Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications.

There is an ongoing debate about the value of animal experiments to inform medical practice, yet there are limited data on how well therapies developed in animal studies translate to humans. We aimed to assess 2 measures of translation across various biomedical fields: (1) The proportion of therapies which transition from animal studies to human application, including involved timeframes; and (2) the consistency between animal and human study results. Thus, we conducted an umbrella review, including English systematic reviews that evaluated the translation of therapies from animals to humans. Medline, Embase, and Web of Science Core Collection were searched from inception until August 1, 2023. We assessed the proportion of therapeutic interventions advancing to any human study, a randomized controlled trial (RCT), and regulatory approval. We meta-analyzed the concordance between animal and human studies. The risk of bias was probed using a 10-item checklist for systematic reviews. We included 122 articles, describing 54 distinct human diseases and 367 therapeutic interventions. Neurological diseases were the focus of 32% of reviews. The overall proportion of therapies progressing from animal studies was 50% to human studies, 40% to RCTs, and 5% to regulatory approval. Notably, our meta-analysis showed an 86% concordance between positive results in animal and clinical studies. The median transition times from animal studies were 5, 7, and 10 years to reach any human study, an RCT, and regulatory approval, respectively. We conclude that, contrary to widespread assertions, the rate of successful animal-to-human translation may be higher than previously reported. Nonetheless, the low rate of final approval indicates potential deficiencies in the design of both animal studies and early clinical trials. To ameliorate the efficacy of translating therapies from bench to bedside, we advocate for enhanced study design robustness and the reinforcement of generalizability.

Performance of two-dimensional shear wave elastography and transient elastography compared to liver biopsy for staging of liver fibrosis.

BACKGROUND: Staging of liver fibrosis traditionally relied on liver histology; however, transient elastography (TE) and more recently two-dimensional shear wave elastography (2D-SWE) evolved to noninvasive alternatives. Hence, we evaluated the diagnostic accuracy of 2D-SWE assessed by the Canon Aplio i800 ultrasound system using liver biopsy as reference and compared the performance to TE. METHODS: In total, 108 adult patients with chronic liver disease undergoing liver biopsy, 2D-SWE and TE were enrolled prospectively at the University Hospital Zurich. Diagnostic accuracies were evaluated using the area under the receiver operating characteristic (AUROC) analysis, and optimal cut-off values by Youden's index. RESULTS: Diagnostic accuracy of 2D-SWE was good for significant (≥F2; AUROC 85.2%, 95% confidence interval (95%CI):76.2-91.2%) as well as severe fibrosis (≥F3; AUROC 86.8%, 95%CI: 78.1-92.4%) and excellent for cirrhosis (AUROC 95.6%, 95%CI: 89.9-98.1%), compared to histology. TE performed equally well (significant fibrosis: 87.5%, 95%CI: 77.7-93.3%; severe fibrosis: 89.7%, 95%CI: 82.0-94.3%; cirrhosis: 96%, 95%CI: 90.4-98.4%), and accuracy was not statistically different to 2D-SWE. 2D-SWE optimal cut-off values were 6.5, 9.8 and 13.1 kPa for significant fibrosis, severe fibrosis and cirrhosis, respectively. CONCLUSIONS: Performance of 2D-SWE was good to excellent and well comparable with TE, supporting the application of this 2D-SWE system in the diagnostic workup of chronic liver disease.

2D pelvic floor ultrasound imaging in identifying levator ani muscle trauma agrees highly with 4D ultrasound imaging.

INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the agreement between 2D and 4D translabial ultrasound (TLUS) technique in showing levator ani muscle (LAM) states after vaginal birth. METHODS: In a prospective observational cohort study between March 2017 and April 2019 we evaluated LAM states (intact, hematoma, partial, complete avulsion) of primiparous women having given birth vaginally with singletons in vertex presentation ≥ 36+0 gestational weeks by using 2D and 4D TLUS within 1-4 days postpartum (assessment A1) and again 6-10 weeks postpartum (assessment A2). Cohen's Kappa analysis was performed for each side separately to evaluate the test agreement between the two ultrasound techniques at every assessment period. RESULTS: A total of 224 women participated at A1 and 213 at A2. The agreement between the two ultrasound techniques was good to very good at A1 (Cohen`s kappa right-sided 0.78, left-sided 0.82) and very good at A2 (Cohen`s kappa both sides 0.88). The agreement was best when assessing an intact LAM or a complete avulsion (Cohen`s kappa between 0.78-0.92 for complete avulsions). CONCLUSIONS: The comparison between 2D and 4D TLUS showed a good to very good agreement in LAM trauma immediately after birth as well as 6-10 weeks postpartum. Therefore, 2D ultrasound could also be a valuable method for demonstrating a LAM abnormality and could be used in settings where 3D/4D ultrasound equipment is not available.

The evolution of levator ani muscle trauma over the first 9 months after vaginal birth.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the evolution of levator ani muscle (LAM) trauma over the first 9 months after birth and to evaluate their agreement between different assessment periods. METHODS: From March 2017 to April 2019 we prospectively evaluated LAM states (intact, hematoma, partial or complete avulsion) of primiparous women after vaginal birth by using 4D translabial ultrasound (TLUS) at three different assessment periods. All women were examined 1-4 days (A1) and 6-10 weeks (A2) postpartum, and women with a trauma additionally 6-9 months postpartum (A3). Cohen's Kappa analysis was performed to evaluate the test agreement between the assessment periods. RESULTS: Thirty-two percent of the women at A1 had a LAM trauma and 24% at A2. The higher number of LAM injuries at A1 can be explained by hematomas (14%), of which 51% spontaneously resolved at A2, 35% revealed themselves as partial, and 12% as complete avulsions. At A3, we observed anatomical improvement from complete to partial avulsions (23%) and few partial avulsions changed into an intact LAM (3%); none of the complete avulsions changed into an intact LAM. The agreement of 4D TLUS between A1 and A2 was moderate to good (0.64 for the right-sided LAM/0.60 for the left-sided LAM) and between A2 and A3 good to very good (0.76 right-sided/0.84 left-sided). CONCLUSIONS: Levator ani muscle trauma can reliably be diagnosed during all assessment periods. However, the agreement between A1 and A2 was only moderate to good. This can be explained by hematomas inside the LAM that were only observed early postpartum. We observed some anatomical improvement at A3, but no complete avulsion improved to an intact LAM.

The histologic presentation of hepatitis E reflects patients' immune status and pre-existing liver condition.

Infection with the hepatitis E virus (HEV) is one of the main causes of acute hepatitis worldwide. Given that, the histopathology of hepatitis E is relatively poorly characterized, and it is unclear what exactly determines its remarkable variability. The aim of our study was a systematic analysis of hepatitis E histology, especially with regard to the clinical setting. Fifty-two liver samples (48 biopsies, 1 liver explant, 3 autopsy livers) from 41 patients with molecularly proven hepatitis E (28 HEV genotype (gt) 3, three gt 1, one gt 4 and 9 undetermined gt) were systematically evaluated for 33 histopathologic features. Following one approach, the biopsies were assigned to one of five generic histologic patterns. In another approach, they were subjected to hierarchical clustering. We found that 23/41 (56%) patients were immunocompromised, whereas 18 (44%) had no known immunosuppression. Five patients (12%) had pre-existing liver disease (LD). The histopathologic spectrum ranged from almost normal to acute, chronic, and steato-hepatitis to subtotal necrosis, and was thus distributed across all five generic patterns. Hierarchical clustering, however, identified three histopathologic clusters (C1-C3), which segregated along the immune status and pre-existing LD: C1 comprised mostly patients with pre-existing LD; histology mainly reflected the respective LD without pointing to the additional hepatitis E. C2 comprised mostly immunocompetent patients; histology mainly displayed florid hepatitis. C3 comprised mostly immunocompromised patients; histology mainly displayed smoldering hepatitis. Accordingly, C1-C3 differed markedly with respect to their clinical and histopathologic differential diagnoses. Hierarchical clustering suggests three groups with distinct histopathologies, indicating biologically different manifestations of hepatitis E. The association of histopathologic changes with the patient's immune status and pre-existing LD plausibly explains the diversity of hepatitis E histopathology, and suggests that these factors are the crucial underlying determinants. We expect our results to improve patient management by guiding the clinico-pathologic diagnosis of hepatitis E.

How do sustained birth tears after vaginal birth affect birth tear patterns in a subsequent birth?

Background Tears are common after vaginal birth, and different impact factors are known. However, the impact of tears from a previous birth to the tears of a subsequent birth is unknown. Therefore, we aimed to evaluate the distribution of birth tear patterns according to the sustained tears in a previous birth, in addition to other impact factors. Methods In a retrospective cohort study, we evaluated all women up to parity 4 with subsequent vaginal, singleton births of vertex presentation at ≥37 + 0 gestational weeks between 1/2005 and 12/2016. Their tears were grouped into tear patterns and were analyzed by parity. Tear patterns in the subsequent births were analyzed in association to the patterns of the previous births and impact factors were evaluated. Results We counted 4017 births in 1855 women [P1: 1368 (34.1%), P2: 1730 (43.1%), P3: 741 (18.4%), P4: 178 (4.4%)]. The frequency of tears and episiotomies decreased with higher parity, whereas the frequency of intact perineum increased. Twenty-eight different unique tear patterns were found. We could show that birth tear patterns changed with increasing parity and were associated with sustained tears in a previous birth. In addition, some impact factors on tear patterns could be identified. Conclusion The distribution of the single tear types is in accordance with the current literature. However, it is new that distinct tear patterns are associated to sustained tear patterns of previous births. Furthermore, we demonstrated some weak associations of tear patterns to certain impact factors, such as more episiotomies, low-grade perineal or vaginal tears isolated or in combination with other tears with increasing fetal weight and head circumference in the higher parities, and with a longer duration of the second stage and the pushing phase in lower parities.

Neutrophile-to-Lymphocyte Ratio (NLR) Identifies Patients with Coronavirus Infectious Disease 2019 (COVID-19) at High Risk for Deterioration and Mortality-A Retrospective, Monocentric Cohort Study.

Among people infected with SARS-CoV-2, the determination of clinical features associated with poor outcome is essential to identify those at high risk of deterioration. Here, we aimed to investigate clinical phenotypes of patients hospitalized due to COVID-19 and to examine the predictive value of the neutrophil-to-lymphocyte ratio (NLR) in a representative patient collective of the Swiss population. We conducted a retrospective monocentriccohort study with patients hospitalized due to COVID-19 between 27 February and 31 December 2020. Data were analyzed descriptively, using the binary logistic regression model, proportional odds logistic regression model, competing risk analysis, and summary measure analysis. A total of 454 patients were included in our study. Dyspnea, elevated respiratory rate, low oxygen saturation at baseline, age, and presence of multiple comorbidities were associated with a more severe course of the disease. A high NLR at baseline was significantly associated with disease severity, unfavorable outcome, and mortality. In non-survivors, NLR further increased during hospital stay, whereas in survivors, NLR decreased. In conclusion, our data emphasize the importance of accurate history taking and clinical examination upon admission and confirm the role of baseline NLR as a surrogate marker for increased disease severity, unfavorable outcome, and mortality in patients hospitalized due to infection with SARS-CoV-2.

The incremental value of the contribution of a biostatistician to the reporting quality in health research-A retrospective, single center, observational cohort study.

BACKGROUND: The reporting quality in medical research has recently been critically discussed. While reporting guidelines intend to maximize the value from funded research, and initiatives such as the EQUATOR network have been introduced to advance high quality reporting, the uptake of the guidelines by researchers could be improved. The aim of this study was to assess the contribution of a biostatistician to the reporting and methodological quality of health research, and to identify methodological knowledge gaps. METHODS: In a retrospective, single center, observational cohort study, two groups of publications were compared. The group of exposed publications had an academic biostatistician on the author list, whereas the group of non-exposed publications did not include a biostatistician of the evaluated group. Rating of reporting quality was done in blinded fashion and in duplicate. The primary outcome was a sum score based on six dimensions, ranging between 0 (worst) and 11 (best). The study protocol was reviewed and approved as a registered report. RESULTS: There were 131 publications in the exposed group published between 2017 and 2018. Of these, 95 were either RCTs, observational, or prediction / prognostic studies. Corresponding matches in the group of non-exposed publications were identified in a reproducible manner. Comparison of reporting quality overall revealed a 1.60 (95%CI from 0.92 to 2.28, p <0.0001) units higher reporting quality for exposed publications. A subgroup analysis within study types showed higher reporting quality across all three study types. CONCLUSION: Our study is the first to report an association of a higher reporting quality and methodological strength in health research publications with a biostatistician on the author list. The higher reporting quality persisted through subgroups of study types and dimensions. Methodological knowledge gaps were identified for prediction / prognostic studies, and for reporting on statistical methods in general and missing values, specifically.

Is reporting quality in medical publications associated with biostatisticians as co-authors? A registered report protocol.

BACKGROUND: Quality in medical research has recently been criticized for being low, especially in observational research. Methodology is increasingly difficult, but collaboration between clinical researchers and biostatisticians may improve research and reporting quality. The aim of this study is to quantify the value of a biostatistician in the team of authors. METHODS: Single-center, retrospective observational study following the STROBE reporting guidelines. We will systematically review all medical publications with biostatisticians from our center as co-authors or authors and review corresponding papers without biostatisticians from our center during the same time range. We will compare aspects of reporting quality, overall and for the three study types observational, randomized trial, and prognostic separately. DISCUSSION: We anticipate that the results of the study will raise awareness of the importance of high methodological quality, as well as appropriate reporting quality in clinical research. CONCLUSION: Our study will have a direct impact on our center by making each of us more aware of the reporting guidelines for various research designs. This in turn will enhance reporting quality in future research with our involvement. Our study will also raise awareness of the important role that biostatisticians play in the design and analysis of health research projects.

Pathology of Echinococcosis: A Morphologic and Immunohistochemical Study on 138 Specimens With Focus on the Differential Diagnosis Between Cystic and Alveolar Echinococcosis.

Infection of humans by the larval stage of the tapeworms Echinococcus granulosus sensu lato or Echinococcus multilocularis causes the life-threatening zoonoses cystic echinococcosis (CE) and alveolar echinococcosis (AE). Although cystic liver lesions are a hallmark of both diseases, course, prognosis, and patients' management decisively differ between the two. The wide and overlapping spectrum of morphologies and the limited availability of ancillary tools are challenges for pathologists to reliably diagnose and subtype echinococcosis. Here, we systematically and quantitatively recorded the pathologic spectrum in a clinically and molecularly defined echinococcosis cohort (138 specimens from 112 patients). Immunohistochemistry using a novel monoclonal antibody (mAbEmG3) was implemented, including its combined application with the mAbEm2G11. Six morphologic criteria sufficiently discriminated between CE and AE: size of smallest (CE/AE: >2/≤2 mm) and largest cyst (CE/AE: >25/≤25 mm), thickness of laminated layer (CE/AE: >0.15/≤0.15 mm) and pericystic fibrosis (CE/AE: >0.6/≤0.6 mm), striation of laminated layer (CE/AE: moderate-strong/weak), and number of cysts (CE/AE: ≤9/>9). Combined immunohistochemistry with mAbEm2G11 (E. multilocularis specific) and mAbEmG3 (reactive in AE and CE) was equally specific as and occasionally more sensitive than polymerase chain reaction. On the basis of these findings, we developed a diagnostic algorithm for the differential diagnosis of echinococcosis. In summary, we have not only identified the means to diagnose echinococcosis with greater certainty, but also defined morphologic criteria, which robustly discriminate between CE and AE. We expect our findings to improve echinococcosis diagnostics, especially of challenging cases, beneficially impacting the management of echinococcosis patients.