This article proposes a narrative of city contestations beyond policy and programs. It considers why Indian metro elites, large land developers and international donors paradoxically lobby for ...comprehensive planning when confronting ‘vote bank politics’ by the poor. Poor groups, claiming public services and safeguarding territorial claims, open up political spaces that appropriate institutions and fuel an economy that builds complex alliances. Such spaces, here termed ‘occupancy urbanism’, are materialized by land shaped into multiple de‐facto tenures deeply embedded in lower bureaucracy. While engaging the state, these locality politics remain autonomous of it. Such a narrative views city terrains as being constituted by multiple political spaces inscribed by complex local histories. This politics is substantial and poses multiple crises for global capital. Locally embedded institutions subvert high‐end infrastructure and mega projects. ‘Occupancy urbanism’ helps poor groups appropriate real estate surpluses via reconstituted land tenure to fuel small businesses whose commodities jeopardize branded chains. Finally, it poses a political consciousness that refuses to be disciplined by NGOs and well‐meaning progressive activists and the rhetoric of ‘participatory planning’. This is also a politics that rejects ‘developmentalism’ where ‘poverty’ is ghettoized via programs for ‘basic needs’ allowing the elite ‘globally competitive economic development’.
Résumé
Cet article rend compte des contestations urbaines au‐delà de l’action publique et des programmes. Il porte sur les raisons pour lesquelles les élites métropolitaines indiennes, de gros aménageurs fonciers et des donateurs internationaux plaident paradoxalement pour un urbanisme complet lorsque la politique de vote bank se heurtent aux pauvres. Ces groupes, qui réclament des services publics et gardent des revendications territoriales, ouvrent des espaces politiques qui s’approprient des institutions et alimentent une économie aux alliances complexes. Ces espaces, dénommés “urbanisme d’occupation”, sont matérialisés par des terrains formés de multiples occupations de fait, profondément ancrées dans les échelons inférieurs de l’administration. Même si elle implique l’État, la politique de ces localités demeure autonome à son égard. D’après cet exposé, les terrains urbains sont constitués de nombreux espaces politiques aux historiques locaux complexes. Cette politique, non négligeable, est source de problèmes pour le capital mondial. En effet, des institutions ancrées au plan local bouleversent d’énormes projets d’infrastructure haut de gamme. “L’urbanisme d’occupation” aide les groupes pauvres à s’approprier les excédents immobiliers grâce à des modes de jouissance fonciers reconstitués pour stimuler de petites entreprises dont les produits menacent des chaînes de marque. Enfin, elle suscite une conscience politique qui refuse la discipline des ONG ou des partisans progressistes bien intentionnés, de même que la rhétorique de “l’aménagement participatif”. Cette politique rejette aussi un “développementalisme” où la pauvreté est “ghettoïsée” par des programmes en faveur des “besoins fondamentaux” qui permettent aux élites un “développement économique compétitif au plan mondial”.
VACTERL/VATER Association Solomon, Benjamin D
Orphanet journal of rare diseases,
08/2011, Letnik:
6, Številka:
1
Journal Article
Recenzirano
Odprti dostop
VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal ...fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.
Treatment strategies for patients with advanced solid tumors have traditionally been based on three different paradigms: surgery, cytotoxics (chemotherapy or radiation therapy) and targeted ...therapies. Immunotherapy has emerged as a novel treatment paradigm in our armamentarium. Unfortunately, most patients still do not benefit from immunotherapy. These patients often have “cold tumors” characterized by a paucity of effector T cells in the tumor microenvironment, low mutational load, low neoantigen burden and often an immunosuppressive tumor microenvironment. TIGIT is an immunoreceptor inhibitory checkpoint that has been implicated in tumor immunosurveillance. Expression of TIGIT has been demonstrated in both NK cells and T cells and plays a role in their activation and maturation. TIGIT competes with immunoactivator receptor CD226 (DNAM-1) for the same set of ligands: CD155 (PVR or poliovirus receptor) and CD112 (Nectin-2 or PVRL2). TIGIT’s role in tumor immunosurveillance is analogous to the PD-1/PD-L1 axis in tumor immunosuppression. Both TIGIT and PD-1 are upregulated in a variety of different cancers. Anti-TIGIT antibodies have demonstrated synergy with anti-PD-1/PD-L1 antibodies in pre-clinical models. Currently, there are multiple first-in-man phase I trials hoping to exploit this new pathway and improve response rates with existing immunotherapies.
Large-language models like ChatGPT have recently received a great deal of attention. One area of interest pertains to how these models could be used in biomedical contexts, including related to human ...genetics. To assess one facet of this, we compared the performance of ChatGPT versus human respondents (13,642 human responses) in answering 85 multiple-choice questions about aspects of human genetics. Overall, ChatGPT did not perform significantly differently (p = 0.8327) than human respondents; ChatGPT was 68.2% accurate, compared to 66.6% accuracy for human respondents. Both ChatGPT and humans performed better on memorization-type questions versus critical thinking questions (p < 0.0001). When asked the same question multiple times, ChatGPT frequently provided different answers (16% of initial responses), including for both initially correct and incorrect answers, and gave plausible explanations for both correct and incorrect answers. ChatGPT's performance was impressive, but currently demonstrates significant shortcomings for clinical or other high-stakes use. Addressing these limitations will be important to guide adoption in real-life situations.
Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with
-positive non-small-cell lung cancer (NSCLC). The efficacy of ...lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced
-positive NSCLC is unclear.
We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced
-positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.
The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval CI, 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively.
In an interim analysis of results among patients with previously untreated advanced
-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.).
There are thousands of different clinical genetic tests currently available. Genetic testing and its applications continue to change rapidly for multiple reasons. These reasons include technological ...advances, accruing evidence about the impact and effects of testing, and many complex financial and regulatory factors.
This article considers a number of key issues and axes related to the current and future state of clinical genetic testing, including targeted versus broad testing, simple/Mendelian versus polygenic and multifactorial testing models, genetic testing for individuals with high suspicion of genetic conditions versus ascertainment through population screening, the rise of artificial intelligence in multiple aspects of the genetic testing process, and how developments such as rapid genetic testing and the growing availability of new therapies for genetic conditions may affect the field.
Genetic testing is expanding and evolving, including into new clinical applications. Developments in the field of genetics will likely result in genetic testing becoming increasingly in the purview of a very broad range of clinicians, including general paediatricians as well as paediatric subspecialists.
Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1. ...We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive non-small-cell lung cancer (NSCLC).
In this open-label, single-arm, phase 1–2 trial, we enrolled patients (aged ≥18 years) with histologically or cytologically confirmed advanced ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28 hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov, NCT01970865.
Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21·1 months (IQR 15·2–30·3). 13 (62%; 95% CI 38–82) of 21 TKI-naive patients and 14 (35%; 21–52) of 40 patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in seven (64%; 95% CI 31–89) of 11 TKI-naive patients and 12 (50%; 29–71) of 24 previous crizotinib-only patients. The most common grade 3–4 treatment-related adverse events were hypertriglyceridaemia (13 19% of 69 patients) and hypercholesterolaemia (ten 14%). Serious treatment-related adverse events occurred in five (7%) of 69 patients. No treatment-related deaths were reported.
Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent.
Pfizer.
Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or ...illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.
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