Computerized acoustic cardiographic insights into the pericardial knock in constrictive pericarditis

BACKGROUND: One of the clinical hallmarks of constrictive pericarditis is the pericardial knock, a high-pitched early diastolic heart sound. Making the clinical diagnosis of constrictive pericarditis is challenging, as is accurate auscultation of the pericardial knock. HYPOTHESIS: We sought to assess the utility of a computerized acoustic cardiographic device in the assessment of the pericardial knock in patients with constrictive pericarditis. METHODS: We report a case series in which computerized acoustic cardiography (Audicor, Inovise Medical Inc., Portland, OR) is performed in patients with constrictive pericarditis. RESULTS: Three patients with constrictive pericarditis underwent computerized acoustic cardiographic recordings at the time of cardiac catheterization. In each case, initial physical examination by the internist and referring cardiologist did not appreciate a pericardial knock. Acoustic cardiography demonstrated a high-pitched early diastolic sound in each case. Time-frequency representation analyses showed the high-frequency components of the pericardial knock sound. Repeat acoustic cardiography demonstrated resolution of the pericardial knock after pericardiectomy in two patients. CONCLUSIONS: Non-invasive computerized acoustic cardiography can demonstrate the high-pitched pericardial knock in patients with constrictive pericarditis. This may aid the bedside assessment of patients with diastolic heart failure, improving the clinician's ability to appreciate the ausculatory findings in constrictive pericarditis.     

Treatment algorithms in Crohn's – Up,down or something else?

Crohn's disease is a chronic, progressive and disabling condition. New therapeutic goals have emerged in Crohn's disease such as the need to look beyond symptoms by achieving mucosal healing that is known to be associated with better outcomes. Anti-TNF (Tumour Necrosis Factor) therapy is the most potent drug class to induce and maintain mucosal healing in Crohn's disease. Recent evidence indicates that the efficacy profile of thiopurines has been overestimated while the increased risk of malignancies (lymphoma, non-melanoma skin cancers, myeloid disorders) has been underestimated. Methotrexate is well-tolerated, but its potential for disease modification is unknown. Achieving mucosal healing in patients with early Crohn's disease might be the best way to change disease course and patients' life. In 2014, anti-TNF treatment should be the first-line therapy in patients with Crohn's disease who suffer from severe and/or complicated disease and in those with poor prognostic factors. In the remaining patients, a rapid step-up approach based on a tight monitoring is recommended.     

Step‐down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis

Objective

To evaluate the feasibility and outcome of the step‐down approach using either cyclosporin A (CSA) or methotrexate (MTX) as maintenance therapy following 6 months treatment with these 2 agents in combination in early, nonerosive rheumatoid arthritis (RA).

Methods

Fifty‐seven patients younger than 65 years with early, nonerosive RA were first treated with CSA and MTX in combination for 6 months. They were then randomly stepped down to single‐agent maintenance treatment for another 18 months. Safety, clinical efficacy, survival on treatment, and radiographic progression were evaluated.

Results

When being treated with combination therapy, 7 of the 57 patients (12.3%) withdrew because of adverse events. Of the remaining 50 patients, 42 (84.0%) were American College of Rheumatology (ACR) 20% responders, 30 (60.0%) were ACR 50% responders, and 23 (46.0%) were ACR 70% responders. At month 6, 22 patients were randomized to CSA and 27 to MTX. During this trial period, the treatment was discontinued by 16 patients taking CSA (mainly because of loss of efficacy) and by 4 taking MTX. At month 24, the probability (± SEM) of survival on treatment was 0.273 ± 0.09 for CSA and 0.852 ± 0.07 for MTX. Of the 6 CSA patients who completed the trial, 4 (66.7%) were ACR 20% responders, and 3 (50%) were both ACR 50% and ACR 70% responders. Of the 23 completers in the MTX arm, 21 (91.3%) were ACR 20% responders, 18 (78.3%) were ACR 50%, and 10 (43.5%) were ACR 70% responders. The treatment was not responsible for severe adverse events. Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups.

Conclusion

Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX. Because this treatment did not prevent some radiographic progression, other approaches (e.g., step‐up approach) may be more appropriate in early RA.

     

Critical slowing down suggests that the western Greenland Ice Sheet is close to a tipping point

The Greenland Ice Sheet (GrIS) is a potentially unstable component of the Earth system and may exhibit a critical transition under ongoing global warming. Mass reductions of the GrIS have substantial impacts on global sea level and the speed of the Atlantic Meridional Overturning Circulation, due to the additional freshwater caused by increased meltwater runoff into the northern Atlantic. The stability of the GrIS depends crucially on the positive melt-elevation feedback (MEF), by which melt rates increase as the overall ice sheet height decreases under rising temperatures. Melting rates across Greenland have accelerated nonlinearly in recent decades, and models predict a critical temperature threshold beyond which the current ice sheet state is not maintainable. Here, we investigate long-term melt rate and ice sheet height reconstructions from the central-western GrIS in combination with model simulations to quantify the stability of this part of the GrIS. We reveal significant early-warning signals (EWS) indicating that the central-western GrIS is close to a critical transition. By relating the statistical EWS to underlying physical processes, our results suggest that the MEF plays a dominant role in the observed, ongoing destabilization of the central-western GrIS. Our results suggest substantial further GrIS mass loss in the near future and call for urgent, observation-constrained stability assessments of other parts of the GrIS.

During the last century, the Greenland Ice Sheet (GrIS) has lost mass at an accelerating rate (1, 2). The mass loss is caused by solid ice discharge into the North Atlantic and surface melting due to increasing temperatures. The relative contribution of the latter has increased from 42% before 2005 to 68% between 2009 and 2012, and surface runoff caused 84% of the increase in mass reduction since 2009 (3). The complete melting of the GrIS would cause a global sea level rise of more than 7 m (4, 5). Continued melting of the GrIS has been suggested to potentially lead to a collapse of the Atlantic Meridional Overturning Circulation via increased freshwater flux into the North Atlantic (6, 7), which may, in turn, trigger a cascade of transitions in additional tipping elements such as the Amazon rainforest and the tropical monsoon systems (6, 8–10).In addition to the centennial-scale variability associated with the increasing trend in mean temperatures related to anthropogenic climate change, the pace of mass loss has decadal-scale fluctuations caused by natural variations in external oceanic and atmospheric forcing. The imprints of these natural, decadal-scale fluctuations are spatially heterogeneous across the GrIS. Since the early 2000s, periods of persistently negative phases of the North Atlantic Oscillation (NAO) and a positive phase of the East Atlantic Pattern (11) have led to a weakening and southward shift of the jet stream, and more persistent blocking (12) over Greenland during summer, resulting in overall increased mass reduction rates (2, 13). On the other hand, a slowing down of mass loss since 2013—which inverted again in 2019—was caused by more periods with a persistent positive NAO (14). Moreover, recent observations show that the Jakobshavn glacier has been advancing again since 2016 due to anomalous wintertime heat loss in the boundary current around southern Greenland (15). However, these natural fluctuations do not have a sustained impact on melt rates comparable to the longer-term trend toward overall increasing melt rates caused by anthropogenic global warming (Fig. 1A).Open in a separate windowFig. 1.(A) Summer sea level temperatures from the Ilulissat station in CWG (25) (blue curves) and Arctic temperature anomalies (26) (red curves). The linear trend of the station data (dashed blue curve) corresponds to 1.3 °C warming per century. Arctic temperature anomalies are shown only for comparison; only the station data (blue curves) are used for our analysis. (B) Melt rates from the CWG ice core stack (blue curve) and the NU peninsula core (red curve), given as z scores with respect to a normal distribution (18). (C) Detrended logarithmic CWG (blue curve) and NU (red curve) melt rates. A Gaussian filter with bandwidth σ=30 y was used for detrending. The runoff and melt time series are preprocessed in this way before computing the EWS indicators to exclude potential biases by underlying trends; in particular, we take the logarithm of the melt rates in order to account for skewed data distributions. (D) The variance of the CWG (blue curves) and NU (red curves) melt rates. (E) The AC1 of the CWG (blue curves) and NU (red curves) melt rates. Note that the AC1, despite a significantly positive trend, appears to have at least temporarily stabilized in the last few decades. It should be noted, however, that the AC1 is generally influenced by (multi)decadal variability (27). The window size for computing the variance and the AC1 is w=70 y, and values are plotted at the windows’ endpoints. Data for the first w=70 y are omitted to ensure that all windows contain the same number of data points. The dashed lines in D and E indicate linear trends of the variance and AC1, and P values for positive slopes as determined from a phase surrogate test are indicated in the legend (see Materials and Methods). The statistical significance of the positive trends is robust across wide ranges of the bandwidth σ and the sliding window size (SI Appendix, Fig. S1).Early model simulations suggest that melting of the GrIS is inevitable beyond a critical global mean temperature threshold of 0.8 °C to 3.2 °C above preindustrial levels, with a best estimate of 1.6 °C (16). More recent comprehensive modeling results show that, for the representative concentration pathway 8.5 (RCP8.5), the GrIS melts entirely until AD 3000 (5). Arctic temperatures have increased more than the global average (17) (Fig. 1A), and the nonlinear increase in GrIS melt rates and runoff that have recently been detected (18) (Fig. 1B) suggests that the critical temperature threshold may be closer than previously thought. We emphasize that the surface mass balance turning negative is not a necessary condition for stability loss, and the temperature may reach a critical threshold years before a turning point in the mass balance (16).Idealized models of critical transitions in natural systems suggest that the loss of stability of an equilibrium (fixed point) is observable before the abrupt transition (19). In dynamical systems with random forcing, one can show that, if a system approaches a bifurcation where an equilibrium point loses its stability, the variance of the fluctuations around the equilibrium will increase, as will the characteristic decay time of the autocorrelation function of these fluctuations. The change in dynamics that occurs as stability is lost is often called critical slowing down, and the associated statistical precursor signs in terms of rising variance and lag-one autocorrelation (AC1) are called early-warning signals (EWS) (19). Such statistical EWS associated with critical slowing down are, for example, detectable in the temperature proxy from the North Greenland Ice Core Project before several of the Dansgaard–Oeschger events of the last glacial interval (20, 21), as well as before other abrupt transitions in past climates (22). In the context of anthropogenic global warming, EWS are expected to precede potential abrupt transitions in the Earth system’s major tipping elements, such as the polar ice sheets, the Atlantic Meridional Overturning Circulation, or the tropical monsoon systems (23). We investigate here a possible tipping point for the GrIS based on the theory of critical slowing down.In the following, we will first show that central-western Greenland (CWG) melt rates exhibit robust and significant EWS. We then reconstruct the corresponding CWG ice sheet height changes and show that they can be captured well by a simple model focusing on the melt elevation feedback (MEF). We then demonstrate that pronounced EWS can also be found in the fluctuations of the reconstructed ice sheet height around the equilibrium of the model and show that these EWS are consistent with the theoretical expectations provided by the MEF model.     

婴幼儿应用左侧头低位颈外静脉采血的效果观察

[目的]探讨左侧头低位颈外静脉采血应用于婴幼儿的效果。[方法]将200例需要采血的婴幼儿随机分为观察组和对照组,对照组按照传统的方法选择头皮或四肢静脉采血,观察组采用左侧头低位颈外静脉采血,比较两组婴幼儿的一次穿刺成功率、一次采血标本达标率、皮下淤血率及婴幼儿家属的满意度。[结果]观察组一次穿刺成功率、一次采血达标率高于对照纽（P〈0．05）,皮下淤血率低于对照组（P〈0．05）;两组婴幼儿家属满意度差异无统计学意义（P〉0．05）。[结论]左侧头低位颈外静脉采血较传统采血穿刺成功率高、标本达标率高、并发症少．     

Advances in the Management of Pediatric Asthma: A Review of Recent FDA Drug Approvals and Label Updates

Children have the highest prevalence of asthma of any age group. In the United States during 2001, there were 12.6 million physician and hospital outpatient visits for asthma treatment, of which almost 5 million involved children 18 years and younger. Therapeutic advances in pediatric asthma could improve patient outcomes and potentially reduce the burden on health care systems. Efforts to obtain efficacy and safety data in pediatric populations and develop pediatric formulations of asthma treatments have been encouraged by the FDA and clinicians. This article reviews the newest additions to asthma therapies approved for use in children, including an inhaled corticosteroid, some long-acting β₂-agonists, some leukotriene-receptor blockers, and a single-isomer, short-acting β₂-agonist.     

Ⅱ级安全柜垂直下降气流速度的数值模拟优化

国家标准YY-0569中规定Ⅱ级生物安全柜下降气流平均速度为0．25～0．5m／s，前窗流入气流平均流速应不低于0．5m／s，本文通过CFD软件对这个速度范围是否会产生外溢进行气流模拟，经数据分析得出了更优的气流速度范围为0．25—0．405m／s。     

用跳台法和避暗法观察药物对学习和记忆获得的影响

采用跳台和避暗法，观察康维命（ＣＶＭ）对小鼠学习和记忆获得的影响。结果表明，ＣＶＭ能提高小鼠的学习和记忆获得能力。两种方法均可用于促进学习记忆试验新药品的筛选，跳台法可观察对学习和记忆获得的影响，避暗法仅可观察对记忆获得的影响     

An extension of the continual reassessment method using decision theory.

The primary goal of a phase I trial is to find the maximally tolerated dose (MTD) of a treatment. The MTD is usually defined in terms of a tolerable probability, q(*), of toxicity. Our objective is to find the highest dose with toxicity risk that does not exceed q(*), a criterion that is often desired in designing phase I trials. This criterion differs from that of finding the dose with toxicity risk closest to q(*), that is used in methods such as the continual reassessment method. We use the theory of decision processes to find optimal sequential designs that maximize the expected number of patients within the trial allocated to the highest dose with toxicity not exceeding q(*), among the doses under consideration. The proposed method is very general in the sense that criteria other than the one considered here can be optimized and that optimal dose assignment can be defined in terms of patients within or outside the trial. It includes as an important special case the continual reassessment method. Numerical study indicates the strategy compares favourably with other phase I designs.