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C126322002

Internal medicine

https://doi.org/10.1159/000453569

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.

C126322002

Internal medicine

https://doi.org/10.1159/000468530

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

Magnesium Replacement Improves the Metabolic Profile in Obese and Pre-Diabetic Patients with Mild-to-Moderate Chronic Kidney Disease: A 3-Month, Randomised, Double-Blind, Placebo-Controlled Study

Epidemiological studies have associated low dietary Mg2+ intake with insulin resistance (IR) and increased risk for metabolic syndrome; however, the effect of Mg2+ supplementation on IR has not been adequately investigated. This study aimed to investigate the effects of oral Mg2+ supplementation on insulin sensitivity (IS) and serum lipids.<br />Forty-eight patients with mild uncomplicated hypertension participated in the study. Among them, 24 subjects were assigned to 600 mg of pidolate Mg2+ daily in addition to lifestyle recommendations for a 12-week period, and another 24 age- and sex-matched controls were only given lifestyle recommendations. At baseline and study-end, blood sampling for determination of fasting glucose and insulin levels, serum lipids and other standard laboratory tests, as well as an oral glucose tolerance test (OGTT) for estimation of IS indices, were performed in all subjects.<br />In the Mg2+ supplementation group the OGTT-derived IS indices of Stumvoll, Matsuda and Cedercholm in were increased between baseline baseline and study-end. In contrast, none of these parameters were changed in the control group. Reductions in total cholesterol, LDL-cholesterol and triglyceride levels, along with a parallel increase in HDL-cholesterol levels, were evident at study-end in the intervention group, but not in the control group.<br />This study suggests that oral Mg2+ supplementation improves IS and lipid profile in mildly hypertensive patients. These potential beneficial effects of Mg2+ on associated metabolic factors could be helpful for patients with hypertension in terms of overall cardiovascular risk reduction.

C126322002

Internal medicine

https://doi.org/10.1056/nejm199309303291401

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus

Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.

C126322002

Internal medicine

https://doi.org/10.1159/000454668

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

The “Golden Age” of Probiotics: A Systematic Review and Meta-Analysis of Randomized and Observational Studies in Preterm Infants

This review reports the beneficial effects, observed in our clinical studies, of Bifidobacterium breve for premature infants, and children with cancers undergoing chemotherapy. To investigate the protective effects of B. breve (M-16V) as a probiotic on necrotizing enterocolitis (NEC) and infection in premature infants, we carried out a clinical study in 338 very low birth weight infants over a five-year period. These patients were supplemented with B. breve starting several hours after birth (Bifido group). 226 premature infants served as controls. Infants of the Bifido group were administered B. breve in a daily dose of 1×10(9) cells/day. The incidence of NEC was significantly reduced in the Bifido group (nil) compared with that in controls (6 cases, P<0.01). Infection also decreased significantly. Thus, administration of B. breve as a probiotic looks to be a very effective treatment for preventing NEC and infection in preterm infants. Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of chemotherapy treatment. To evaluate the effects of the administration of B. breve (BBG-01, another strain than that used in the study of premature infants), a clinical study was performed to ascertain whether it attenuated intestinal mucositis in children with cancers on chemotherapy. A placebo-controlled trial was performed in patients with malignancies admitted for chemotherapy (n=42), who were randomised into two groups receiving probiotic or placebo. The frequency of fever and the use of intravenous antibiotics were significantly lower in the Bifido group than the placebo group. The B. breve administration enhanced the colonisation of anaerobes. Disruption of the intestinal microbiota after chemotherapy, such as the increase in the population levels of Enterobacteriaceae, was more pronounced in the placebo group. In conclusion, these data suggest that administration of B. breve is an effective approach to attenuating chemotherapy-induced mucositis in children with cancers. The study results strongly suggest that B. breve administration as a probiotic is an effective therapy for the prevention of NEC and infection in premature infants, and also a promising treatment for attenuating chemotherapy-induced mucositis in children with cancers.

C126322002

Internal medicine

https://doi.org/10.1056/nejmoa043330

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety.Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival.A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.

C126322002

Internal medicine

https://doi.org/10.1056/nejmoa012512

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin

Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes.

C126322002

Internal medicine

https://doi.org/10.1001/jama.2020.1585

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

<h3>Importance</h3> In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. <h3>Objective</h3> To describe the epidemiological and clinical characteristics of NCIP. <h3>Design, Setting, and Participants</h3> Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. <h3>Exposures</h3> Documented NCIP. <h3>Main Outcomes and Measures</h3> Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. <h3>Results</h3> Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 10⁹/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). <h3>Conclusions and Relevance</h3> In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.

C126322002

Internal medicine

https://doi.org/10.1001/jama.288.3.321

medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial

ContextDespite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.ObjectiveTo assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.DesignEstrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.InterventionsParticipants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).Main Outcomes MeasuresThe primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.ResultsOn May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.ConclusionsOverall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

C199539241

Law

https://doi.org/10.1137/070710111

system of rules and guidelines, generally backed by governmental authority

Power-Law Distributions in Empirical Data

Power-law distributions occur in many situations of scientific interest and have significant consequences for our understanding of natural and man-made phenomena. Unfortunately, the detection and characterization of power laws is complicated by the large fluctuations that occur in the tail of the distribution—the part of the distribution representing large but rare events—and by the difficulty of identifying the range over which power-law behavior holds. Commonly used methods for analyzing power-law data, such as least-squares fitting, can produce substantially inaccurate estimates of parameters for power-law distributions, and even in cases where such methods return accurate answers they are still unsatisfactory because they give no indication of whether the data obey a power law at all. Here we present a principled statistical framework for discerning and quantifying power-law behavior in empirical data. Our approach combines maximum-likelihood fitting methods with goodness-of-fit tests based on the Kolmogorov–Smirnov (KS) statistic and likelihood ratios. We evaluate the effectiveness of the approach with tests on synthetic data and give critical comparisons to previous approaches. We also apply the proposed methods to twenty-four real-world data sets from a range of different disciplines, each of which has been conjectured to follow a power-law distribution. In some cases we find these conjectures to be consistent with the data, while in others the power law is ruled out.

C199539241

Law

https://doi.org/10.1080/00107510500052444

system of rules and guidelines, generally backed by governmental authority

Power laws, Pareto distributions and Zipf's law

Abstract When the probability of measuring a particular value of some quantity varies inversely as a power of that value, the quantity is said to follow a power law, also known variously as Zipf's law or the Pareto distribution. Power laws appear widely in physics, biology, earth and planetary sciences, economics and finance, computer science, demography and the social sciences. For instance, the distributions of the sizes of cities, earthquakes, forest fires, solar flares, moon craters and people's personal fortunes all appear to follow power laws. The origin of power-law behaviour has been a topic of debate in the scientific community for more than a century. Here we review some of the empirical evidence for the existence of power-law forms and the theories proposed to explain them. Acknowledgments The author would like to thank Petter Holme, Cris Moore and Erik van Nimwegen for useful conversations, and Lada Adamic for the Web site hit data. This work was funded in part by the National Science Foundation under grant number DMS – 0405348. Notes *Power laws also occur in many situations other than the statistical distributions of quantities. For instance, Newton's famous 1/r 2 law for gravity has a power-law form with exponent α = 2. While such laws are certainly interesting in their own way, they are not the topic of this paper. Thus, for instance, there has in recent years been some discussion of the ‘allometric’ scaling laws seen in the physiognomy and physiology of biological organisms [Citation17], but since these are not statistical distributions they will not be discussed here. †http://linkage.rockefeller.edu/wli/zipf/. ‡This can be done using the so-called transformation method. If we can generate a random real number r uniformly distributed in the range 0 ⩽ r < 1, then x = xmin (1 – r)−1/α−1 is a random power-law-distributed real number in the range xmin ⩽ x < ∞ with exponent α. Note that there has to be a lower limit xmin on the range; the power-law distribution diverges as x→0—see section 2.1. *See http://www.hpl.hp.com/research/idl/papers/ranking/ for a useful discussion of these and related points. †The most common words in this case are, in order, ‘the’, ‘of’, ‘and’, ‘a’ and ‘to’, and the same is true for most written English texts. Interestingly, however, it is not true for spoken English. The most common words in spoken English are, in order, ‘I’, ‘and’, ‘the’, ‘to’ and ‘that’ [Citation22]. *Sometimes the tail is also cut off because there is, for one reason or another, a limit on the largest value that may occur. An example is the finite-size effects found in critical phenomena—see section 4.5. In this case, Equationequation (5) must be modified [Citation20]. †Significantly more tenuous claims to power-law behaviour for other quantities have appeared elsewhere in the literature, for instance in the discussion of the distribution of the sizes of electrical blackouts [Citation31,Citation32]. These however I consider insufficiently substantiated for inclusion in the present work. *Also called the Eulerian integral of the first kind. †This can be demonstrated by approximating the Γ-functions of Equationequation (19) using Sterling's formula. *This argument is sometimes called the ‘monkeys with typewriters' argument, the monkey being the traditional exemplar of a random typist. *Gambler's ruin is so called because a gambler's night of betting ends when his or her supply of money hits zero (assuming the gambling establishment declines to offer him or her a line of credit). †The enthusiastic reader can easily derive this result for him or herself by expanding using the binomial theorem. *Modern phylogenetic analysis, the quantitative comparison of species' genetic material, can provide a picture of the evolutionary tree and hence allow the accurate ‘cladistic’ assignment of species to taxa. For prehistoric species, however, whose genetic material is not usually available, determination of evolutionary ancestry is difficult, so classification into taxa is based instead on morphology, i.e. on the shapes of organisms. It is widely accepted that such classifications are subjective and that the taxonomic assignments of fossil species are probably riddled with errors. †To be fair, I consider the power law for the distribution of genus lifetimes to fall in the category of ‘tenuous’ identifications to which I alluded in the second footnote on p. 9. This theory should be taken with a pinch of salt. *Yule's analysis of the process was considerably more involved than the one presented here, essentially because the theory of stochastic processes as we now know it did not yet exist in his time. The master equation method we employ is a relatively modern innovation, introduced in this context by Simon [Citation35].

C199539241

Law

https://doi.org/10.5860/choice.44-2056

system of rules and guidelines, generally backed by governmental authority

Frontiers of justice: disability, nationality, species membership

rather "as a nexus of distinctive sensibilities, cares, and concerns that are expressed in distinctive patterns of emotional and practical response" (p.236).Drawing on Philippa Foot and Simone Weil, Wiggins draws out the moral significance of solidarity and recognition."In recognizing another person, we recognize not merely a subject of consciousness but a being who will seek to interpret us even as we seek to interpret him or her" (p.243).The priority of primitive aversions, with which Wiggins began, is then linked to acts that violate solidarity and deny recognition.What if we must violate basic deontological rules to prevent catastrophe?Wiggins responds with a fifth moral category "subsuming the ordinary passably virtuous agent's concern to preserve the very conditions under which human civilization will survive and/or ordinary morality can make its characteristic demands on normal human life" (p.259).It is a mistake, as consequentialists do, to model the whole of morality on these emergency cases.Wiggins resolutely defends a "piecemeal" approach to morality."[T]hose who despise the piecemeal . . .cut themselves off from all sorts of truths that bear closely on the questions they ask. . . .In so far as the case for morality can be stated briefly, all that can be said is that, in a way already illustrated, it is the most enterprising and durable expression that a human being will find for the benevolent dispositions he or she can discover within himself or herself " (p.265).This intriguing book is not aimed at teenage undergraduates, who will find Wiggins a very difficult and frustrating read.Ethics would certainly not be a suitable text for introductory ethics classes.Its target audience is rather those who, while beginners in philosophy, are not beginners in life.Such readers will still find Wiggins challenging (and, at times, opaque and old-fashioned), but they may also find him an intriguing and provocative guide as they seek to apply moral philosophy to moral life.

C199539241

Law

https://doi.org/10.1007/978-3-0348-8629-1

system of rules and guidelines, generally backed by governmental authority

Numerical Methods for Conservation Laws

These notes developed from a course on the numerical solution of conservation laws first taught at the University of Washington in the fall of 1988 and then at ETH during the following spring. The ove

C199539241

Law

https://doi.org/10.5124/jkma.2014.57.11.899

system of rules and guidelines, generally backed by governmental authority

World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects

Published research in English-language journals are increasingly required to carry a statement that the study has been approved and monitored by an Institutional Review Board in conformance with 45 CFR 46 standards if the study was conducted in the United States. Alternative language attesting conformity with the Helsinki Declaration is often included when the research was conducted in Europe or elsewhere. The Helsinki Declaration was created by the World Medical Association in 1964 (ten years before the Belmont Report) and has been amended several times. The Helsinki Declaration differs from its American version in several respects, the most significant of which is that it was developed by and for physicians. The term "patient" appears in many places where we would expect to see "subject." It is stated in several places that physicians must either conduct or have supervisory control of the research. The dual role of the physician-researcher is acknowledged, but it is made clear that the role of healer takes precedence over that of scientist. In the United States, the federal government developed and enforces regulations on researcher; in the rest of the world, the profession, or a significant part of it, took the initiative in defining and promoting good research practice, and governments in many countries have worked to harmonize their standards along these lines. The Helsinki Declaration is based less on key philosophical principles and more on prescriptive statements. Although there is significant overlap between the Belmont and the Helsinki guidelines, the latter extends much further into research design and publication. Elements in a research protocol, use of placebos, and obligation to enroll trials in public registries (to ensure that negative findings are not buried), and requirements to share findings with the research and professional communities are included in the Helsinki Declaration. As a practical matter, these are often part of the work of American IRBs, but not always as a formal requirement. Reflecting the socialist nature of many European counties, there is a requirement that provision be made for patients to be made whole regardless of the outcomes of the trial or if they happened to have been randomized to a control group that did not enjoy the benefits of a successful experimental intervention.

C199539241

Law

https://doi.org/10.5194/acp-15-4399-2015

system of rules and guidelines, generally backed by governmental authority

Compilation of Henry's law constants (version 4.0) for water as solvent

Abstract. Many atmospheric chemicals occur in the gas phase as well as in liquid cloud droplets and aerosol particles. Therefore, it is necessary to understand the distribution between the phases. According to Henry's law, the equilibrium ratio between the abundances in the gas phase and in the aqueous phase is constant for a dilute solution. Henry's law constants of trace gases of potential importance in environmental chemistry have been collected and converted into a uniform format. The compilation contains 17 350 values of Henry's law constants for 4632 species, collected from 689 references. It is also available at http://www.henrys-law.org.