Secondary Primary Cancer Risk After Radiation Therapy in Rectal Cancer: A Population-Based Cohort Study With Propensity Score Matching.

BACKGROUND: It remains unclear whether radiation therapy (RT) has an impact on the development of secondary primary cancer (SC) in rectal cancer (RC) patients, especially within the true pelvis. AIM: To examine the incidence of SC in a population-based cohort of RC after surgical treatment with or without radiation therapy (RT, NRT). PATIENTS AND METHODS: The epidemiological cohort consisting of 13,919 RC patients with primary M0 stage diagnosed between 1998 and 2019 was collected from cancer registry data of Upper Bavaria. Competing risk analyses were conducted regarding the development of SC on 11 687 first malignancies, stratified by RT/NRT. A propensity score (PS) was generated by logistic regression modeling of RT to repeat competing risk analyses on a PS-matched cohort. RESULTS: The median age (interquartile range) of the epidemiological cohort was 68.9 years (60.4-76.7). About 60.8%, were men, 38.7% had UICC III, 35.8% of tumors were localized lower than 8 cm, 41.3% underwent RT. Only 17.1% of patients older than 80 years at diagnosis received RT. In general, RT patients were 5 years younger than NRT patients (65.9 years [58.0-73.0] vs. 71.3 years [62.4-79.2], P < .0001). The 20-year cumulative incidence of SC was 16.5% in RT and 17.4% in NRT patients (P = .2298). Men with RT had a lower risk of prostate cancer (HR = 0.55, 95%CI [0.34-0.91], P = .0168). In the PS-matched cohort, RT patients had a significantly higher risk of bladder cancer during follow-up (10-year cumulative incidence of 1.1% vs. 0.6% in NRT). The direction of the RT effects in men and women and different tumor sites may cancel each other. CONCLUSION: A protective effect of RT in rectal cancer patients on developing prostate SC by half is reproduced. Further analyses studying the long-term SC risks of RT should essentially focus on stratification by sex, and focus on more recent data.

Higher Prevalence of Adverse Childhood Experiences in Transgender Than in Cisgender Individuals: Results from a Single-Center Observational Study.

Adverse childhood experiences (ACE) have been shown to have a tremendous negative impact on health outcomes later in life. This study presents data on the prevalence of ACEs, psychological distress, and trauma-related symptoms in transgender and gender-diverse (TGD) people compared to cisgender people. TGD adults (n = 35) and a matched sample of nonpsychiatric hospital patients (n = 35) were surveyed between September 2018 and March 2019. Participants completed the Maltreatment and Abuse Chronology of Exposure Scale to assess ACEs, as well as the Brief Symptom Inventory and the Essener Trauma Inventory to assess psychological distress and trauma-related symptoms. TGD patients reported a higher number of ACEs than cisgender patients (0.7 vs. 2.4; p < 0.001; d = 0.94). A total of 28.6% of TGD vs. 5.7% cisgender patients reported four or more ACEs (p < 0.001). The most common forms of ACEs were parental abuse (54.3%) and peer abuse (54.3%). No significantly increased prevalence of sexual abuse was found (p > 0.05). TGD patients also reported a higher prevalence of depression (48.4% vs. 5.7%, p < 0.001), posttraumatic stress disorder symptoms (59.4% vs. 13.8%, p < 0.001), and anxiety (58.1% vs. 28.6%, p = 0.016). Health care providers should be aware of and assess ACEs, especially in vulnerable groups such as TGD people, and create a safe place through open-minded, affirming care.

A Multitool for Circular Economy: Fast Ring-Opening Polymerization and Chemical Recycling of (Bio)polyesters Using a Single Aliphatic Guanidine Carboxy Zinc Catalyst.

Invited for this month's cover is the group of Professor Sonja Herres-Pawlis at the RWTH Aachen (Germany). The cover image illustrates the complex yet flexible circular economy of (bio)plastics and the role of a Zn-based catalyst therein. The Research Article itself is available at 10.1002/cssc.202300192.

Integrated Analysis of the RASH Study with the Use of the "Burden of Therapy" (BOTh®TM) Methodology-A Novel Tool for Assessing Adverse Events in Metastatic Pancreatic Cancer.

This analysis of the RASH trial (NCT01729481) aimed at gaining a better understanding of the "Burden of Therapy" (BOTh®TM) in pancreatic ductal adenocarcinoma (PDAC). In the RASH study, 150 patients with newly diagnosed metastatic PDAC were treated with gemcitabine plus erlotinib (gem/erlotinib) for four weeks. Patients who developed a skin rash during this four-week run-in phase continued with the gem/erlotinib treatment, while rash-negative patients were switched to FOLFIRINOX. The study demonstrated a 1-year survival rate of rash-positive patients who received gem/erlotinib as first-line treatment that was comparable to previous reports of patients receiving FOLFIRINOX. To understand whether these comparable survival rates may be accompanied by better tolerability of the gem/erlotinib treatment compared to FOLFIRINOX, the BOTh®TM methodology was used to continuously quantify and depict the burden of therapy generated by treatment emergent events (TEAEs). Sensory neuropathy was significantly more common in the FOLFIRINOX arm, and prevalence as well as severity increased over time. In both arms, the BOTh®TM associated with diarrhea decreased over the course of treatment. The BOTh®TM caused by neutropenia was comparable in both arms but decreased in the FOLFIRINOX arm over time, possibly due to chemotherapy dose reductions. Overall, gem/erlotinib was associated with a slightly higher overall BOTh®TM, but the difference was not statistically significant (p = 0.6735). In summary, the BOTh®TM analysis facilitates the evaluation of TEAEs. In patients fit for intense chemotherapeutic regimens, FOLFIRINOX is associated with a lower BOTh®TM than gem/erlotinib.

Attachment Trauma Is Associated with White Matter Fiber Microstructural Alterations in Adolescents with Anorexia Nervosa before and after Exposure to Psychotherapeutic and Nutritional Treatment.

In the present study, we explore the role of attachment for microstructural white matter (WM) changes in adolescents with anorexia nervosa (AN) before and after exposure to short-term and nutritional treatment. The case sample consisted of 22 female adolescent inpatients with AN (mean age: 15.2 ± 1.2 years) and the control sample were 18 gender-matched healthy adolescents (mean age: 16.8 ± 0.9 years). We performed a 3T MRI in the patient group during the acute state of AN and after weight restoration (duration: 2.6 ± 1 months) and compared the data to a healthy control group. To classify attachment patterns, we used the Adult Attachment Projective Picture System. In the patient sample, over 50% were classified with an attachment trauma/unresolved attachment status. Prior to treatment exposure, fractional anisotropy (FA) reductions and concordant mean diffusivity (MD) increases were evident in the fornix, the corpus callosum and WM regions of the thalamus, which normalized in the corpus callosum and the fornix post-therapy in the total patient sample (p < 0.002). In the acute state, patients with an attachment trauma demonstrated significant FA decreases compared to healthy controls, but no MD increases, in the corpus callosum and cingulum bilaterally, which remained decreased after therapy. Attachment patterns seem to be associated with region-specific changes of WM alterations in AN.

A Multitool for Circular Economy: Fast Ring-Opening Polymerization and Chemical Recycling of (Bio)polyesters Using a Single Aliphatic Guanidine Carboxy Zinc Catalyst.

A new aliphatic hybrid guanidine N,O-donor ligand (TMGeech) and its zinc chloride complex ([ZnCl2 (TMGeech)]) are presented. This complex displays high catalytic activity for the ring-opening polymerization (ROP) of lactide in toluene, exceeding the toxic industry standard tin octanoate by a factor of 10. The high catalytic activity of [ZnCl2 (TMGeech)] is further demonstrated under industrially preferred melt conditions, reaching high lactide conversions within seconds. To bridge the gap towards a sustainable circular (bio)economy, the catalytic activity of [ZnCl2 (TMGeech)] for the chemical recycling of polylactide (PLA) by alcoholysis in THF is investigated. Fast production of different value-added lactates at mild temperatures is demonstrated. Selective PLA degradation from mixtures with polyethylene terephthalate (PET) and a polymer blend, catalyst recycling, and a detailed kinetic analysis are presented. For the first time, chemical recycling of post-consumer PET producing different value-added materials is demonstrated using a guanidine-based zinc catalyst. Therefore, [ZnCl2 (TMGeech)] is a promising, highly active multitool, not only to implement a circular (bio)plastics economy, but also to tackle today's ongoing plastics pollution.

Evaluation of visual food stimuli paradigms on healthy adolescents for future use in fMRI studies in anorexia nervosa.

BACKGROUND: Mostly, visual food stimuli paradigms for functional Magnetic Resonance Imaging are used in studies of eating disorders. However, the optimal contrasts and presentation modes are still under discussion. Therefore, we aimed to create and analyse a visual stimulation paradigm with defined contrast. METHODS: In this prospective study, a block-design fMRI paradigm with conditions of randomly altering blocks of high- and low-calorie food images and images of fixation cross was established. Food pictures were rated in advance by a group of patients diagnosed with anorexia nervosa to address the dedicated perception of patients with eating disorders. To optimize the scanning procedure and fMRI contrasts we have analysed neural activity differences between high-calorie stimuli versus baseline (H vs. X), low-calorie stimuli versus baseline (L vs. X) and high- versus low-calorie stimuli (H vs. L). RESULTS: By employing the developed paradigm, we were able to obtain results comparable to other studies and analysed them with different contrasts. Implementation of the contrast H versus X led to increased blood-oxygen-level-dependent signal (BOLD) mainly in unspecific areas, such as the visual cortex, the Broca´s area, bilaterally in the premotor cortex and the supplementary motor area, but also in thalami, insulae, the right dorsolateral prefrontal cortex, the left amygdala, the left putamen (p < .05). When applying the contrast L versus X, an enhancement of the BOLD signal was detected similarly within the visual area, the right temporal pole, the right precentral gyrus, Broca´s area, left insula, left hippocampus, the left parahippocampal gyrus, bilaterally premotor cortex and thalami (p < .05). Comparison of brain reactions regarding visual stimuli (high- versus low-calorie food), assumed to be more relevant in eating disorders, resulted in bilateral enhancement of the BOLD signal in primary, secondary and associative visual cortex (including fusiform gyri), as well as angular gyri (p < .05). CONCLUSIONS: A carefully designed paradigm, based on the subject's characteristics, can increase the reliability of the fMRI study, and may reveal specific brain activations elicited by this custom-built stimuli. However, a putative disadvantage of implementing the contrast of high- versus low-calorie stimuli might be the omission of some interesting outcomes due to lower statistical power. Trial registration NCT02980120.

Although the relationship with food is crucial for living, its underlying mechanisms (e.g., neurological, cognitive, physiological) are still not fully discovered. The development of functional magnetic resonance imaging made it possible to explore brain's responses to images of food. However, a proper methodological analysis of the research paradigm is still lacking. Here, we present the optimization of visual food stimuli paradigms achieved by comparison of neural activations of 20 female healthy adolescents after applying particular contrasts (i.e., high- versus low-calorie food images, high-calorie food images versus baseline, low-calorie food images versus baseline). Application of the contrast high- versus low-calorie food images resulted in stronger neural activation in visual cortex (including fusiform gyri) and angular gyri. This study highlights the importance of choosing a proper contrast regarding the study hypothesis, as it may induce more specific results. However, it may lead to loss of some outcomes, due to lower statistical power. Additionally, we have performed an evaluation of visual food stimuli chosen by patients diagnosed with anorexia nervosa. They have selected images of the most and the least willingly eaten meals. Although they didn't know the exact calorie content, they chose intuitively photos later classified as extremely high- or low-caloric.

Experiments and Modeling on the Stain-Controlled Time- and Temperature-Dependent Cyclic Ratchetting Plasticity of the Nickel-Based Superalloy IN100.

In this paper, the time- and temperature-dependent cyclic ratchetting plasticity of the nickel-based alloy IN100 is experimentally investigated in strain-controlled experiments in the temperature range from 300 °C to 1050 °C. To this end, uniaxial material tests are performed with complex loading histories designed to activate phenomena as strain rate dependency, stress relaxation as well as the Bauschinger effect, cyclic hardening and softening, ratchetting and recovery from hardening. Plasticity models with different levels of complexity are presented that consider these phenomena, and a strategy is derived to determine the multitude of temperature-dependent material properties of the models in a step-by-step procedure based on sub-sets of experimental data of isothermal experiments. The models and the material properties are validated based on the results of non-isothermal experiments. A good description of the time- and temperature-dependent cyclic ratchetting plasticity of IN100 is obtained for isothermal as well as non-isothermal loading with models including ratchetting terms in the kinematic hardening law and the material properties obtained with the proposed strategy.

The other colon cancer: a population-based cohort study of appendix tumour trends and prognosis.

AIM: Appendiceal neoplasms are rare subtypes of colorectal tumours that mainly affect younger patients some 20 years earlier than other colon tumours. The aim of this study was to gain more insight into the histological subtypes of this rare disease and include cases previously excluded, such as mucinous neoplasia. METHOD: The cohort study included 1097 patients from the Munich Cancer Registry (MCR) diagnosed between 1998 and 2020. Joinpoint analysis was used to determine trend in incidence. Baseline demographic comparisons and survival analyses using competing risk and univariate/multivariate methods were conducted according to tumour histology: adenocarcinoma (ADENO), neuroendocrine neoplasia (NEN), mixed adeno-neuroendocrine carcinoma (MANEC), and low- (LAMN) and high-grade mucinous neoplasia (HAMN). RESULTS: Up to 2016 the number of cases increased significantly [annual per cent change (APC) = 6.86, p < 0.001] followed by a decline in the following years (APC = -14.82, p = 0.014; average APC = 2.5, p = 0.046). Comparison of all patients showed that NEN (48.4%) and mucinous neoplasms (11.6%) had a considerably better prognosis than ADENO (36.0%) and MANEC (3.0%, p < 0.0001). A multivariate analysis within the NEN and ADENO subgroups revealed that further histological classification was not prognostically relevant, while older age and regional tumour spread at diagnosis were associated with a poor prognosis. ADENO histology with high tumour grade and appendectomy only was also associated with poorer survival. CONCLUSION: Appendiceal neoplasms are histologically heterogeneous; however, this diversity becomes less relevant compared with the marked difference from cancers of the remaining colon. The previously observed increase in cases appears to be abating; fewer cases of appendicitis and/or appendectomies or changes in histopathological assessment may be behind this trend.

Practices to support co-design processes: A case-study of co-designing a program for children with parents with a mental health problem in the Austrian region of Tyrol.

Forms of collaborative knowledge production, such as community-academic partnerships (CAP), have been increasingly used in health care. However, instructions on how to deliver such processes are lacking. We aim to identify practice ingredients for one element within a CAP, a 6-month co-design process, during which 26 community- and 13 research-partners collaboratively designed an intervention programme for children whose parent have a mental illness. Using 22 published facilitating and hindering factors for CAP as the analytical framework, eight community-partners reflected on the activities which took place during the co-design process. From a qualitative content analysis of the data, we distilled essential practices for each CAP factor. Ten community- and eight research-partners revised the results and co-authored this article. We identified 36 practices across the 22 CAP facilitating or hindering factors. Most practices address more than one factor. Many practices relate to workshop design, facilitation methods, and relationship building. Most practices were identified for facilitating 'trust among partners', 'shared visions, goals and/or missions', 'effective/frequent communication', and 'well-structured meetings'. Fewer practices were observed for 'effective conflict resolution', 'positive community impact' and for avoiding 'excessive funding pressure/control struggles' and 'high burden of activities'. Co-designing a programme for mental healthcare is a challenging process that requires skills in process management and communication. We provide practice steps for delivering co-design activities. However, practitioners may have to adapt them to different cultural contexts. Further research is needed to analyse whether co-writing with community-partners results in a better research output and benefits for participants.

[Inpatient care capacities in child and adolescent psychiatry-increase in emergency admissions during the COVID-19 pandemic?] / Stationäre Versorgungskapazitäten in der Kinder- und Jugendpsychiatrie ­ Zunahme der Akutaufnahmen während der COVID-19 Pandemie?

The COVID-19 pandemic and the accompanying containment measures have had a fundamental impact on the mental health of children and adolescents. In the present study, the emergency admissions of the first two Corona years (2020/21) at the Department for Child and Adolescent Psychiatry Hall i. T./Innsbruck were retrospectively analysed and compared with the two years before the COVID-19 pandemic (2018/19). There was no change in the total number of emergency admissions in 2020 compared to 2019 before Corona, but in 2021 emergency admissions increased by 40.1%. The pre-Corona (2018/19) gender ratio of 65.4% girls to 34.6% boys did not change in 2020. In 2021, the proportion of girls increased to 74.4%. In the COVID-19 pandemic, acute suicidality increased (+48.3%) while aggression decreased (-51.0%). Acute intoxications increased in the first Corona year and decreased again in 2021. The present study results show that the mental health needs of children and adolescents increased significantly in the course of the COVID-19 pandemic and that this was also reflected in child and adolescent psychiatry. The increased demands must now be met with appropriate care and prevention measures as well as sufficient child and adolescent psychiatric bed capacities in order to mitigate the longer-term psychosocial effects of the COVID-19 pandemic as best as possible.

[Cannabis use in adolescents : Narrative Review and Position paper of the "Addiction Disorders in Adolescents" task force of the Austrian Society for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy (ÖGKJP)]. / Cannabisgebrauch bei Jugendlichen : Übersicht und Positionspapier der Arbeitsgruppe "Suchtstörungen im Jugendalter" der Österreichischen Gesellschaft für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (ÖGKJP).

BACKGROUND: Cannabis is the illegal drug most frequently used by Minors in Austria. Due to the gradual decriminalization and legalization that has taken place in many European countries in recent years, the ÖGKJP would like to take a balanced and scientifically based stand on the complex issue of cannabis use and abuse among young people. METHODS: The authors searched the medline for current studies using searches tailored to each specific subtopic. Furthermore, recognized compendiums were quoted. RESULTS: While occasional recreational use of cannabis in adults with completed brain maturation and no risk profile for mental disorders is likely to be relatively harmless, early initiation of use with regular use and the increasingly available, highly potent cannabis varieties can lead to explicit and sometimes irreversible neurocognitive brain dysfunction. CONCLUSION: Legalisation of cannabis consumption for minors needs to be objected to due to the risks of the expected damage in the area of brain development. At the same time, however, it is important to establish sensible legal regulations in order to be able to adequately counteract the fact that over 30% of all European young people occasionally consume cannabis. We are also clearly recommending to not criminalize cannabis users and provide necessary support to vulnerable and addicted cannabis users.

[A three-country comparison of mental health and treatment options of children and adolescents with mental health problems in times after the COVID-19 pandemic]. / Die psychische Gesundheit unserer Kinder und Jugendlichen und deren Behandlungsmöglichkeiten im Drei-Länder-Vergleich (Ö, D, CH) unter Berücksichtigung der Veränderungen durch die COVID-19-Pandemie.

BACKGROUND AND RESEARCH QUESTION: The Austrian Society for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy (ÖGKJP) is publishing a series of articles in a special issue of Neuropsychiatrie dealing with the current provision of care in child and adolescent psychiatry. Aim of this article is to give an overview of provision of care for children and adolescents with mental health problems in Austria, Germany, and Switzerland and then draw conclusions for the Austrian child and adolescent psychiatric care landscape. METHOD: First, epidemiologic data as well as different traditions and treatment philosophies and their effect for provision of care in child and adolescent psychiatry in Austria, Germany and Switzerland are presented. Subsequently, data of provided child and adolescent psychiatric care in Austria and Germany are presented and related to each other. RESULTS AND CONCLUSIONS: On the basis of the data presented, the current deterioration of mental health in children and adolescents due to the pandemic as well as the deficit of available inpatient beds (0.03-0.09) there is an urgent need for action in Austrian provision of child and adolescent psychiatric care. An improvement of the structural deficits in the child and adolescent psychiatric research and care landscape, a significant increase of capacities for inpatient treatment, day-care as well as outpatient treatment with establishment of modern treatment options such as home treatment is necessary.

Outcome Quality After Colorectal Cancer Resection in Certified Colorectal Cancer Centers­Patient-Reported and Short-Term Clinical Outcomes.

BACKGROUND: In this observational study, patient-reported outcomes and short-term clinical outcome parameters in patients with colorectal cancer were studied 12 months after the start of treatment. Outcomes were also compared across German Certified Colorectal Cancer Centres. METHODS: Data were collected from 4239 patients with colorectal cancer who had undergone elective tumor resection in one of 102 colorectal cancer centers and had responded to a quality-of-life questionnaire before treatment (EORTC QLQ-C30 and -CR29). 3142 (74.1%) of these patients completed a post-treatment questionnaire 12 months later. Correlation analyses were calculated and case-mix adjusted comparisons across centers were made for selected patient-reported outcomes, anastomotic insufficiency, and 30-day-mortality. RESULTS: At 12 months, mild improvements were seen in mean quality-of-life scores (66 vs. 62 points), constipation (16 vs. 19), and abdominal pain (15 vs. 17). Worsening was seen in physical function (75 vs. 82) and pain (22 vs. 19). Better patient-reported outcomes at 12 months were associated with better scores before treatment. Better results in at least three of the five scores were associated with male sex, higher educational level, higher age, and private health insurance. Major worsening of fecal incontinence was seen among patients with rectal cancer without a stoma. The largest differences across centers were found with respect to physical function. Anastomotic insufficiency was found in 4.3% of colon cancer patients and 8.2% of rectal cancer patients. 1.9% of patients died within 30 days after their resection. CONCLUSION: Clinicians can use these findings to identify patients at higher risk for poorer patient-reported outcomes. The differences among cancer centers that were found imply that measures for quality improvement would be desirable.

Multi-crystal native-SAD phasing at 5 keV with a helium environment.

De novo structure determination from single-wavelength anomalous diffraction using native sulfur or phospho-rus in biomolecules (native-SAD) is an appealing method to mitigate the labor-intensive production of heavy-atom derivatives and seleno-methio-nyl substitutions. The native-SAD method is particularly attractive for membrane proteins, which are difficult to produce and often recalcitrant to grow into decent-sized crystals. Native-SAD uses lower-energy X-rays to enhance anomalous signals from sulfur or phospho-rus. However, at lower energies, the scattering and absorption of air contribute to the background noise, reduce the signals and are thus adverse to native-SAD phasing. We have previously demonstrated native-SAD phasing at an energy of 5 keV in air at the NSLS-II FMX beamline. Here, the use of a helium path developed to reduce both the noise from background scattering and the air absorption of the diffracted X-ray beam are described. The helium path was used for collection of anomalous diffraction data at 5 keV for two proteins: thaumatin and the membrane protein TehA. Although anomalous signals from each individual crystal are very weak, robust anomalous signals are obtained from data assembled from micrometre-sized crystals. The thaumatin structure was determined from 15 microcrystals and the TehA structure from 18 microcrystals. These results demonstrate the usefulness of a helium environment in support of native-SAD phasing at 5 keV.

AMX - the highly automated macromolecular crystallography (17-ID-1) beamline at the NSLS-II.

The highly automated macromolecular crystallography beamline AMX/17-ID-1 is an undulator-based high-intensity (>5 × 1012 photons s-1), micro-focus (7 µm × 5 µm), low-divergence (1 mrad × 0.35 mrad) energy-tunable (5-18 keV) beamline at the NSLS-II, Brookhaven National Laboratory, Upton, NY, USA. It is one of the three life science beamlines constructed by the NIH under the ABBIX project and it shares sector 17-ID with the FMX beamline, the frontier micro-focus macromolecular crystallography beamline. AMX saw first light in March 2016 and started general user operation in February 2017. At AMX, emphasis has been placed on high throughput, high capacity, and automation to enable data collection from the most challenging projects using an intense micro-focus beam. Here, the current state and capabilities of the beamline are reported, and the different macromolecular crystallography experiments that are routinely performed at AMX/17-ID-1 as well as some plans for the near future are presented.

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro).

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic tem-per-ature or room tem-per-ature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple tem-per-atures from cryogenic to physiological, and another at high humidity. We inter-rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for Mpro, including a mobile zinc ion inter-leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra-molecular network bridging the active site and dimer inter-face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.

FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases - The PARLIM trial (AIO KRK 0314).

PURPOSE: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomised, controlled, open-label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases. EXPERIMENTAL DESIGN: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 weeks of biweekly mFOLFOX6 plus panitumumab followed by 12 weeks of panitumumab alone) was considered active if the two-year PFS rate was ≥65%. Based on historical data, a two-year PFS rate of 50% was estimated in the control arm (12 weeks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994. RESULTS: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The primary endpoint was missed with a two-year PFS of 35.7% with FOLFOX plus panitumumab and 30.6% in the control arm. In comparative analyses, trends towards improved PFS (HR 0.83; 95%CI, 0.52-1.33; P = 0.44) and OS (HR 0.70; 95% CI, 0.34-1.46; P = 0.34) were observed in favour of the panitumumab-based study arm. No new or unexpected safety signals were observed with FOLFOX plus panitumumab following liver resection. CONCLUSION: The PARLIM trial failed to demonstrate a two-year PFS rate of 65% after resection of colorectal liver metastases. The positive trends in survival endpoints may support future trials evaluating treatment with anti-EGFR agents after resection of liver metastases.

Serial crystallography with multi-stage merging of thousands of images.

KAMO and BLEND provide particularly effective tools to automatically manage the merging of large numbers of data sets from serial crystallography. The requirement for manual intervention in the process can be reduced by extending BLEND to support additional clustering options such as the use of more accurate cell distance metrics and the use of reflection-intensity correlation coefficients to infer `distances' among sets of reflections. This increases the sensitivity to differences in unit-cell parameters and allows clustering to assemble nearly complete data sets on the basis of intensity or amplitude differences. If the data sets are already sufficiently complete to permit it, one applies KAMO once and clusters the data using intensities only. When starting from incomplete data sets, one applies KAMO twice, first using unit-cell parameters. In this step, either the simple cell vector distance of the original BLEND or the more sensitive NCDist is used. This step tends to find clusters of sufficient size such that, when merged, each cluster is sufficiently complete to allow reflection intensities or amplitudes to be compared. One then uses KAMO again using the correlation between reflections with a common hkl to merge clusters in a way that is sensitive to structural differences that may not have perturbed the unit-cell parameters sufficiently to make meaningful clusters. Many groups have developed effective clustering algorithms that use a measurable physical parameter from each diffraction still or wedge to cluster the data into categories which then can be merged, one hopes, to yield the electron density from a single protein form. Since these physical parameters are often largely independent of one another, it should be possible to greatly improve the efficacy of data-clustering software by using a multi-stage partitioning strategy. Here, one possible approach to multi-stage data clustering is demonstrated. The strategy is to use unit-cell clustering until the merged data are sufficiently complete and then to use intensity-based clustering. Using this strategy, it is demonstrated that it is possible to accurately cluster data sets from crystals that have subtle differences.

Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (Mpro also known as 3CLpro) is a primary drug target, due to its essential role in maturation of the viral polyproteins. In this study, we provide crystallographic evidence, along with some binding assay data, that three clinically approved anti hepatitis C virus drugs and two other drug-like compounds covalently bind to the Mpro Cys145 catalytic residue in the active site. Also, molecular docking studies can provide additional insight for the design of new antiviral inhibitors for SARS-CoV-2 using these drugs as lead compounds. One might consider derivatives of these lead compounds with higher affinity to the Mpro as potential COVID-19 therapeutics for further testing and possibly clinical trials.