mobility involved in weight-bearing asymmetry and lesions are related to weight-bearing asymmetry in patients with early-onset stroke remains unclear. To investigate the difference between weight-bearing in the early phase after stroke categorized as symmetrical or nonsymmetrical regarding impairments, balance, walking, and independence, and any lesion location difference. This cross-sectional study included 46 persons with hemiparetic stroke within 3 weeks from onset undergoing inpatient rehabilitation and classified into symmetrical, paretic, and non-paretic groups. We performed posturographic, functional, mobility, and lesion location assessments on participants once the evaluation was possible. The symmetrical, paretic, and non-paretic groups included 14, 11, and 21 patients, respectively. The non-paretic group had lesser mean % body weight in maximum lateral weight-bearing to the paretic direction (79% versus 55%, p <.001), motor function of the hip lower limb (64 versus 58, p =.003) per the Stroke Impairment Assessment Set, Trunk Impairment Scale (18 versus 15, p =.020), and Berg Balance Scale (42 versus 32, p =.047) than the paretic group with more lesions in the insula (55% versus 0%, p <.001) and parietal cortex (36% versus 0%, p =.009) than the non-paretic group. The non-paretic group had low dynamic balance, severe motor paresis, and trunk dysfunction. The paretic group had lesions in the insula or parietal cortex. [ABSTRACT FROM AUTHOR]

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Background: Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR = 1–hazard ratio or VERR = 1–risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure. Methods: Power of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. Results: In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power. Conclusions: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis. Trial registrations: NCT00866619, NCT02663700, NCT02143934. [ABSTRACT FROM AUTHOR]

The R1 addendum to ICH E9 (E9-R1) provides guidance on the definition of estimands in clinical drug development. While the E9-R1 has seen uptake in randomized late-stage clinical trials, its implementation in early clinical development remains sporadic potentially jeopardizing clarity, consistency, and coherency in early phase. In this article, we call for a more systematic use of the estimand thinking in phase 1 dose escalation oncology trials. In these adaptive trials, the primary clinical objective is usually to characterize the dose-toxicity relationship and to ascertain the maximum tolerated dose (MTD). One estimand of interest is the probability of dose-limiting toxicity (DLT). Intercurrent events (ICE) interfering with the existence or interpretation of DLT outcomes are common in these studies. Three types of ICEs are reviewed in detail: treatment discontinuation for reasons not related to toxicity (e.g. disease progression), treatment discontinuation due to adverse events which would not qualify as DLT, and dose modifications or omissions. The concept of replacement of non-DLT evaluable participants, often used so far, is not an acceptable general solution to ICEs in dose escalation studies. To address clinically relevant questions, adequate ICE handling strategies and estimators aligned to these settings should be used. [ABSTRACT FROM AUTHOR]

Receptor occupancy in targeted tissues measures the proportion of receptors occupied by a drug at equilibrium and is sometimes used as a surrogate of drug efficacy to inform dose selection in clinical trials. We propose to incorporate data on receptor occupancy from a phase I study in healthy volunteers into a phase II proof‐of‐concept study in patients, with the objective of using all the available evidence to make informed decisions. A minimal physiologically based pharmacokinetic modeling is used to model receptor occupancy in healthy volunteers and to predict it in the patients of a phase II proof‐of‐concept study, taking into account the variability of the population parameters and the specific differences arising from the pathological condition compared to healthy volunteers. Then, given an estimated relationship between receptor occupancy and the clinical endpoint, an informative prior distribution is derived for the clinical endpoint in both the treatment and control arms of the phase II study. These distributions are incorporated into a Bayesian dynamic borrowing design to supplement concurrent phase II trial data. A simulation study in immuno‐inflammation demonstrates that the proposed design increases the power of the study while maintaining a type I error at acceptable levels for realistic values of the clinical endpoint. [ABSTRACT FROM AUTHOR]

Abstract Background Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback. Results The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required.Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7–H4.In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided.

Objective: This study aims to investigate the topical steroid regimen after small incision lenticule extraction (SMILE) for its effect on very early restoration of visual quality. Methods: A total of 180 patients (360 eyes) who underwent SMILE were enrolled. These patients were randomly assigned to three groups, with 60 patients in each group. The only difference among these three groups was the administration of 0.1% fluorometholone (FML) eye drops within two hours after SMILE: no FML in group A, 0.1% FML once every hour in group B and 0.1% FML once every half hour in group C. The corrected distance visual acuity (CDVA), objective scattering index (OSI), modulation transfer function (MTF) cut-off, Strehl ratio (SR) and incidence of subjective symptoms were evaluated preoperatively, at 2, 4 and 24 h and one week after SMILE. Results: The CDVA, MTF cut-off and SR values were significantly higher in group C, when compared to the other two groups, at 2 and 4 h after SMILE (p < 0.05). Furthermore, the OSI and incidence of subjective symptoms were significantly lower in group C, when compared to the other two groups, at 2 and 4 h after SMILE (p < 0.05). However, no significant differences in CDVA, MTF cut-off, SR, OSI and the incidence of subjective symptoms were detected among the three groups at 24 h and one week after SMILE (p > 0.05). Conclusion: The administration of 0.1% FML eye drops every half hour within two hours after SMILE accelerates the restoration of visual and optical quality, and reduces the incidence of subjective symptoms during the very early phase after surgery. [ABSTRACT FROM AUTHOR]

The COVID-19 outbreak involved a spread of prediction efforts, especially in the early pandemic phase. A better understanding of the epidemiological implications of the different models seems crucial for tailoring prevention policies. This study aims to explore the concordance and discrepancies in outbreak prediction produced by models implemented and used in the first wave of the epidemic. To evaluate the performance of the model, an analysis was carried out on Italian pandemic data from February 24, 2020. The epidemic models were fitted to data collected at 20, 30, 40, 50, 60, 70, 80, 90, and 98 days (the entire time series). At each time step, we made predictions until May 31, 2020. The Mean Absolute Error (MAE) and the Mean Absolute Percentage Error (MAPE) were calculated. The GAM model is the most suitable parameterization for predicting the number of new cases; exponential or Poisson models help predict the cumulative number of cases. When the goal is to predict the epidemic peak, GAM, ARIMA, or Bayesian models are preferable. However, the prediction of the pandemic peak could be made carefully during the early stages of the epidemic because the forecast is affected by high uncertainty and may very likely produce the wrong results. [ABSTRACT FROM AUTHOR]

Background: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. Results: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/). [ABSTRACT FROM AUTHOR]

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required. Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7–H4. In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided. • Antibody-drug conjugates (ADCs) show improved efficacy and therapeutic index (80 /85). • To exploit ADCs, identifying optimal target antigens (Ags) is fundamental (77 /85). • In BC, ADC targeting HER2 (i.e., T-DM, T-DXd) and TROP-2 (i.e., SG) are approved (84 /85). • HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7–H4 are promising target candidates. (85 /85). • For such promising Ags, biology, preclinical and early clinical data are provided (85 /85). [ABSTRACT FROM AUTHOR]

Abstract Background Our randomized controlled clinical trial will explore the potential of bazedoxifene plus conjugated estrogen to modulate breast tissue-based risk biomarkers as a surrogate for breast cancer risk reduction. This paper investigates the statistical design features of the trial and the rationale for the final choice of its design. Group sequential designs are a popular design approach to allow a trial to stop early for success or futility, potentially saving time and money over a fixed trial design. While Bayesian adaptive designs enjoy the same properties as group sequential designs, they have the added benefit of using prior information as well as inferential interpretation conditional on the data. Whether a frequentist or Bayesian trial, most adaptive designs have interim analyses that allow for early stopping, typically utilizing only the primary endpoint. A drawback to this approach is that the study may not have enough data for adequate comparisons of a single, key secondary endpoint. This can happen, for example, if the secondary endpoint has a smaller effect than the primary endpoint. Methods In this paper, we investigate a trial design called two-endpoint adaptive, which stops early only if a criterion is met for primary and secondary endpoints. The approach focuses the final analysis on the primary endpoint but ensures adequate data for the secondary analysis. Our study has two arms with a primary (change in mammographic fibroglandular volume) and secondary endpoint (change in mammary tissue Ki-67). Results We present operating characteristics including power, trial duration, and type I error rate and discuss the value and risks of modeling Bayesian group sequential designs with primary and secondary endpoints, comparing against alternative designs. The results indicate that the two-endpoint adaptive design has better operating characteristics than competing designs if one is concerned about having adequate information for a key secondary endpoint. Discussion Our approach balances trial speed and the need for information on the single, key secondary endpoint.

Abstract Background Fibroproliferative repair starts early in the inflammatory phase of acute respiratory distress syndrome (ARDS) and indicates a poor prognosis. Lumican, a small leucine-rich proteoglycan, is implicated in homeostasis and fibrogenesis, but its role in ARDS is unclear. Methods Bronchoalveolar lavage fluid (BALF) samples were obtained from ARDS patients (n = 55) enrolled within 24 h of diagnosis and mechanically ventilated (n = 20) and spontaneously breathing (n = 29) control subjects. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse models were intratracheally administered an adeno-associated virus (AAV) vector expressing lumican shRNA. Primary human lung fibroblasts (HLF) and small airway epithelial cells (SAECs) were cultured with tumour necrosis factor (TNF)-α or lumican. Luminex/ELISA, histochemistry/immunohistochemistry, immunofluorescence microscopy, quantitative real-time PCR, and western blotting were performed. Results Lumican levels were significantly higher in the BALF of ARDS patients than in that of ventilated or spontaneously breathing controls (both p

Summary: Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33–76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered) [ABSTRACT FROM AUTHOR]

Background: Our randomized controlled clinical trial will explore the potential of bazedoxifene plus conjugated estrogen to modulate breast tissue-based risk biomarkers as a surrogate for breast cancer risk reduction. This paper investigates the statistical design features of the trial and the rationale for the final choice of its design. Group sequential designs are a popular design approach to allow a trial to stop early for success or futility, potentially saving time and money over a fixed trial design. While Bayesian adaptive designs enjoy the same properties as group sequential designs, they have the added benefit of using prior information as well as inferential interpretation conditional on the data. Whether a frequentist or Bayesian trial, most adaptive designs have interim analyses that allow for early stopping, typically utilizing only the primary endpoint. A drawback to this approach is that the study may not have enough data for adequate comparisons of a single, key secondary endpoint. This can happen, for example, if the secondary endpoint has a smaller effect than the primary endpoint.Methods: In this paper, we investigate a trial design called two-endpoint adaptive, which stops early only if a criterion is met for primary and secondary endpoints. The approach focuses the final analysis on the primary endpoint but ensures adequate data for the secondary analysis. Our study has two arms with a primary (change in mammographic fibroglandular volume) and secondary endpoint (change in mammary tissue Ki-67).Results: We present operating characteristics including power, trial duration, and type I error rate and discuss the value and risks of modeling Bayesian group sequential designs with primary and secondary endpoints, comparing against alternative designs. The results indicate that the two-endpoint adaptive design has better operating characteristics than competing designs if one is concerned about having adequate information for a key secondary endpoint.Discussion: Our approach balances trial speed and the need for information on the single, key secondary endpoint. [ABSTRACT FROM AUTHOR]

Background: Scintigraphy is used for overall assessment of gastric emptying. Adherence to an international consensus protocol is recommended to ensure quality; however, this has not been widely adopted because preparation of the "egg‐beater" meal is inconvenient in clinical practice. In this report, we audit the tolerability and the results of gastric emptying scintigraphy with the 400 ml Tc‐99 m‐labeled liquid nutrient Nottingham Test Meal (NTM). Methods: Results from 330 consecutive adult, non‐diabetic patients with dyspeptic symptoms referred for gastric scintigraphy were analyzed. Gastric half‐emptying time (T50) and validated measurements of early‐ and late‐phase gastric emptying were acquired. Postprandial sensations of fullness, bloating, heartburn, nausea, and epigastric pain were recorded using 100 mm visual analog scales (VAS) before and 0, 30, and 90 min after NTM ingestion. Results were compared with those previously obtained in healthy subjects. Key Results: Almost all (98%) of the patients were able to consume the 400 ml NTM. Considering early‐ and late‐phase gastric emptying, frequently observed patterns included normal early‐ with slow late‐phase (25%) and fast early‐ with slow late‐phase emptying (27%). Abnormal score of fullness and/ or dyspeptic symptoms were observed in 88% of dyspeptic patients. Abnormal fullness at T0 (after completed drink ingestion) was associated with slow late phase of gastric emptying, especially in women. Conclusions: Gastric scintigraphy with the NTM is simple to perform and well tolerated. Whether the identified abnormal gastric emptying patterns could predict different treatment outcome in patients with functional dyspepsia is the subject of ongoing prospective studies. [ABSTRACT FROM AUTHOR]

Abstract Background For decades there has been a continuous increase in the number of people receiving welfare benefits for being outside the work force due to mental illness. There is sufficient evidence for the efficacy of Individual Placement and Support (IPS) for gaining and maintaining competitive employment. Yet, IPS is still not implemented as routine practice in public community mental health services. Knowledge about implementation challenges as experienced by the practitioners is limited. This study seeks to explore the experiences of the front-line workers, known as employment specialists, in the early implementation phase. Methods Qualitative data were collected through field notes and five focus group interviews. The study participants were 45 IPS employment specialists located at 14 different sites in Northern Norway. Transcripts and field notes were analysed by thematic analyses. Results While employment specialists are key to the implementation process, implementing IPS requires more than creating and filling the role of the employment specialist. It requires adjustments in multiple organisations. The new employment specialist then is a pioneer of service development. Some employment specialists found this a difficult challenge, and one that did not correspond to their expectations going into this role. Others appreciated the pioneering role. IPS implementation also challenged the delegation of roles and responsibilities between sectors, and related legal frameworks related to confidentiality and access. The facilitating role of human relationships emphasised the importance of social support which is an important factor in a healthy work environment. Rural areas with long distances and close- knit societies may cause challenges for implementation. Conclusion The study provides increased understanding on what happens in the early implementation phase of IPS from the employment specialists’ perspective. Results from this study can contribute to increased focus on job satisfaction, turnover and recruitment of employment specialists, factors which have previously been shown to influence the success of IPS. The greatest challenge for making “IPS efficacy in trials” become “IPS effectiveness in the real world” is implementation, and this study has highlighted some of the implementation issues.

Background: International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking.Methods: A National Cancer Institute-sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma.Results: Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established.Conclusions: The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma. [ABSTRACT FROM AUTHOR]

Background: Fibroproliferative repair starts early in the inflammatory phase of acute respiratory distress syndrome (ARDS) and indicates a poor prognosis. Lumican, a small leucine-rich proteoglycan, is implicated in homeostasis and fibrogenesis, but its role in ARDS is unclear.Methods: Bronchoalveolar lavage fluid (BALF) samples were obtained from ARDS patients (n = 55) enrolled within 24 h of diagnosis and mechanically ventilated (n = 20) and spontaneously breathing (n = 29) control subjects. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse models were intratracheally administered an adeno-associated virus (AAV) vector expressing lumican shRNA. Primary human lung fibroblasts (HLF) and small airway epithelial cells (SAECs) were cultured with tumour necrosis factor (TNF)-α or lumican. Luminex/ELISA, histochemistry/immunohistochemistry, immunofluorescence microscopy, quantitative real-time PCR, and western blotting were performed.Results: Lumican levels were significantly higher in the BALF of ARDS patients than in that of ventilated or spontaneously breathing controls (both p < 0.0001); they were correlated with the PaO2/FiO2 ratio and levels of proinflammatory cytokines (interleukin-6, interleukin-8, and TNF-α) and profibrotic factors (fibronectin, alpha-1 type I collagen [COL1A1], and alpha-1 type III collagen [COL3A1]). Lumican expression was enhanced in the alveolar walls and airway epithelium in the ALI mouse model. Murine lumican levels were also linked to proinflammatory and profibrotic cytokine levels in the BALF. In vitro, TNF-α induced the synthesis and secretion of lumican in HLF. In turn, lumican increased the expression of alpha-smooth muscle actin (α-SMA), COL1A1, and COL3A1 in HLF, upregulated α-SMA and COL3A1, downregulated E-cadherin, and caused spindle-shaped morphological changes in SAECs. Moreover, increased ERK phosphorylation and Slug were noted in both HLF and SAECs treated with lumican. In vivo, AAV-mediated knockdown of lumican inhibited the pulmonary production of fibronectin and COL3A1 and alleviated lung fibrotic lesions in LPS-challenged mice.Conclusions: Pulmonary lumican levels were increased early in human and experimental ARDS and linked to disease severity and inflammatory fibrotic processes. Lumican triggers the transdifferentiation of lung fibroblasts into myofibroblasts and epithelial-mesenchymal transition in SAECs, possibly via the ERK/Slug pathway. Knockdown of pulmonary lumican attenuated extracellular matrix deposition in ALI mice. Overall, lumican promotes fibrotic responses in the early phase of ARDS, suggesting its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines., Protocol: Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings., Discussion: This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder., Competing Interests: Competing interests: In the last three years SL has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Neurotorium, Otsuka, NovoNordisk, Recordati, Rovi, Teva; JP from uniQure. The other authors declare that they have no competing interests. MH is a part-time employee of Get.On Institut für Gesundheitstrainings GmbH/HelloBetter., (Copyright: © 2024 Feber L et al.)

Abstract Background Mental burden due to the SARS-CoV-2 pandemic has been widely reported for the general public and specific risk groups like healthcare workers and different patient populations. We aimed to assess its impact on mental health during the early phase by comparing pandemic with prepandemic data and to identify potential risk and protective factors. Methods For this systematic review and meta-analyses, we systematically searched PubMed, PsycINFO, and Web of Science from January 1, 2019 to May 29, 2020, and screened reference lists of included studies. In addition, we searched PubMed and PsycINFO for prepandemic comparative data. Survey studies assessing mental burden by the SARS-CoV-2 pandemic in the general population, healthcare workers, or any patients (eg, COVID-19 patients), with a broad range of eligible mental health outcomes, and matching studies evaluating prepandemic comparative data in the same population (if available) were included. We used multilevel meta-analyses for main, subgroup, and sensitivity analyses, focusing on (perceived) stress, symptoms of anxiety and depression, and sleep-related symptoms as primary outcomes. Results Of 2429 records retrieved, 104 were included in the review (n = 208,261 participants), 43 in the meta-analysis (n = 71,613 participants). While symptoms of anxiety (standardized mean difference [SMD] 0.40; 95% CI 0.15–0.65) and depression (SMD 0.67; 95% CI 0.07–1.27) were increased in the general population during the early phase of the pandemic compared with prepandemic conditions, mental burden was not increased in patients as well as healthcare workers, irrespective of COVID-19 patient contact. Specific outcome measures (eg, Patient Health Questionnaire) and older comparative data (published ≥5 years ago) were associated with increased mental burden. Across the three population groups, existing mental disorders, female sex, and concerns about getting infected were repeatedly reported as risk factors, while older age, a good economic situation, and education were protective. Conclusions This meta-analysis paints a more differentiated picture of the mental health consequences in pandemic situations than previous reviews. High-quality, representative surveys, high granular longitudinal studies, and more research on protective factors are required to better understand the psychological impacts of the SARS-CoV-2 pandemic and to help design effective preventive measures and interventions that are tailored to the needs of specific population groups.

The ability to accurately predict the early progression of hemorrhagic fever with renal syndrome (HFRS) is crucial for reducing morbidity and mortality rates in severely affected patients. However, the utility of biomarkers for predicting clinical outcomes remains elusive in HFRS. The aims of the current study were to analyze the serum levels of immune function-related proteins and identify novel biomarkers that may help ascertain clinical outcomes of HFRS. Enzyme-linked immunosorbent assay, Luminex, and bioanalyzer assays were used to quantitatively detect 15 biomarkers in 49 serum samples of 26 patients with HFRS. High hemoglobin (HGB) and low urine output (UO) levels were identified as potential biomarkers associated with the acute HFRS. The serum soluble urokinase plasminogen activator receptor (suPAR) and C-X-C motif chemokine ligand 10 (CXCL10) values increased in the early phase of diseases. Elevated suPAR, interleukin-10 (IL-10), CXCL10, and decreased transforming growth factor-beta 3 (TGF-β3) were representative predictors of the disease severity. Upregulation of the HGB showed a significant correlation with high levels of suPAR and CXCL10. Reduced UO positively correlated with increased suPAR, CXCL10, and TGF-β2, and decreased vascular endothelial growth factor and TGF-β3. The changing HGB and UO criteria, high suPAR, IL-10, CXCL10, and low TGF-β3 of HFRS raise significant awareness for physicians regarding prospective biomarkers for monitoring early warning signs of HFRS. This study provides critical insights into the clinical and immunological biomarkers for disease severity and progression in patients with HFRS to identify early predictions of fatal outcomes. [ABSTRACT FROM AUTHOR]

Pemigatinib is a potent inhibitor of the fibroblast growth factor receptor (FGFR) family of receptors that is approved for the treatment of cholangiocarcinoma with FGFR2 fusion or other rearrangements. Data from a first‐in‐human clinical study were used to assess the potential for pemigatinib to produce clinically significant effects on heart rate (HR) and cardiac repolarization (QTc). A central tendency analysis for electrocardiogram (ECG) outliers and a plasma concentration‐QTc analysis were conducted to assess cardiac safety in the first‐in‐human pemigatinib study (FIGHT‐101; NCT02393248). The study included 113 participants who received at least one dose of pemigatinib as monotherapy and had at least one pair of plasma pharmacokinetic (PK) and ECG data points collected. Timed 12‐lead ECGs were performed within 15 min of PK blood draws. The ECG parameters for each dose group in the study varied within expectations for patients with advanced malignancies. Categorical analysis of QT interval corrected for HR by Fridericia's method did not reveal dose dependence in the incidence of outliers, and the results of the central tendency and concentration‐QTc analyses did not suggest a dose‐ or concentration‐dependent drug effect. Least squares mean change from baseline in HR was small and did not indicate a clinically relevant effect on HR, and no effect was observed on cardiac conduction as assessed by PR and QRS intervals. In conclusion, pemigatinib does not exhibit any clinically significant prolongation of QTc or dose‐dependent changes in HR. Clinical trial registration: ClinicalTrials.gov NCT02393248. [ABSTRACT FROM AUTHOR]

Summary: Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next‐generation sequencing studies demonstrated important insights into therapy resistance. [ABSTRACT FROM AUTHOR]

Pemigatinib is a potent inhibitor of the fibroblast growth factor receptor (FGFR) family of receptors that is approved for the treatment of cholangiocarcinoma with FGFR2 fusion or other rearrangements. Data from a first-in-human clinical study were used to assess the potential for pemigatinib to produce clinically significant effects on heart rate (HR) and cardiac repolarization (QTc). A central tendency analysis for electrocardiogram (ECG) outliers and a plasma concentration-QTc analysis were conducted to assess cardiac safety in the first-in-human pemigatinib study (FIGHT-101; NCT02393248). The study included 113 participants who received at least one dose of pemigatinib as monotherapy and had at least one pair of plasma pharmacokinetic (PK) and ECG data points collected. Timed 12-lead ECGs were performed within 15 min of PK blood draws. The ECG parameters for each dose group in the study varied within expectations for patients with advanced malignancies. Categorical analysis of QT interval corrected for HR by Fridericia's method did not reveal dose dependence in the incidence of outliers, and the results of the central tendency and concentration-QTc analyses did not suggest a dose- or concentration-dependent drug effect. Least squares mean change from baseline in HR was small and did not indicate a clinically relevant effect on HR, and no effect was observed on cardiac conduction as assessed by PR and QRS intervals. In conclusion, pemigatinib does not exhibit any clinically significant prolongation of QTc or dose-dependent changes in HR. Clinical trial registration: ClinicalTrials.gov NCT02393248 [ABSTRACT FROM AUTHOR]

Background: For decades there has been a continuous increase in the number of people receiving welfare benefits for being outside the work force due to mental illness. There is sufficient evidence for the efficacy of Individual Placement and Support (IPS) for gaining and maintaining competitive employment. Yet, IPS is still not implemented as routine practice in public community mental health services. Knowledge about implementation challenges as experienced by the practitioners is limited. This study seeks to explore the experiences of the front-line workers, known as employment specialists, in the early implementation phase. Methods: Qualitative data were collected through field notes and five focus group interviews. The study participants were 45 IPS employment specialists located at 14 different sites in Northern Norway. Transcripts and field notes were analysed by thematic analyses. Results: While employment specialists are key to the implementation process, implementing IPS requires more than creating and filling the role of the employment specialist. It requires adjustments in multiple organisations. The new employment specialist then is a pioneer of service development. Some employment specialists found this a difficult challenge, and one that did not correspond to their expectations going into this role. Others appreciated the pioneering role. IPS implementation also challenged the delegation of roles and responsibilities between sectors, and related legal frameworks related to confidentiality and access. The facilitating role of human relationships emphasised the importance of social support which is an important factor in a healthy work environment. Rural areas with long distances and close- knit societies may cause challenges for implementation. Conclusion: The study provides increased understanding on what happens in the early implementation phase of IPS from the employment specialists' perspective. Results from this study can contribute to increased focus on job satisfaction, turnover and recruitment of employment specialists, factors which have previously been shown to influence the success of IPS. The greatest challenge for making "IPS efficacy in trials" become "IPS effectiveness in the real world" is implementation, and this study has highlighted some of the implementation issues. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority., Materials and Methods: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments., Results: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082)., Conclusions: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction older patients represent the majority of cancer patients but are under-represented in trials, particularly early phase clinical trials (EPCTs). Material and Methods observational retrospective study of patients referred for EPCTs (January–December 2018) at a specialist cancer centre in the UK. The primary aim was to analyse the successful enrolment into EPCTs according to age (<65/65+). The secondary aims were to identify enrolment obstacles and the outcomes of enrolled patients. Patient data were analysed at: referral; in-clinic assessment and after successful enrolment. Among patients assessed in clinic, a sample was defined by randomly matching the older cohort with the younger cohort (1:1) by tumour type. Results 555 patients were referred for EPCTs with a median age of 60 years, of whom 471 were assessed in new patient clinics (38% were 65+). From those assessed, a randomly tumour-matched sample of 318 patients (159 per age cohort) was selected. Older patients had a significantly higher comorbidity score measured by ACE-27 (P  < 0.0001), lived closer to the hospital (P  = 0.045) and were referred at a later point in their cancer management (P  = 0.002). There was no difference in suitability for EPCTs according to age with overall 84% deemed suitable. For patients successfully enrolled into EPCTs, there was no difference between age cohorts (20.1 vs. 22.6% for younger and older, respectively; P =  0.675) and no significant differences in their safety and efficacy outcomes. Discussion older age did not affect the enrolment into EPCTs. However, the selected minority referred for EPCTs suggests a pre-selection upstream by primary oncologists. [ABSTRACT FROM AUTHOR]

Adaptive designs are gaining popularity in early phase clinical trials because they enable investigators to change the course of a study in response to accumulating data. We propose a novel design to simultaneously monitor several endpoints. These include efficacy, futility, toxicity and other outcomes in early phase, single-arm studies. We construct a recursive relationship to compute the exact probabilities of stopping for any combination of endpoints without the need for simulation, given pre-specified decision rules. The proposed design is flexible in the number and timing of interim analyses. A R Shiny app with user-friendly web interface has been created to facilitate the implementation of the proposed design. [ABSTRACT FROM AUTHOR]

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To determine the characteristics of the early phase of psoriatic arthritis (PsA), we conducted a subanalysis of a retrospective survey of Japanese patients. In this study, we enrolled patients with early onset within either 2 years or 1 year from onset among the 1282 patients with PsA that had previously been reported. Among the total reported PsA patients, 304 (23.7%) were diagnosed with less than 2 years of onset of joint manifestation. The male : female ratio was 1.9:1, mean age at onset of cutaneous psoriasis 40.2 years, and that of joint manifestation 50.3 years. Age of less than 20 years at cutaneous psoriasis onset was observed in 22 cases, while that at joint manifestation was observed in two cases. Plaque‐type psoriasis accounted for 90.1%, followed by psoriasis erythroderma (3.9%), pustular psoriasis (3.9%), and nail psoriasis (1.3%). Polyarthritis was the most common joint manifestation (32.9%), followed by distal interphalangeal (DIP) type (29.6%), oligoarthritis type (27.3%), and ankylosing spondylitis type (4.9%). Enthesitis was observed in 27.3% and dactylitis in 61.8%. Biologics were used in 168 cases (55.3%). By contrast, 199 patients (15.5%) were diagnosed within 1 year of onset of joint manifestation, among whom polyarthritis was the most common (30.7%). Biologics were used in 50.8%. In conclusion, the present study showed that the frequency of early PsA within 2 years of onset accounted for 23.7%, and those within 1 year of onset was 15.5% among the Japanese patients with PsA. Polyarthritis was the most common in early PsA patients. [ABSTRACT FROM AUTHOR]

Objective: The burden of suicidal behavior is anticipated to increase as a sequela of the COVID-19 pandemic. However, there is limited evidence on suicidal behavior among healthcare workers, an at-risk population. Our study aimed to investigate suicidal ideation in terms of the rate and associated factors in a sample of Malaysian healthcare workers during the early-phase of the COVID-19 pandemic.Methods: A subpopulation analysis (N = 171) was conducted within a larger, nation-wide cross-sectional study of Malaysian healthcare worker psychological distress from March 18–21, 2020. Current suicidal ideation was measured with item 9 of the Patient Health Questionnaire-9 (PHQ-9). The following independent variables were assessed: socio-demographic profile, occupation and service-related factors, health-anxiety (Health Anxiety Inventory, HAI), lifetime anxiety disorder and severity of depression (PHQ-9).Results: The proportion of healthcare workers with current suicidal ideation (19/171) and clinical depression (17/171) were 11.1 and 9.9%, respectively. Multivariable analysis showed that clinical depression was the most significant factor associated with current suicidal ideation (p < 0.001, OR = 55.983, 95% CI = 9.015–347.671) followed by mild (subthreshold) depression (p = 0.001, OR = 115.984, 95% CI = 2.977–85.804). Service duration of more than 10 years was associated with significantly less suicidal ideation (p = 0.049, OR = 0.072, 95% CI = 0.005–0.993).Conclusions: Depression (subthreshold and especially within the clinical range) and early-career status (

Objective: The burden of suicidal behavior is anticipated to increase as a sequela of the COVID-19 pandemic. However, there is limited evidence on suicidal behavior among healthcare workers, an at-risk population. Our study aimed to investigate suicidal ideation in terms of the rate and associated factors in a sample of Malaysian healthcare workers during the early-phase of the COVID-19 pandemic. Methods: A subpopulation analysis (N = 171) was conducted within a larger, nation-wide cross-sectional study of Malaysian healthcare worker psychological distress from March 18–21, 2020. Current suicidal ideation was measured with item 9 of the Patient Health Questionnaire-9 (PHQ-9). The following independent variables were assessed: socio-demographic profile, occupation and service-related factors, health-anxiety (Health Anxiety Inventory, HAI), lifetime anxiety disorder and severity of depression (PHQ-9). Results: The proportion of healthcare workers with current suicidal ideation (19/171) and clinical depression (17/171) were 11.1 and 9.9%, respectively. Multivariable analysis showed that clinical depression was the most significant factor associated with current suicidal ideation (p < 0.001, OR = 55.983, 95% CI = 9.015–347.671) followed by mild (subthreshold) depression (p = 0.001, OR = 115.984, 95% CI = 2.977–85.804). Service duration of more than 10 years was associated with significantly less suicidal ideation (p = 0.049, OR = 0.072, 95% CI = 0.005–0.993). Conclusions: Depression (subthreshold and especially within the clinical range) and early-career status (<10 years in service) may be target areas of early intervention for reduction of suicidal ideation amongst healthcare workers who have served during the COVID-19 pandemic. Further research is warranted to elucidate specific occupational stressors related to COVID-19 work conditions to tailor appropriate suicide preventive strategies in this population. [ABSTRACT FROM AUTHOR]

Background: Mental burden due to the SARS-CoV-2 pandemic has been widely reported for the general public and specific risk groups like healthcare workers and different patient populations. We aimed to assess its impact on mental health during the early phase by comparing pandemic with prepandemic data and to identify potential risk and protective factors.Methods: For this systematic review and meta-analyses, we systematically searched PubMed, PsycINFO, and Web of Science from January 1, 2019 to May 29, 2020, and screened reference lists of included studies. In addition, we searched PubMed and PsycINFO for prepandemic comparative data. Survey studies assessing mental burden by the SARS-CoV-2 pandemic in the general population, healthcare workers, or any patients (eg, COVID-19 patients), with a broad range of eligible mental health outcomes, and matching studies evaluating prepandemic comparative data in the same population (if available) were included. We used multilevel meta-analyses for main, subgroup, and sensitivity analyses, focusing on (perceived) stress, symptoms of anxiety and depression, and sleep-related symptoms as primary outcomes.Results: Of 2429 records retrieved, 104 were included in the review (n = 208,261 participants), 43 in the meta-analysis (n = 71,613 participants). While symptoms of anxiety (standardized mean difference [SMD] 0.40; 95% CI 0.15-0.65) and depression (SMD 0.67; 95% CI 0.07-1.27) were increased in the general population during the early phase of the pandemic compared with prepandemic conditions, mental burden was not increased in patients as well as healthcare workers, irrespective of COVID-19 patient contact. Specific outcome measures (eg, Patient Health Questionnaire) and older comparative data (published ≥5 years ago) were associated with increased mental burden. Across the three population groups, existing mental disorders, female sex, and concerns about getting infected were repeatedly reported as risk factors, while older age, a good economic situation, and education were protective.Conclusions: This meta-analysis paints a more differentiated picture of the mental health consequences in pandemic situations than previous reviews. High-quality, representative surveys, high granular longitudinal studies, and more research on protective factors are required to better understand the psychological impacts of the SARS-CoV-2 pandemic and to help design effective preventive measures and interventions that are tailored to the needs of specific population groups. [ABSTRACT FROM AUTHOR]

The Australian clinical trials sector has grown steadily over the past decade, particularly with respect to early phase trials where Australia's research capacity, capability and quality of research is revered. With an increase in the number of internationally sponsored clinical research projects being conducted in Australia, particularly in the early phase setting, there has been a corresponding growth in the number of clinical research sites conducting early phase clinical trials. Australian researchers are guided by a multitude of research codes, guidance and statements which govern the conduct of clinical trials. Although international guidance regarding the conduct of early phase clinical trials exists, there is currently no single source outlining best practice recommendations for the conduct of early phase clinical trials in Australia.In recognition of this Clinical Trials: Impact & Quality (CT:IQ), a collaborative of sector stakeholders, convened a project team with comprehensive knowledge of the Australian clinical trials sector and particularly early phase research, to evaluate and collate broadly applicable and implementable guidance for the conduct of early phase clinical trials. Although the initial intent was to create guidance specific to early phase, we recognize the project outcomes are more broadly implementable irrespective of the research phase and are intended to support all clinical research sites to conduct high-quality clinical trials in Australia.

The ability to accurately predict the early progression of hemorrhagic fever with renal syndrome (HFRS) is crucial for reducing morbidity and mortality rates in severely affected patients. However, the utility of biomarkers for predicting clinical outcomes remains elusive in HFRS. The aims of the current study were to analyze the serum levels of immune function-related proteins and identify novel biomarkers that may help ascertain clinical outcomes of HFRS. Enzyme-linked immunosorbent assay, Luminex, and bioanalyzer assays were used to quantitatively detect 15 biomarkers in 49 serum samples of 26 patients with HFRS. High hemoglobin (HGB) and low urine output (UO) levels were identified as potential biomarkers associated with the acute HFRS. The serum soluble urokinase plasminogen activator receptor (suPAR) and C-X-C motif chemokine ligand 10 (CXCL10) values increased in the early phase of diseases. Elevated suPAR, interleukin-10 (IL-10), CXCL10, and decreased transforming growth factor-beta 3 (TGF-β3) were representative predictors of the disease severity. Upregulation of the HGB showed a significant correlation with high levels of suPAR and CXCL10. Reduced UO positively correlated with increased suPAR, CXCL10, and TGF-β2, and decreased vascular endothelial growth factor and TGF-β3. The changing HGB and UO criteria, high suPAR, IL-10, CXCL10, and low TGF-β3 of HFRS raise significant awareness for physicians regarding prospective biomarkers for monitoring early warning signs of HFRS. This study provides critical insights into the clinical and immunological biomarkers for disease severity and progression in patients with HFRS to identify early predictions of fatal outcomes.

During drug evaluation trials, information from clinical trials previously conducted on another population, indications or schedules may be available. In these cases, it might be desirable to share information by efficiently using the available resources. In this work, we developed an adaptive power prior with a commensurability parameter for using historical or external information. It allows, at each stage, full borrowing when the data are not in conflict, no borrowing when the data are in conflict or "tuned" borrowing when the data are in between. We propose to apply our adaptive power prior method to bridging studies between Caucasians and Asians, and we focus on the sequential adaptive allocation design, although other design settings can be used. We weight the prior information in two steps: the effective sample size approach is used to set the maximum desirable amount of information to be shared from historical data at each step of the trial; then, in a sort of Empirical Bayes approach, a commensurability parameter is chosen using a measure of distribution distance. This approach avoids elicitation and computational issues regarding the usual Empirical Bayes approach. We propose several versions of our method, and we conducted an extensive simulation study evaluating the robustness and sensitivity to prior choices. [ABSTRACT FROM AUTHOR]

In the early phase of a development process, several concept variations are developed to overcome technical problems. Despite this, only one concept makes the final selection. In this study, a theoretical process model providing an early-phase, structured proceeding guideline was adapted for use in a development process in order to simplify concept selection. This adapted process model enables a more time-efficient and transparent early-phase development process. Furthermore, it presents an opportunity for the relationship between design engineers and simulation engineers to be improved. The adapted process model was validated by using a combination of simulated models and expert interviews. [ABSTRACT FROM AUTHOR]

Background: A subset of Hashimoto's thyroiditis (HT), reported as immunoglobulin G4 (IgG4) thyroiditis, is characterized by IgG4+ plasma cell-rich inflammation and marked sclerotic changes, which suggests a close relationship with immunoglobulin G4-related disease (IgG4-RD). However, to date, there is no consensus regarding the cutoff values used to define a significant IgG4+ plasma cell count in thyroid inflammation. We, therefore, sought to validate both the cutoff value of the comprehensive diagnostic criteria (CVC) and the cutoff value of thyroid-specific diagnostic criteria (CVT) for diagnosing IgG4 thyroiditis. Methods: One hundred twenty cases of HT were retrospectively reviewed. According to the CVC (IgG4+ plasma cells >10/HPF (high-power field) and IgG4+/IgG+ plasma cell ratio >40%) and the CVT (IgG4+ plasma cells >20/HPF and IgG4+/IgG+ plasma cell ratio >30%), cases were subclassified as IgG4 thyroiditis or non-IgG4 thyroiditis. Clinical, serological, sonographic, and histopathological characteristics of the two subsets, and the cases diagnosed as IgG4 thyroiditis using different thresholds were compared. Results: Both the CVC and CVT identified the same set of distinct clinical, laboratory, and sonographic features of the cases diagnosed as IgG4 thyroiditis. All 120 cases of HT were able to be divided into four distinct groups. Group A included the 25 cases who were assigned as IgG4 thyroiditis by both the CVC and CVT, whereas Group D included the 85 cases who did not meet either of the cutoff values. Group B and Group C comprised the borderline cases who only met one of the two thresholds. Based on histological evaluation, the cases in Group B who met the CVT demonstrated similar histological features of IgG4 thyroiditis. Conclusions: Although both of the cutoff values can efficiently distinguish IgG4 thyroiditis from its non-IgG4 counterpart, the thyroid-specific cutoff value (CVT, IgG4+ plasma cells >20/HPF, and IgG4+/IgG+ plasma cell ratio >30%) can better identify borderline cases of HT with more fibrotic changes, which may represent an early phase lesion of IgG4 thyroiditis. We propose a new series of clinical and pathological diagnostic clues for both endocrinologists and pathologists to improve the early recognition of IgG4 thyroiditis. [ABSTRACT FROM AUTHOR]

The primary objective of the assessment of novel proteins is to evaluate whether they are safe to consume, including potential allergenicity. As part of a suite of assessments, the in vitro digestion of protein has been seen as a useful exercise. Thus, in line with the guidance offered by the EFSA GMO Panel we are using an early phase and a late phase gastric simulation as well as a simulation of the infant gastric compartment, all followed by intestinal phases. These digestion scenarios were used with a panel of 10 proteins from plant and animal origin that were proteins with distinct allergenic potential. The results from the SDS-PAGE and densitometry show significant and mainly expected differences between the different digestion scenarios. The milk proteins were fully digested in the intestinal phase but the BLG was largely resistant to pepsin. In contrast, the egg proteins showed significant persistence except under late phase conditions. For the plant proteins, KTI and ConA were largely resistant to all conditions whereas LIP and AP were only resistant to infant conditions. Similarly, Ara h 1 showed some resistance to infant gastric conditions. The LC-MS analysis of peptides was able to highlight a number of clusters where differences were seen between the digestion scenarios and these could in some cases be mapped onto the primary sequence and where relevant compared with known allergenic epitopes. Under the different digestion scenarios, we were able to show significant differences in the persistence of peptides larger than 9 amino acids and significant overlap of abundant peptides from early phase intestinal digestion and known epitopes for a number of proteins. Although, linking these differences to immunological responses (epitope mapping) still seems to be quite challenging, there are clear differences between scenarios and strong potential for improved risk assessment. [ABSTRACT FROM AUTHOR]