Intuition and concrete particularity in Kant's transcendental aesthetic

By transcendental aesthetic, Kant means “the science of all principles of a priori sensibility” (A 21/B 35). These, he argues, are the laws that properly direct our judgments of taste (B 35 – 36 fn.), i.e. our aesthetic judgments as we ordinarily understand that notion in the context of contemporary art. Thus the first part of the Critique of Pure Reason, entitled the Transcendental Aesthetic, enumerates the necessary presuppositions of, among other things, our ability to make empirical judgments about particular works of art. These presuppositions are sensible rather than intellectual because on Kant’s view, all intellection that considers objects of any kind, whether abstract or concrete, must at base connect to actual, material objects with which we come into direct contact; and this we can do only through sensibility (A 19/B 33). Thus the following discussion explores what Kant claims must be true of us in order to make the sorts of aesthetic judgments we make, rather than any particular class or quality of aesthetic judgments itself. On Kant’s view, what must be true of us in order to make aesthetic judgments is not different from what must be true of us in order to make any other kind of judgment about empirical objects

It Costs But It Saves the Family

The facts in this interesting story are based on a thesis written by M rs. McCordic for her master’ s degree in Home Management, which she received from Iowa State College in June. Her thesis included a survey of uses o f electrical equipment by Wisconsin and Iowa farm families. Upon receiving her degree, Mrs. McCordic returned to her position as home management specialist in the University of Wisconsin Extension Service

The Politics of Land Ownership in NSW: A Case Study

From 1885 to 1965, successive New South Wales governments made repeated attempts to break up large pastoral estates into family farms. This policy, which became known as closer settlement, was expected to address a range of pressing social and economic problems. This thesis takes a case study approach to assess the impact of this policy in a specific area, the county of Sandon on the NSW northern tablelands. It tests, at the local level, current theory and models of the land question, with the aim of furthering comprehension of this central issue in the development of New South Wales. From the passing of the Crown Lands Act 1884, the NSW government was increasingly intrusive in determining where land settlement should take place, who was permitted to acquire Crown land, and how large their farms should be. By the turn of the century, the attention of both the government and the community at large became focussed on the need to buy back land locked up in the large pastoral estates to create family farms for those who did not already own land. Under legislation passed from 1901 onwards, across the state many thousands of acres of freehold and leasehold land were compulsorily and voluntarily resumed for this purpose. In the county of Sandon, this resulted in some private subdivisions in response to the threat of compulsory resumption, a voluntary resumption in the late 1930s, and both voluntary and compulsory resumptions to provide farms for returned servicemen and women after the two world wars. The impact of closer settlement in the county of Sandon was marginal, in terms of the expected outcomes. A First World War soldier settlement at Kentucky in the south of the county resulted in an increase in the production of stone and pome fruit and a modest increase in population, with many of the soldier settlers being attracted from outside the district. A modest number of settlers came from outside the district to take farms created by the voluntary and compulsory resumptions in the late 1930s and following the Second World War, but otherwise there was no significant population increase. Over time successful farmers bought out their neighbours, and by 1965 most were engaged in the enterprise which had characterised the district in the first half of the nineteenth century, the grazing of sheep and cattle. Thus, there was no long-term change in agricultural output in the county. Based on this evidence, a new model of land settlement is proposed, that there are three forces which interact to determine the size of rural properties: ∙ Government policy which was aimed at creating family farms of what was known as ‘a home maintenance area’, that is, just large enough to support a family in average conditions, undertaking an enterprise best suited to their land; ∙ A tendency for more successful farmers to purchase additional land and so increase the size of their holdings, or to eventually provide farms for their children; and, ∙ A tendency for farms, over time, to either enlarge or contract to a size which is the most efficient. While it would seem that the first force would be the most powerful, since governments had the power to legislate a maximum farm size, the experience in the county of Sandon demonstrated that this was not the case, as there was a marked trend towards properties of an efficient size. Thus, this study has demonstrated that the policy of closer settlement had little impact on the pattern of land settlement

Dynamic changes in methadone utilisation for opioid use disorder treatment: a retrospective observational study during the COVID-19 pandemic

Objectives: Opioid use disorder (OUD) is a major public health concern in the USA, resulting in high rates of overdose and other negative outcomes. Methadone, an OUD treatment, has been shown to be effective in reducing the risk of overdose and improving overall health and quality of life. This study analysed the distribution of methadone for the treatment of OUD across the USA over the past decade and through the COVID-19 pandemic. Design: Retrospective observational study using secondary data analysis of the Drug Enforcement Administration and Medicaid Databases. Setting: USA. Participants: Patients who were dispensed methadone at US opioid treatment programmes (OTPs). Primary and secondary outcome measures: The primary outcomes were the overall pattern in methadone distribution and the number of OTPs in the USA per year. The secondary outcome was Medicaid prescriptions for methadone. Results: Methadone distribution for OUD has expanded significantly over the past decade, with an average state increase of +96.96% from 2010 to 2020. There was a significant increase in overall distribution of methadone to OTP from 2010 to 2020 (+61.00%, p\u3c0.001) and from 2015 to 2020 (+26.22%, p\u3c0.001). However, the distribution to OTPs did not significantly change from 2019 to 2021 (-5.15%, p=0.491). There was considerable state-level variation in methadone prescribing to Medicaid patients with four states having no prescriptions. Conclusions: There have been dynamic changes in methadone distribution for OUD. Furthermore, pronounced variation in methadone distribution among states was observed, with some states having no OTPs or Medicaid coverage. New policies are urgently needed to increase access to methadone treatment, address the opioid epidemic in the USA and reduce overdose deaths

A Rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to informwarfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding,”

Purpose: Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding. Methods: Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications. Results: Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing. Conclusions: The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues. Genet Med 2008:10(2):89 -98

Aquaporin 5 Interacts with Fluoride and Possibly Protects Against Caries

Aquaporins (AQP) are water channel proteins and the genes coding for AQP2, AQP5, and AQP6 are clustered in 12q13. Since AQP5 is expressed in serous acinar cells of salivary glands, we investigated its involvement in caries. DNA samples from 1,383 individuals from six groups were studied. Genotypes of eight single nucleotide polymorphisms covering the aquaporin locus were tested for association with caries experience. Interaction with genes involved in enamel formation was tested. The association between enamel microhardness at baseline, after creation of artificial caries lesion, and after exposure to fluoride and the genetic markers in AQP5 was tested. Finally, AQP5 expression in human whole saliva, after exposure to fluoride in a mammary gland cell line, which is known to express AQP5, and in Wistar rats was also verified. Nominal associations were found between caries experience and markers in the AQP5 locus. Since these associations suggested that AQP5 may be inhibited by levels of fluoride in the drinking water that cause fluorosis, we showed that fluoride levels above optimal levels change AQP5 expression in humans, cell lines, and rats. We have shown that AQP5 is involved in the pathogenesis of caries and likely interact with fluoride.Fil: Anjomshoaa, Ida. University of Pittsburgh; Estados UnidosFil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados UnidosFil: Deeley, Kathleen. University of Pittsburgh; Estados UnidosFil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Mereb, Juan C.. Provincia de Río Negro. Ministerio de Salud. Hospital de Área El Bolsón ; ArgentinaFil: Leite, Aline L.. Universidade de Sao Paulo; BrasilFil: Barreta, Priscila A. T.. Universidade de Sao Paulo; BrasilFil: Silva, Thelma L.. Universidade de Sao Paulo; BrasilFil: Dizak, Piper. University of Pittsburgh; Estados UnidosFil: Ruff, Timothy. University of Pittsburgh; Estados UnidosFil: Patir, Asli. İstanbul Medipol Üniversitesi; TurquíaFil: Koruyucu, Mine. İstanbul Üniversitesi; TurquíaFil: Abbasoğlu, Zerrin. Yeditepe Üniversitesi; TurquíaFil: Casado, Priscila L.. Universidade Federal Fluminense; BrasilFil: Brown, Andrew. University of Pittsburgh; Estados UnidosFil: Zaky, Samer H.. University of Pittsburgh; Estados UnidosFil: Bayram, Merve. İstanbul Medipol Üniversitesi; TurquíaFil: Küchler, Erika C.. University of Pittsburgh; Estados UnidosFil: Cooper, Margaret E.. University of Pittsburgh; Estados UnidosFil: Liu, Kai. University of Pittsburgh; Estados UnidosFil: Marazita, Mary L.. University of Pittsburgh; Estados UnidosFil: Tanboğa, İlknur. Marmara Üniversitesi; TurquíaFil: Granjeiro, José M.. Universidade Federal Fluminense; Brasil. Instituto Nacional de Metrologia, Qualidade e Tecnologia; BrasilFil: Seymen, Figen. İstanbul Üniversitesi; TurquíaFil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Fundación Oswaldo Cruz; BrasilFil: Orioli, Iêda M.. Universidade Federal do Rio de Janeiro; BrasilFil: Sfeir, Charles. University of Pittsburgh; Estados UnidosFil: Owyang, Hongjiao. Marmara Üniversitesi; TurquíaFil: Rabelo Buzalaf, Marilia Afonso. Universidade de Sao Paulo; BrasilFil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unido

Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.

OBJECTIVE: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. METHODS: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). RESULTS: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. CONCLUSIONS: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation

Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research