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Background: Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome–positive leukemias. Herein, we report the long‐term follow‐up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Methods: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6‐month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Results: Fifty‐one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21–75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2–25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second‐line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6‐month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24‐month event‐free survival rate was 97%. After a median follow‐up of 128 months, the 10‐year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Conclusion: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio‐/vaso‐occlusive and other severe toxicities. Treatment with ponatinib in the frontline setting of chronic myeloid leukemia in chronic phase was associated with high molecular response rates, with 12‐month cumulative rates of major molecular response and MR4 of 82% and 72%, respectively. However, it was associated with an increased incidence of toxicity, in particular serious grade 2‐3 cardiovascular adverse events in 16% of the patients. [ABSTRACT FROM AUTHOR]

Although terrorist disengagement is a dynamic process, this study proposes the likelihood of a continuity in the prevailing factors influencing exit from terrorism and the prevailing dimensions which initially influenced violent radicalization. Through the analysis of two contrasting cases featuring third-generation Muslims formerly involved in jihadist activities in Spain, we assess a connection between the prevailing push and pull factors which sparked individuals to cease their terrorist engagement and the predominant dimensions that earlier prompted the radicalization which led them to terrorist involvement. Drawing from in-depth interviews with the two former jihadists, Hassan and Omar, conducted while they were serving prison sentences for terrorism offences, we suggest that the significance of ideology and network in, respectively, their journeys from Islamic fundamentalism towards jihadism is similarly reflected in their accounts of ending jihadist involvement, even in the presence of secondary factors that also play a role in such a complex process.

This article explores the characteristics of Jewish third-generation (post-Shoah) experiential writing through the poetry collection Under månen (2020) by author Hanna Rajs. Discussing the portrayal of Jewish identity, coupled with a specific generational situatedness, twice removed from the Shoah yet carrying the responsibility of its memory into the future, the article reveals how the lyrical subject negotiates belonging and memory on various levels: individual, familial, communal, and collective. By engaging with acts of self-positioning, the subject travels dynamically across temporal and spatial borders through memory. This, in turn, underlines the forward direction of third-generation writing as well as its outward reach, combining cultural and communicative memory and playing with lyric address. The poetry drives readers to engage with memory of the Shoah and the experience of being Jewish today as mediated through one lyrical subject's lens.

In addressing the issue of narrative ethics and its intersection with writing and remembering the Holocaust from a position of historical and generational distance, this paper probes challenges of third-generation Holocaust representation. For this generation of postmemory, Auschwitz has become the defining marker of Holocaust memory. Even for those whose memories do not directly lead them back there, the collective lens retains this focal point. In demonstrating that memory need not rely on what has become a generic site of pain, I explore options for 'leaving' Auschwitz, as it were, while still preserving Holocaust memory continuity. In doing so, I focus on two contrasting examples of Holocaust narrative, authored respectively by Heather Morris and Eduardo Halfon, citing Esther Jilovsky's parameters of thirdgeneration narrative. I conclude that leaving Auschwitz behind, metaphorically, as well as contextually, need not be the end of Holocaust history, rather a signalling of a different path forward in respect to its ethical, respectful and meaningful preservation. [ABSTRACT FROM AUTHOR]

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies. [ABSTRACT FROM AUTHOR]

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This article presents a theoretical formulation that names an experience that is common to many third-generation protagonists in the literature written by the grandchildren of Holocaust survivors: postnostalgia. Postnostalgia is an adopted "nostalgia"—though it not actually nostalgia—for a place and a time that descendants have never lived but long for as if they have. This almost-form of "nostalgia" is powerful because it is an affective and persistent response to the particular places to which they are connected, given how their families once occupied those milieus. This article treats Jonathan Safran Foer's Everything Is Illuminated, which serves as a representation of how third-generation protagonists commonly attempt to discover pre-Shoah life by visiting the sites of family life in their family's native lands. This formulation of postnostalgia offers insight into how survivors' descendants in third-generation literature have responded to their inherited traumas, elucidating the common phenomenon of what is referred to as "pilgrimages" to sites of pre-Shoah family life. [ABSTRACT FROM AUTHOR]

Background/objective: The purpose of this study was to report the outcomes of a clinical trial conducted in Japan to assess the safety and effectiveness of third-generation autologous chondrocyte implantation (ACI) using IK-01 (CaReS™), which does not require flap coverage, in the treatment of patients with focal cartilage injury of the knee. Methods: This was an open label, exploratory clinical trial. Patients were enrolled between June 2012 and September 2016. The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 52 weeks after implantation. The IKDC, Lysholm, and visual analog scale (VAS) scores were evaluated at the time of screening and at 4, 12, 24, 36, and 52 weeks after implantation. Improvements from the baseline scores were evaluated using the equation “(postoperative score) − (preoperative score).” Magnetic resonance imaging (MRI) was performed at 2, 12, 24, and 52 weeks after implantation, and MRI measurements were evaluated using T1 rho and T2 mapping. Results: Nine patients were enrolled in this study and were examined for safety. Product quality did not satisfy the specification in one patient, and bacterial joint infection occurred in one patient. As a result, seven patients were included in the outcome analyses. The mean IKDC score significantly improved from 36.4 preoperatively to 74.1% at 52 weeks after implantation (p

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

Abstract Background As the use of nanopore sequencing for metagenomic analysis increases, tools capable of performing long-read taxonomic classification (ie. determining the composition of a sample) in a fast and accurate manner are needed. Existing tools were either designed for short-read data (eg. Centrifuge), take days to analyse modern sequencer outputs (eg. MetaMaps) or suffer from suboptimal accuracy (eg. CDKAM). Additionally, all tools require command line expertise and do not scale in the cloud. Results We present BugSeq, a novel, highly accurate metagenomic classifier for nanopore reads. We evaluate BugSeq on simulated data, mock microbial communities and real clinical samples. On the ZymoBIOMICS Even and Log communities, BugSeq (F1 = 0.95 at species level) offers better read classification than MetaMaps (F1 = 0.89–0.94) in a fraction of the time. BugSeq significantly improves on the accuracy of Centrifuge (F1 = 0.79–0.93) and CDKAM (F1 = 0.91–0.94) while offering competitive run times. When applied to 41 samples from patients with lower respiratory tract infections, BugSeq produces greater concordance with microbiological culture and qPCR compared with “What’s In My Pot” analysis. Conclusion BugSeq is deployed to the cloud for easy and scalable long-read metagenomic analyses. BugSeq is freely available for non-commercial use at https://bugseq.com/free .

Purpose: The aim of our study was to prospectively evaluate the role of third-generation, dual-source, dual-energy computed tomography (DECT) in the characterization of renal calculi, with ex vivo renal stone evaluation using Fourier transform infrared spectroscopy (IS) as the reference standard. Material and methods: In our study 50 patients with history suggestive of renal calculi were subjected to DECT using 100 kVp and Sn150 kVp. With DECT, renal stone attenuation at low and high kVp was attained, and the attenuation ratios were measured. The result of DECT was compared with IS to identify the chemical composition of the extracted renal stones. IBM SPSS version 22 was used for statistical analysis. Results: In our study, the mean attenuation ratio of the renal stone was 1.57 ± 0.25. Out of 50 patients, the stones of 39 patients were predicted as calcium-containing stones, in 4 patients as cystine stones, and in 7 as uric acid stones on DECT. In IS analysis, 43 patients had calcium-containing stones, and 7 patients had uric acid stones. The accuracy rate of DECT for detecting calcium and uric acid stones in our study were 90% and 100%, respectively. The positive predictive value for the DECT to assess the chemical composition of renal calculi was found to be 92%. Conclusions: Third-generation DECT scan had 100% accuracy in differentiating uric acid stones from non-uric acid stones in our study. Because the treatment is different for different chemical compositions of stones, identification of specific chemical components is very important, and it can be accurately done by DECT. [ABSTRACT FROM AUTHOR]

Genomes represent the starting point of genetic studies. Since the discovery of DNA structure, scientists have devoted great efforts to determine their sequence in an exact way. In this review we provide a comprehensive historical background of the improvements in DNA sequencing technologies that have accompanied the major milestones in genome sequencing and assembly, ranging from early sequencing methods to Next-Generation Sequencing platforms. We then focus on the advantages and challenges of the current technologies and approaches, collectively known as Third Generation Sequencing. As these technical advancements have been accompanied by progress in analytical methods, we also review the bioinformatic tools currently employed in de novo genome assembly, as well as some applications of Third Generation Sequencing technologies and high-quality reference genomes.

Anglophone African poetry has become a significant medium through which African society from the year 2000 to date is mirrored. The younger Anglophone African poets, widely referred to as the poets of the third-generation, have always used their poetry as means to respond to both historical and current socio-political circumstances that tend to distinguish Africa from the rest of the world. Their poetry now constitutes counter-hegemonic discourse against bad leadership in Africa and against corrupt African social and medical institutions. Using Hyginus Ekwuazi's The Monkey's Eyes as a representative poetry of the younger Anglophone African poets, emphasis is made on how the poet depicts the African society and its hospitals. The paper analyzes the collection as a sequel to all other collections of poetry produced by the younger poets at this period. It reveals the condition in which the poetry is produced and how it has responded to the decay in African society and its hospitals. The paper points out that though the older generation of the Anglophone African poets responded to similar socio-political situation, the younger generation of the Anglophone African poets has become the prominent voice in this period and that their poetry provides a clear picture of what is happening in Africa within this time space. Being a new set of voices on the terrain of the Anglophone African poetry, a study of this poetry opens up a new platform upon which this so-called "aesthetic of rage" is appreciated.

Objective To investigate the quasispecies variation characteristics of HBV in Tibetan population based on the third-generation sequencing. Methods An epidemiological investigation of hepatitis B virus was conducted by our department of infectious disease in southern Tibet from May 2016 to July 2017. A total of 24 HBsAg positive subjects were obtained in this investigation and were assignd into the plateau Tibetan group, and then another 24 cases subjected from our outpatient department were recruited and served as the plain Han control group. Their HBV DNA was extracted, and the full virus sequence was amplified to build a whole genome sequencing library, and then sequenced on the third-generation sequencing platform PacBio RSⅡ. Biological information tools such as ClustalW, MEGA and SimPlot were used to analyze the quasispecies characteristics. Results Totally 29 samples were successfully amplified and sequenced finally, including 9 cases from the Tibetan group with an average of 65 quasispecies sequences per sample, and 20 cases from the control group with an average of 124 quasispecies sequences per sample. After comparative analysis, 7 cases (7/9, 77.8%) of typeC/D1 HBV were found in the Tibetan group with recombining at 750 nt by type D4 and type C2 HBV, 1 case of type C/D2 HBV was recombined by type D3 and type C2 HBV at 1 500 nt, and the rest 1 was type C2. The quasispecies complexity and nonsynonymous mutation ratio of HBV preC/C gen was highere in the Tibetan group than the control group. Variation spectrums of nucleic acid were different between the recombinant HBV and the control. The nucleic acid mutation of the C/D recombinant HBV was mainly in EnhⅡ, BCP, and preS regions, while the HBV sequences in the control group were dominated by mutations in preC, S, and X regions besides BCP and preS regions. Conclusion The C/D recombinant strain is the dominant strain of HBV in Tibetans, and C/D1 HBV is more common. The quasispecies complexity and nonsynonymous mutation ratio of HBV preC/C in Tibetans are higher than those of the Han, While the variants of nucleotide mainly occur in the Enh Ⅱ, BCP, and preS regions

Background: As the use of nanopore sequencing for metagenomic analysis increases, tools capable of performing long-read taxonomic classification (ie. determining the composition of a sample) in a fast and accurate manner are needed. Existing tools were either designed for short-read data (eg. Centrifuge), take days to analyse modern sequencer outputs (eg. MetaMaps) or suffer from suboptimal accuracy (eg. CDKAM). Additionally, all tools require command line expertise and do not scale in the cloud. Results: We present BugSeq, a novel, highly accurate metagenomic classifier for nanopore reads. We evaluate BugSeq on simulated data, mock microbial communities and real clinical samples. On the ZymoBIOMICS Even and Log communities, BugSeq (F1 = 0.95 at species level) offers better read classification than MetaMaps (F1 = 0.89–0.94) in a fraction of the time. BugSeq significantly improves on the accuracy of Centrifuge (F1 = 0.79–0.93) and CDKAM (F1 = 0.91–0.94) while offering competitive run times. When applied to 41 samples from patients with lower respiratory tract infections, BugSeq produces greater concordance with microbiological culture and qPCR compared with "What's In My Pot" analysis. Conclusion: BugSeq is deployed to the cloud for easy and scalable long-read metagenomic analyses. BugSeq is freely available for non-commercial use at https://bugseq.com/free. [ABSTRACT FROM AUTHOR]

Objective Previous experimental research has yielded inconclusive findings regarding the effects of Holocaust trauma to survivors’ descendants, while qualitative studies have suggested diverse long‐term impacts of this traumatic past. While the extant literature has focused mainly on Israeli and North American children of survivors, this study drew on theories of transgenerational trauma transmission to explore the lived experiences of six Jewish Australian grandchildren of Holocaust survivors. Method Data from semi‐structured interviews were analyzed using interpretative phenomenological analysis to investigate how the impacts of historical trauma are experienced across generations in an Australian sample. Results The impact of their grandparents’ Holocaust experiences was found to echo across the participants’ affective experiences, their sense of connection to family histories, their understanding of being different to others, and their political and ethical values. An analysis of these findings suggested that the participants define themselves in a collective manner as part of a group of survivors’ descendants, with their post‐Holocaust positioning existing in a state of tension alongside their Australian identity. Conclusions This study extends the literature on transgenerational trauma by shedding light on how the identities of Australian grandchildren of Holocaust survivors continue to be profoundly informed by their identification with familial narratives of trauma, despite their generational distance from the Holocaust.

Many cities engage in diverse experimentation, innovation, and development activities with a broad variety of environments and stakeholders to the benefit of citizens, companies, municipalities, and other organizations. Hence, this article discusses such engagement in terms of next-generation living lab networks in the city context. In so doing, the study contributes to the discussion on living labs by introducing a framework of collaborative innovation networks in cities and suggesting a typology of third-generation living labs. Our framework is characterized by diverse platforms and participation approaches, resulting in four distinctive modes of collaborative innovation networks where the city is: i) a provider, ii) a neighbourhood participator, iii) a catalyst, or iv) a rapid experimenter. The typology is based on an analysis of 118 interviews with participants in six Finnish cities and reveals various ways to organize innovation activities in the city context. In particular, cities can benefit from innovation networks by simultaneously exploiting multiple platforms such as living labs for innovation. We conclude by discussing implications to theory and practice, and suggesting directions for future research.

Anglophone African poetry has become a significant medium through which African society from the year 2000 to date is mirrored. The younger Anglophone African poets, widely referred to as the poets of the third-generation, have always used their poetry as means to respond to both historical and current sociopolitical circumstances that tend to distinguish Africa from the rest of the world. Their poetry now constitutes counter-hegemonic discourse against bad leadership in Africa and against corrupt African social and medical institutions. Using Hyginus Ekwuazi's The Monkey's Eyes as a representative poetry of the younger Anglophone African poets, emphasis is made on how the poet depicts the African society and its hospitals. The paper analyzes the collection as a sequel to all other collections of poetry produced by the younger poets at this period. It reveals the condition in which the poetry is produced and how it has responded to the decay in African society and its hospitals. The paper points out that though the older generation of the Anglophone African poets responded to similar socio-political situation, the younger generation of the Anglophone African poets has become the prominent voice in this period and that their poetry provides a clear picture of what is happening in Africa within this time space. Being a new set of voices on the terrain of the Anglophone African poetry, a study of this poetry opens up a new platform upon which this so-called "aesthetic of rage" is appreciated. [ABSTRACT FROM AUTHOR]

This article examines how Jonathan Safran Foer's first novel Everything is Illuminated, as a post-trauma narrative that challenges its own limits of representation, attempts to make the reader 'access' the Holocaust through a form of 'traumatic realism,' to take Michael Rothberg's concept. This analysis focuses on the figures of silence and absence through the study of place as a 'non-lieu de mémoire,' before exploring the way in which traumatic memory is performed through testimony and its narrative fragmentation. The article concludes by discussing how this literary aesthetics is a way for the author to respond to an ethics of (re)presentation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Previous experimental research has yielded inconclusive findings regarding the effects of Holocaust trauma to survivors’ descendants, while qualitative studies have suggested diverse long‐term impacts of this traumatic past. While the extant literature has focused mainly on Israeli and North American children of survivors, this study drew on theories of transgenerational trauma transmission to explore the lived experiences of six Jewish Australian grandchildren of Holocaust survivors. Method: Data from semi‐structured interviews were analyzed using interpretative phenomenological analysis to investigate how the impacts of historical trauma are experienced across generations in an Australian sample. Results: The impact of their grandparents’ Holocaust experiences was found to echo across the participants’ affective experiences, their sense of connection to family histories, their understanding of being different to others, and their political and ethical values. An analysis of these findings suggested that the participants define themselves in a collective manner as part of a group of survivors’ descendants, with their post‐Holocaust positioning existing in a state of tension alongside their Australian identity. Conclusions: This study extends the literature on transgenerational trauma by shedding light on how the identities of Australian grandchildren of Holocaust survivors continue to be profoundly informed by their identification with familial narratives of trauma, despite their generational distance from the Holocaust. [ABSTRACT FROM AUTHOR]

Many cities engage in diverse experimentation, innovation, and development activities with a broad variety of environments and stakeholders to the benefit of citizens, companies, municipalities, and other organizations. Hence, this article discusses such engagement in terms of next-generation living lab networks in the city context. In so doing, the study contributes to the discussion on living labs by introducing a framework of collaborative innovation networks in cities and suggesting a typology of third-generation living labs. Our framework is characterized by diverse platforms and participation approaches, resulting in four distinctive modes of collaborative innovation networks where the city is: i) a provider, ii) a neighbourhood participator, iii) a catalyst, or iv) a rapid experimenter. The typology is based on an analysis of 118 interviews with participants in six Finnish cities and reveals various ways to organize innovation activities in the city context. In particular, cities can benefit from innovation networks by simultaneously exploiting multiple platforms such as living labs for innovation. We conclude by discussing implications to theory and practice, and suggesting directions for future research. [ABSTRACT FROM AUTHOR]

Reynolds's research examines the ways in which third-generation Holocaust writers, the grandchildren of Holocaust survivors, approach the subject of their own traumatic history and the intergenerational transmission of trauma and memory. Despite the two generational divide that separates the third generation from the preceding two generations of Holocaust writers, the transgenerational transmission of trauma continues to preoccupy contemporary narratives. This research examines the ways the grandchildren of survivors, represented in this paper by Margot Singer and Jonathan Safran Foer, confront and include lost worlds in their narratives as well as their attempts to resurrect these fractured pasts through innovative uses of imaginative leaps. The third generation continues to suffer from the intergenerational transmission of trauma and memory yet discovers innovative ways to share that trauma, evidence of evolving modes of bearing witness. [ABSTRACT FROM AUTHOR]

Algal biomass is a promising raw material for production of third-generation biohydrogen. Few studies have investigated how the concentration of galactose, the main monosaccharide of algae biomass, affects fermentative production of H 2 . We isolated a new culture of H 2 -producing bacterium from an anaerobic sludge. This culture was identified as Clostridium beijerinckii based on the sequence of the 16S rRNA gene and was named C. beijerinckii Br21 (KT626859). The isolated culture produced the highest amount of H 2 at 35 °C and initial pH 7. The isolate used many carbon sources to produce H 2 , including the monosaccharides glucose, galactose, and mannose resulting from algae biomass hydrolysis. For the first time, fermentation batch tests based on galactose as carbon source showed that production of H 2 by a C. beijerinckii strain depended on the concentration of galactose. Galactose at 15 g/L provided the highest rate and yield of H 2 production, 117.45 mL of H 2 /L·h and 2.02 mol of H 2 /mole of galactose, respectively; the main metabolites from galactose fermentation were butyric acid (61%) and acetic acid (24%). Therefore, C. beijerinckii Br21 is a promising candidate for fermentative production of H 2 from galactose and algae biomass. [ABSTRACT FROM AUTHOR]

There is a long history of universities perceiving residences as pivotal in the learning process. Over the last 50 years, the nature and efficacy of residential environments as an educational tool have been extensively researched. However, within some sections of the tertiary residential sector, in the United States, the United Kingdom, New Zealand and Australia, the emphasis has gradually shifted away from the primacy of learning towards a view of accommodation simply in terms of housing. Public–private partnerships, emphasising facilities rather than learning, have proliferated. However, although the context for learning is different, residential environments should meet the same pedagogic standards as coursework. After reviewing the critical literature on the ways in which residences contribute to performance, engagement, retention and transition of students, this article proposes policy and personnel changes that may assist universities to implement effective interventions through second- and third-generation pedagogies. [ABSTRACT FROM PUBLISHER]

Summary: Background: In approximately the year 2000, the results of a number of important studies of non-small-cell lung cancer (NSCLC) were published. Methods: Between July 1992 and December 2003, 223 patients with NSCLC aged ≥70 years received chemotherapy alone as their initial treatment at the National Cancer Center Hospital East. These patients were divided into 2 groups: those that began treatment between 1992 and 1999 (group A) and between 2000 and 2003 (group B). The details of chemotherapy regimens and outcomes were compared. Results: In group A, 83% of patients received platinum-based chemotherapy, two-thirds of these regimens comprised platinum plus second-generation combination chemotherapy. In contrast, although 55% of patients received platinum-based chemotherapy in group B, 41% of patients received non-platinum-based chemotherapy. Among patients in group B, performance status was significantly associated with the selection of platinum-based or non-platinum-based chemotherapy; age was marginally associated with this selection. Median survival time (MST), 1-year survival rate, and 2-year survival rate were 6.7 months, 14%, and 7%, respectively, in group A, and 8.1 months, 35%, and 20% in group B (p =0.0109). Multivariate analysis revealed that clinical stage and administration of salvage chemotherapy were independent prognostic factors. Conclusions: In and after the year 2000, chemotherapy regimens changed greatly and survival of elderly patients significantly improved in our institute, and this improvement appears to be attributable mostly to the effect of salvage chemotherapy. These results suggest that even elderly patients should be offered salvage chemotherapy regardless of age, if possible. [Copyright &y& Elsevier]

The objective of this study was to assess the influence of oral contraceptives (OCs) on the risk of venous thromboembolism (VTE) in young women. A 5-year case-control study including all Danish hospitals was conducted. All women 15–44 years old, suffering a first ever deep venous thrombosis or a first pulmonary embolism (PE) during the period January 1, 1994, to December 30, 1998, were included. Controls were selected annually, 600 per year in 1994–1995 and 1200 per year 1996–1998.Response rates for cases and controls were 87.2% and 89.7%, respectively. After exclusion of nonvalid diagnoses, pregnant women, and women with previous thrombotic disease, 987 cases and 4054 controls were available for analysis.A multivariate, matched analysis was performed. Controls were matched to cases within 1-year age bands. Adjustment was made for confounding influence (if any) from the following variables: age, year, body mass index, length of OC use, family history of VTE, cerebral thrombosis or myocardial infarction, coagulopathies, diabetes, years of schooling, and previous birth.The risk of VTE among current users of OCs was primarily influenced by duration of use, with significantly decreasing odds ratios (OR) over time: <1 year, 7.0 (5.1–9.6); 1–5 years, 3.6 (2.7–4.8); and >5 years, 3.1 (2.5–3.8), all compared with nonusers of OCs. After adjustment for confounders, current use of OCs with second- (levonorgestrel or norgestimate) and third- (desogestrel or gestodene) generation progestins when compared with nonuse resulted in ORs for VTE of 2.9 (2.2–3.8) and 4.0 (3.2–4.9), respectively. After adjusting for progestin types and length of use, the risk decreased significantly with decreasing estrogen dose. With 30–40 μg as reference, 20 and 50 μg products implied ORs of 0.6 (0.4–0.9) and 1.6 (0.9–2.8), respectively (ptrend = 0.02). After correction for duration of use and differences in estrogen dose, the third/second-generation risk ratio was 1.3 (1.0–1.8; p <0.05).In conclusion, use of OCs was associated significantly to the risk of VTE. The risk among current users was reduced by more than 50% during the first years of use. The risk increased more than 100% with increasing estrogen dose, and the difference in risk between users of third- and second-generation OCs, after correction for length of use and estrogen dose, was 33%. [Copyright &y& Elsevier]

Background/objective: The purpose of this study was to report the outcomes of a clinical trial conducted in Japan to assess the safety and effectiveness of third-generation autologous chondrocyte implantation (ACI) using IK-01 (CaReS™), which does not require flap coverage, in the treatment of patients with focal cartilage injury of the knee., Methods: This was an open label, exploratory clinical trial. Patients were enrolled between June 2012 and September 2016. The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 52 weeks after implantation. The IKDC, Lysholm, and visual analog scale (VAS) scores were evaluated at the time of screening and at 4, 12, 24, 36, and 52 weeks after implantation. Improvements from the baseline scores were evaluated using the equation "(postoperative score) - (preoperative score)." Magnetic resonance imaging (MRI) was performed at 2, 12, 24, and 52 weeks after implantation, and MRI measurements were evaluated using T1 rho and T2 mapping., Results: Nine patients were enrolled in this study and were examined for safety. Product quality did not satisfy the specification in one patient, and bacterial joint infection occurred in one patient. As a result, seven patients were included in the outcome analyses. The mean IKDC score significantly improved from 36.4 preoperatively to 74.1% at 52 weeks after implantation (p < 0.0001). The mean Lysholm and VAS scores also significantly improved from 39.6 to 57.4 to 89.6 and 22.9, respectively, after surgery. In the MRI evaluation, the T1 rho and T2 values of the implanted area were similar to those of the surrounding cartilage at 52 weeks after implantation., Conclusions: Third generation ACI (IK-01) can be an effective treatment option for focal cartilage defects of the knee; however, surgeons must pay careful attention to the risk of postoperative joint infection., Competing Interests: None., (© 2022 Asia Pacific Knee, Arthroscopy and Sports Medicine Society. Published by Elsevier (Singapore) Pte Ltd.)

The lentivirus system enables efficient genetic modification of both dividing and non-dividing cells and therefore is a useful tool for elucidating developmental processes and disease pathogenesis. The development of third-generation lentiviruses has resulted in improved biosafety, low immunogenicity, and substantial packaging capabilities. However, because third-generation lentiviruses require successful co-transfection with four plasmids, this typically means that lower titers are attained. This is problematic, as it is often desirable to produce purified lentiviruses with high titers (>1 × 10 8 TU/ml), especially for in vivo applications. The manufacturing process for lentiviruses involves several critical experimental factors that can influence titer, purity, and transduction efficiency. Here, we describe a straightforward, stepwise protocol for the reproducible manufacture of high-titer third-generation lentiviruses (1 × 10 8 to 1 × 10 9 TU/ml). This optimized protocol enhances transgene expression by use of Lipofectamine transfection and optimized serum replacement medium, a single ultracentrifugation step, use of a sucrose cushion, and addition of a histone deacetylation inhibitor. Furthermore, we provide alternate methods for titration analyses, including functional and genomic integration analyses, using common laboratory techniques such as FACS as well as genomic DNA extraction and qPCR. These optimized methods will be beneficial for investigating developmental processes and disease pathogenesis in vitro and in vivo. © 2020 The Authors. Basic Protocol 1: Lentivirus production Support Protocol: Lentivirus concentration Basic Protocol 2: Lentivirus titration Alternate Protocol 1: Determination of viral titration by FACS analysis Alternate Protocol 2: Determination of viral titration by genome integration analysis., (© 2020 The Authors.)

Introduction : Hemophilia A is an inherited disorder that is characterized by decreased or absent factor (F)VIII and an increased risk of bleeding. Clinical presentation of the severe form of the disease includes spontaneous bleeding into the joints and muscles, while patients with milder forms usually exhibit trauma-associated bleeding. The treatment of hemophilia aims to prevent bleeding. A number of clotting FVIII concentrates are available for managing hemophilia A, which have different safety and efficacy characteristics. Advancements in biotechnology have enabled development of recombinant factor concentrates, which thus minimize the risk of transmitting infectious diseases. Turoctocog alfa (NovoEight®, Novo Nordisk A/S, Bagsvaerd, Denmark) was the first third-generation B-domain truncated recombinant FVIII. Areas covered : The manuscript describes the characteristics of turoctocog alfa, as well as its efficacy and safety for prophylaxis and on-demand treatment for patients with severe hemophilia A without inhibitors. Expert opinion : In clinical trials, turoctocog alfa has demonstrated very good efficacy and safety for the prophylaxis and on-demand treatment of hemophilia A patients, as well as high hemostatic activity during surgery and in managing bleeding episodes. Post-marketing studies and real-life data are anticipated to further reinforce the value of long-term prophylaxis, and estimate the incidence of inhibitors to FVIII.

Genomes represent the starting point of genetic studies. Since the discovery of DNA structure, scientists have devoted great efforts to determine their sequence in an exact way. In this review we provide a comprehensive historical background of the improvements in DNA sequencing technologies that have accompanied the major milestones in genome sequencing and assembly, ranging from early sequencing methods to Next-Generation Sequencing platforms. We then focus on the advantages and challenges of the current technologies and approaches, collectively known as Third Generation Sequencing. As these technical advancements have been accompanied by progress in analytical methods, we also review the bioinformatic tools currently employed in de novo genome assembly, as well as some applications of Third Generation Sequencing technologies and high-quality reference genomes., Competing Interests: G.F. had one travel sponsored by Bionano Genomics. A.M.G., G.R.G. and L.G. declare no conflicts of interest., (© 2019 The Authors.)