dataesr/scientific-paragraphs-categorization huggingface dataset:
3 (a) with pulse energies annotated in the figure. The extracted domain size A Domain as a function of pulse energy E is plotted in Fig. 3(b). To quantify the (incident) threshold fluence F 0 for AOS from this measurement, the equation below is used to describe the pulse energy dependence, assuming elliptical laser profiles: 41 r denotes the length of the ellipse, r is the ratio of short and long axes, and E is the pulse energy. The above equation is fitted to all data sets, and F 0 is extracted, as shown in the inset of Fig. 3(b ). We find that F 0 is effectively independent of the Tb thickness with a mean value of 4. 44 mJ/cm 2 at the given Gd thickness of 1 nm. This is somewhat surprising, considering the potential for AOS in pure [Co/Tb] multilayers, where AOS is observed only very close to magnetic compensation.
This project has received funding from the  European Union 's  Horizon 2020 research and innovation programme  under the  Marie Skłodowska-Curie Grant  Agreement Nos. 861300  and  860060. This work was also part of the research program  Gravitation (ZK) program  " Research Center for Integrated Nanophotonics ," which are financed by the  Dutch Research Council (NWO). J. I. acknowledges support from  JSPS Overseas Research Fellowships. Furthermore, this work was supported by the No. ANR-20-CE09-0013 UFO , the  Institute Carnot ICEEL  for the project " CAPMAT " and  FASTNESS , the  R egion Grand Est , the  Metropole Grand Nancy , for the  Chaire PLUS  by the impact project  LUE-N4S , part of the  French PIA  project " Lorraine Universit e d'Excellence " Ref. No. ANR-15-IDEX-04-LUE , the " FEDERFSE Lorraine et Massif Vosges 2014-2020 " for  IOMA a European Union Program , and the  ANR  Project No.
may be advantageous in gaining a more comprehensive determination of surgical fitness and the true physical impact of surgery than subjective metrics. Materials and Methods: Retrospective review of a prospective multicenter ASD database. ASD pts were assessed using timed up and go 6 meter walk time(WT) in seconds and grip strength (GS) in pounds. PROMS included: back/leg pain numerical rating score (NRS), Scoliosis Research Society-22r(SRS-22r), Oswestry Disability Index(ODI), Patient-reported outcomes measurement information system (PROMIS) and the veteran's rand 12(VR-12). Reaching 1 yr ODI minimally clinically important difference (MCID) was determined for each pt. Preand 1yr postop WT, GS, and PROMS were compared. Results: Total pts: WT 200, GS 208. 60% improved in WT(n¼120), 50% improved in GS(n¼104).
001) and rigid or fused of apex segment (-, or +). Either Type I or Type II is further divided into four subtypes: Type IA-, Type IA+, Type IB-, Type IB+, Type IIA-, Type IIA+, Type IIB-, and Type IIB+. Whereas optimal sagittal alignment is subject of debate,"well aligned" patients aren't exempt of MC and factors other than alignment might play an increasingly important role. The objective of this study is to analyse MC rate in well aligned patients and study the relevant risk factors and surgical outcomes associated to MC in this subgroup Materials and Methods: Retrospective analysis of a prospective multicenter ASD Database. Adult ASD patients (Age>55) with more than 2-yrs f-up and immediate postoperative GAP Score 2 were included from a multicenter prospective ASD Database. Continuous and categorical variables were compared and regression models run to identify independent risk factors for MC.
We studied the factors associated with the postoperative improvement of RPV. Materials and Methods: Retrospective analysis of a prospective multicenter ASD database. Selection criteria: operated patients with preoperative severe pelvic retroversion as per GAP-score (RPV<-15º); panlumbar fusions to pelvis; 2 years follow-up. Patients were assigned to groups A or B according to whether they had postoperative improvement in RPV or not, respectively. Differences between groups were analyzed in: baseline demographics, comorbidities, and preoperative sagittal parameters; surgical factors; postoperative sagittal parameters at 6 weeks, 6 months, 1 year, and 2 years. Descriptive statistics, parametric and non-parametric analyses were employed. Results: 177 patients: median age 67 years (61; 72. 5), 86.
Hypofractionation and the Linear Quadratic (LQ) Model The validity of the LQ model at high fraction sizes above approximately 6 Gy is questionable, and alternative radiobiological models are proposed. However, a strong proargument was derived from clinical data from non-small cell lung cancer patients treated with SBRT, either with a single dose or hypofractionated with 3-8 fractions. From the study  [6] , it was evident that the clinically observed increase in tumor could be ascribed to radiation dose escalation, i. e. , an increased Biologically Effective Dose (BED) according to the LQ equation. BED values were calculated for the various hypofractionation schemes including SBRT fraction sizes of 22 Gy. No adaptation or correction was made when using the conventional LQ model. The analysis showed a clear correlation between treatment outcome and the BED, even at extreme high BED values.
Box 6. 5 RT Combined with Chemotherapy • RT and chemotherapy can, when combined, improve locoregional disease control. • Concomitant administration of RT with chemotherapy gives increased early normal tissue toxicity but late toxicity of normal tissues may also be increased. Glioblastoma, esophagogastric cancer  [70, 71]  Hypoxia Oxygen mimetic Nimorazole Head and neck cancer  [72]  a The trial number refers to its citation on https://clinicaltrials. gov/.
gov; NCT03641547) were tested in phase I trials in various solid tumors in an advanced stage setting including esophageal cancer  [58]. As the kinase pocket of ATM is similar to other PIKKs, early attempts to develop specific inhibitors were unsuccessful  [60]. However, the ATM inhibitor AZD1390 is currently undergoing trials in conjunction with RT in glioblastoma patients (NCT03423628). Attempts have also been made to target DNA-PKcs, a key component of the NHEJ repair cascade (see Chap. 3)  [60]. Thus, AZD7648 has been demonstrated to enhance RT effect when combined with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in both tumor cell lines in vitro as well as in tumor-bearing mice. This DNA-PKcs inhibitor is at present tested further in a phase I clinical trial (NCT03907969).
Interfering with Cell Cycle Regulation to Improve RT Response Multiple cyclin-dependent kinase 4 and 6 inhibitors (CDKIs), e. g. , palbociclib, ribociclib, and abemaciclib which alter the cell cycle progression, have become an important new treatment of metastatic-or locally advanced BC including combinations with RT  [63]. Albeit multiple studies are ongoing, no consensus has been reached underpinning the clinical benefit of combining RT with CDKIs  [63]. For palbociclib, there are studies ongoing in BC and HNC, ribociclib is evaluated with RT in multiple trials as is abemaciclib (Table  6. 7 ). In addition, there is an attempt to study abemaciclib in patients with solid tumors that have brain metastasis where CDK genomic testing is done (NCT03994796). The CDK1/2 is in part controlled by the WEE1 G2 checkpoint kinase which via Ser/Th protein phosphorylation blocks their activity resulting in a G2/M cell cycle checkpoint activation.
One of the major classical responses of radiation is the dys-functioning of the cell cycle arrest  [108]. There is a growing body of evidence from the preclinical studies on STS which enhances the efficacy of a wide variety of chemotherapy drugs that are used in treatments of several types of tumors. Some of clinical trials (NCT00757094, NCT00936364, NCT01304251, and NCT01954836) have proven to be safe and feasible with reduction in the chemotherapy associated side effects. Since STS has demonstrated favorable traits to fight cancer, it would be logical to combine STS with RT as it presents clinical gain. In preclinical studies, combining STS with RT has already exhibited enhanced RT effects. Clinical and preclinical trials of STS and RT are also picking pace to exhibit the efficacy of this combination.
• Multiple promising prospective trials are ongoing to further optimize PRRT (e. g. , α-emitters, individualized dosimetry, and SSTR-antagonists). The trial number refers to its citation on https://clinicaltrials. gov/ a significant increase in imaging-based PFS and OS in a randomized controlled trial where it was compared to standard of care (i. e. , chemotherapy, RT and ADT), resulting in the FDA approval of [ 177 Lu]Lu-PSMA-617 for patients with metastatic castration-resistant PCa in  March 2022 [150]. Since PSMA poses such an interesting target for RLT, due to the high overexpression on PCa cells, more PSMA-targeting radioligands are currently under clinical investigation, as summarized in Table  6. 10. The development of RLT is not strictly limited to PCa and targeting PSMA. Several other compounds with other targets are also undergoing clinical trials.
177 Lu-PSMA and radium-223 have also been combined with chemotherapy, although less data are available compared to 177 Lu-DOTATATE. A phase I/II study showed that the alpha-emitter radium-223 (55 kBq/kg every 6 weeks for 5 cycles) in combination with docetaxel (60 mg/m 2 every 3 week) was well tolerated in bone-predominant metastatic castration-resistant prostate cancer patients. Exploratory efficacy data even suggested enhanced antitumor activity in the combination arm [164]. This will be further explored in a phase III clinical trial that is currently recruiting patients (NCT03574571). The combination of 177 Lu-PSMA with docetaxel, a taxane impairing microtubules polymerization dynamics and therefore preventing cell mitosis, is currently evaluated in metastatic hormone-naïve prostate cancer in a randomized phase II study (UpFrontPSMA trial-NCT04343885)  [165].
PARP is involved in the repair of DNA SSBs and has been targeted by PARP inhibitors (PARPi) in combination with chemotherapy and EBRT. Following favorable results from preclinical studies combining 177  , the combination is now assessed in phase I/II clinical trials with 177 Lu-DOTATATE (NCT05053854, NCT04375267, NCT04086485) and 177 Lu-PSMA (NCT03874884). Different treatment schedules are used within the trials, with PARPi commencing either before or after RNT administration, and also with variable duration of PARPi (first few days of each RNT administration or daily continuous administration). Study results are awaited and might already provide some evidence about the optimal treatment schedule to be used. Phase I studies evaluating the combination of 177 Lu-DOTATATE and other DDR inhibitors, such as peposertib (NCT04750954) and triapine (NCT04234568), are also underway.
This finding is significant, as such a combination could be beneficial to patients currently not eligible for peptide receptor radionuclide therapy due to a too low uptake on 68 Ga-DOTA-SSA PET/CT. A synergistic effect of 4-l-[131I]iodo-phenylalanine ( 131 I-IPA) and EBRT has been observed in preclinical models of glioblastoma multiforme, and the first results of a phase I/II trial (IPAX-1 trial-NCT03849105) should be available soon.
Only one dose-limiting toxicity, consisting of a grade 3 rash, was noted in one patient being treated at dose level 2. Phase I and II clinical trials combining 177 Lu-DOTATATE (NCT03325816, NCT04261855, NCT03457948) or 177 Lu-PSMA (PRINCE trial-NCT03658447, NCT03805594) with anti-PD1 or PD-L1 antibodies are under way. There exists a huge potential in terms of a combined regimen with RNT. Promising combination strategies used with EBRT frequently serve as arguments to extrapolate to RNT. However, EBRT and RNT are characterized by major differences such as the delivery route (external versus "internal"), the dose (homogeneous dose versus heterogeneous dose), and the dose rate (very high and constant versus low and exponentially decreasing dose rate). The maximum therapeutic benefit one can derive from RNT will be achieved thanks to clever combinations exploiting synergistic interactions, used in the optimal doses and sequences [173] and using biomarkers with an individualized approach.
The main indications of this therapy are cystic adenoid carcinomas, tumors of the sinuses of the face and salivary glands, mucous malignant melanomas, chordomas and chondrosarcomas of the base of the skull, sarcomas of the axial skeleton and soft tissues, unresectable or in resection incomplete, unresectable local recurrences of rectal cancer, large hepatocarcinomas (diameter greater than 4-5 cm), choroid malignant melanomas and eye tumors, prostate tumors, tumors of the cervix, and stage I NSCLC  [188, 194]. All these pathologies to which carbon therapy is applied form a heterogeneous group for which there is a wide variety of therapeutic approaches ranging from surgery to very high-techRT, with or without the combination of several other treatments. According to the ClinicalTrials. gov website, 31 clinical trials comparing C-ions to either protons or photon therapy were found as recruiting, active or completed.
Background Potential habituation could be a safety concern associated with the long-term use of bisacodyl in patients with constipation. Objective In this study, we evaluated whether patients with constipation who require long-term treatment with bisacodyl will remain on a stable dose when treated for ≥ 28 days. Methods In this retrospective, population-based, observational cohort study, electronic medical record data of adult patients with constipation between January 1, 2011, and December 31, 2019, were collected from The Health Improvement Network French database. Total bisacodyl exposure during the long-term (≥ 28 days) and follow-up (12 months) periods was evaluated. The primary endpoint was the dose change status of bisacodyl during the follow-up period from the initial dose in the long-term cohort.
Results Out of 5725 bisacodyl users in the database, 218 patients qualified to be part of the long-term cohort. A total of 166 (76. 1%), 37 (17%), and 15 (6. 9%) patients were initiated on bisacodyl at 5, 7. 5, and 10 mg, respectively. During the follow-up, most (94%) of the patients remained on the same dose as initially prescribed for the first year. In contrast, only seven (3. 2%) patients had their dose increased (from the initial prescribed dose of 5 mg), and the remaining six (2. 8%) patients decreased their dose (four patients from the 7. 5 mg group and two from the 10 mg group). Conclusion Bisacodyl can be prescribed at a stable dose for > 28 days as most patients remained on their initial prescribed dose during the follow-up period. No signs of habituation were observed in this real-world study.
Extended author information available on the last page of the article Available data on the continuous use of stimulant laxatives do not indicate habituation  [13, 14]. In contrast to more recently approved drugs and polyethylene glycol, available clinical evidence on the long-term use of bisacodyl is limited; hence, real-world data from different sources are helpful to complement the clinical data. Thus, we used information from electronic medical records (EMRs) from The Health Improvement Network (THIN) French database. THIN is a large European database with fully anonymized and non-extrapolated patient data for research on laxatives. This allows for capturing disease management data in realworld practice. In this study, we aimed to investigate whether patients with constipation who require long-term use of bisacodyl remain on a stable dose after continuous long-term utilization beyond 28 days.
Study Design This was a retrospective, population-based, observational cohort study that used patients' EMR data from THIN French database to analyze the long-term management of chronic constipation with bisacodyl in adult patients between January 1, 2011, and December 31, 2019. The database is European General Data Protection Regulation compliant and provides fully anonymized and non-extrapolated physicianlevel patient EMR data of more than 3. 9 million patients per year. Though this database provides patient data at both general practitioner (GP) and specialist level, in this study, we considered only the records of GPs. This study was performed in accordance with the guidelines for the International Conference on Harmonisation, Good Clinical Practice, Good Pharmacoepidemiology Practice, and the Declaration of Helsinki.
Patient Eligibility Criteria The study included adult patients (≥ 18 years of age) diagnosed with constipation and who had exposure to bisacodyl treatment for at least 28 days. Patients were considered eligible if they had at least one event with an International Classification of Diseases 10th Revision (ICD-10) code related to constipation (K590, constipation; K599, functional intestinal disorder, unspecified; or R194, change in bowel habit). Patients prescribed with at least one additional bisacodyl dose during the follow-up period without any missing information on dosage and prescription duration during the index and follow-up periods were eligible to participate in the study. Patients were excluded if they had secondary constipation due to celiac disease or inflammatory bowel diseases; were diagnosed once with irritable bowel syndrome; had at least one drug abuse of laxatives during the baseline period; missed participating in the study follow-up continuously (without an active presence in the database) for 12 months; or lacked a continuous active presence in the database for 6 months during the baseline period.
Study Outcomes Baseline characteristics were defined by patient demographics, medical history, and associated comorbidities commonly recorded in THIN database. The total bisacodyl exposure of at least 28 days was calculated over one single or multiple prescriptions allowing for a maximum gap of 3 days between each prescription in case of multiple prescriptions. Multiple prescriptions were combined into one single continuous treatment using a common programming approach within the database. The gaps of at least 3 days between two single prescriptions were identified to calculate refills and determine the continuous treatment duration. If there was no treatment gap of at least 3 days between two prescriptions, they were considered one single prescription. The duration of this new single prescription represents the total duration of the contributing prescriptions.
Patient Disposition The study enrolled 5725 bisacodyl users from THIN French EMR database. A total of 3863 (67. 5%) patients had longterm bisacodyl exposure, of which 15% of patients (n = 579) had at least one bisacodyl prescription during the 1-year follow-up period; 7. 0% (n = 270) had continuous enrolment for 6 months during the baseline period, and 5. 8% (n = 224) had continuous enrolment for 12 months during the follow-up period. Bisacodyl dose and exposure duration were available for 218 (5. 6%) patients during both the index and follow-up periods (long-term cohort) (Fig. 1 ).
These misperceptions by physicians are mainly due to historical, anecdotal evidence and unwarranted fears  [22]. Chronic constipation is a common condition that impairs the quality of life of men and women of all ages  [23]. Hence, safe and clinically effective treatment over a prolonged period is necessary to control constipation symptoms for a longer duration. Furthermore, the existing epidemiological studies indicated that there was no risk with frequent use of stimulant laxatives  [10, 22, [24] [25] [26]. Herein, we described the results of a retrospective observational study of long-term bisacodyl prescription in patients diagnosed and followed by GP for constipation. Our study provides unpublished data on the long-term exposure of bisacodyl in treating constipation using data from THIN French EMR database.
The use of an EMR database containing rich and detailed longitudinal clinical records allowed assessment of disease burden and disease management by the French GPs from a real-world perspective. THIN French database has well-populated data on prescription duration and has been widely used for observational research, including utilization studies, assessment of treatment patterns, and prescription reasons. This study has significant limitations. (i) Bisacodyl is available as both a prescription drug and OTC. THIN French EMR database does not capture OTC data, and thus only included patients who received bisacodyl via prescription. These patients might have more severe, difficult to manage constipation compared with OTC users. (ii) EMR databases are limited to information provided by GPs and specialists who are "part of the network"; this prevents a complete real-world picture of any clinical question studied.
In France, GPs are the main/central referent outside primary care. (iii) The database does not provide full information about the techniques used for disease diagnosis; it only provides the diagnosis results. (iv) Potential selection bias could also be a limitation due to the retrospective nature of the study; however, sensitivity analysis confirmed that no bias was induced by inclusion and exclusion criteria on the profile of our analysis population. Through the database, we explored dose changes of bisacodyl after continuous long-term utilization for at least 28 days and the characteristics of patients with constipation. Approximately 95% of the total population was confirmed for constipation with the help of ICD-10 coding. The ICD-10 code gives a clear impression of the investigated population (Supplementary Table  S1 , see ESM).
Out of the total bisacodyl users identified in THIN French EMR database, nearly three quarters had at least one long-term bisacodyl exposure for at least 28 days during the eligibility period. Among the 218 patients who were designated as the long-term cohort, the most common initial treatment dose of bisacodyl was 5 mg (76. 1%), and this indicates that most prescriptions followed the advice to start with the lower 5 mg dose as given in the product leaflet and the summary of product characteristics  [9, 18]. Results from the baseline parameters suggested that the overall population in the long-term cohort is consistent with the population with chronic constipation described previously  [1] ; the majority of patients were elderly and female (62. 4%) with an average body mass index (BMI) of 28.
In this study, a small proportion of patients either increased or decreased their dose within the approved dose range (except for one whose dose increased to 15 mg). Of note, no repeated increases in the bisacodyl dose were observed despite a considerable proportion of patients with comedications and comorbidities. These associated comorbidities might have deteriorated and led to a dose increase in these patients. Using an existing real-world database reflecting primary care management, this type of real-world study offers an opportunity to look into long-term data and, therefore, complements the available data. Overall, the study results for France are consistent with those of a previous real-world study conducted in Germany, which showed that bisacodyl could be prescribed for long-term use with well-maintained efficacy  [13].
Moreover, we observe an impairment of calcium channel transport and a cell metabolism imbalance leading to cellular edema that harms cardiomyocytes  [9]. Currently, more than 130 different mutations causing ATTRv amyloidosis are reported. The clinical presentation depends on the type of mutation. However, the peripheral nervous system and the heart are commonly affected  [10]. Patients with ATTRv are often diagnosed after the 6th decade of life. Val122Ile, present in 3. 4% of the African Americans, is the most common mutation in the United States, followed by Thr60 Ala, which is found in individuals of Irish descent. In France, a recent national registry data showed that 8% of patients referred for hypertrophic cardiomyopathy are TTR mutated  [11]. ATTRwt is primarily seen in elderly persons and mainly manifests itself with the phenotype of cardiomyopathy.