Myoclonus

Now compatible with all major RFID kit and tray systems LAKE ZURICH, Ill.--(BUSINESS WIRE)-- Fresenius Kabi announced today it has introduced +RFID smart labels for Diprivan® (Propofol) Injectable Emulsion, USP, 200 mg per 20 mL in single-dose vials, sold in the United States. The +RFID labels are now fully compatible with all major RFID kit and tray systems in the U.S. This press release features multimedia. View the full release here: Fresenius Kabi Diprivan® (Propofol) Injectable Emulsion, USP, 200 mg per 20 mL in single-dose vials, now compatible with all major RFID kit and tray systems. (Photo: Business Wire) The launch expands Fresenius Kabi’s industry-leading +RFID portfolio of fully interoperable labeled medications. The use of radio-frequency identification (RFID) label technology eliminates the need to tag medicines manually which saves time and supports a safe, more efficient medication inventory process. Fresenius Kabi is the first pharmaceutical manufacturer to adopt GS1's EPC Tag Data Standard (TDS) to enhance interoperability. GS1 Standards for identifying, capturing and sharing supply chain data help ensure product and inventory information is accessible, accurate and easy to understand. Diprivan, the most prescribed propofol anesthetic in the U.S.1, was the first Fresenius Kabi product introduced with RFID labels in 2020 for use with some RFID kit and tray systems. The drug is now certified for use with all RFID systems and is available immediately to order through wholesalers and direct from Fresenius Kabi. To meet the highest standards of performance and quality, in addition to the company’s own testing, Diprivan +RFID has been tested by the Axia Institute of Michigan State University and certified by the ARC RFID lab of Auburn University. Fresenius Kabi is expanding its portfolio of fully compatible +RFID products based on demand from hospitals. In a recent study by the ASHP Foundation, nearly nine in 10 hospitals that participated reported they are already using RFID technology or are evaluating it. “We are dedicated to supporting our customers in the adoption of RFID technology that enhances patient care, improves efficiency and streamlines workflows for pharmacists,” said John Ducker, president and CEO of Fresenius Kabi USA. The company has also released newly labeled Vasopressin Injection, USP 20 units per 1 mL in single-dose vials with +RFID smart labels, adding to the company’s growing portfolio of products compatible with all major RFID kit and tray systems. About Diprivan® (Propofol), Injectable Emulsion, USP Indications and Usage – DIPRIVAN® (Propofol), Injectable Emulsion, USP is an intravenous general anesthetic and sedation drug for use in adults for initiation and maintenance of Monitored Anesthesia Care (MAC) sedation, combined sedation and regional anesthesia, and Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients. DIPRIVAN is also indicated for induction of general anesthesia for patients greater than or equal to 3 years of age and for maintenance of general anesthesia for patients greater than or equal to 2 months of age. Important Safety Information DIPRIVAN is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN components, and also in patients with allergies to eggs, egg products, soybeans or soy products. DIPRIVAN is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established. DIPRIVAN is not recommended for induction of anesthesia in patients below the age of 3 years or for maintenance of anesthesia in patients below the age of 2 months because its safety and effectiveness have not been established in those populations. Use of DIPRIVAN has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension occur rarely following DIPRIVAN administration. Strict aseptic technique must always be maintained during handling. DIPRIVAN is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate (EDTA) to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP standards. Failure to use aseptic technique when handling DIPRIVAN was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. A DIPRIVAN vial is never to be accessed more than once or used on more than one person. DIPRIVAN has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. Diprivan should not be coadministered through the same IV catheter with blood or plasma because compatibility has not been established. For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients. Administer DIPRIVAN with caution in patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Very rarely the use of DIPRIVAN may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. When DIPRIVAN is administered to an epileptic patient, there is a risk of seizure during the recovery phase. Attention should be paid to minimize pain on administration of Diprivan. Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (less than 1%). Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN administration. Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN was one of the induction agents used. For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), DIPRIVAN should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management. Patients should be continuously monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. Abrupt discontinuation of DIPRIVAN prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. In pediatric patients, abrupt discontinuation of DIPRIVAN following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia, agitation, and jitteriness have also been observed. For both adult and pediatric ICU sedation, DIPRIVAN infusion has been associated with Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes and/or cardiac failure. Since DIPRIVAN is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when DIPRIVAN is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. EDTA is a strong chelator of trace metals – including zinc. DIPRIVAN should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses. At high doses (2 grams to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Monitor patients at risk for renal impairment. There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN, although a causal relationship is unknown. Neurosurgical Anesthesia: When DIPRIVAN is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decrease in cerebral perfusion pressure. Cardiac Anesthesia: Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Pediatric Neurotoxicity: Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is unclear. Adverse reactions reported with an incidence greater than 1% were: bradycardia, arrhythmia, tachycardia, hypotension, decreased cardiac output, hypertension, movement, apnea, respiratory acidosis during weaning, rash, pruritus, burning/stinging or pain at injection site, and hyperlipemia. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or . DIPRIVAN is not recommended for obstetrics, including Cesarean section deliveries. DIPRIVAN crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN may be associated with neonatal depression. DIPRIVAN is not recommended for use in nursing mothers because Propofol has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of propofol are not known. This Important Safety Information does not include all the information needed to use DIPRIVAN® (Propofol), Injectable Emulsion, USP safely and effectively. Please see full prescribing information for DIPRIVAN® (Propofol), Injectable Emulsion, USP at . References 1. Data on file. About Fresenius Kabi Fresenius Kabi ( ) is a global health care company that specializes in injectable medicines, biosimilars, and technologies for infusion, transfusion, and clinical nutrition. The company’s products and services are used to help care for patients with critical and chronic conditions. The company’s U.S. headquarters is in Lake Zurich, Illinois. The company’s global headquarters is in Bad Homburg, Germany. To learn about U.S. career opportunities at Fresenius Kabi, visit us at and follow us on LinkedIn.

在过去的十年里，技术的进步极大地增强了我们在规模上测量基本生物过程的能力。由此产生的数据量需要越来越多针对多维生物数据集分析的机器学习方法。 近日，国际四大医学期刊之首的《新英格兰医学杂志》（NEJM）发表了一篇题为：Artificial Intelligence in Molecular Medicine（分子医学中的人工智能）的综述论文。 新的方法，如基因组测序和质谱技术，大大增加了科学家和医疗专业人员获取更精确诊断和增强治疗精准度所需的分子数据的数量。虽然在DNA和RNA的基因测序方面取得了最大的进展，但蛋白质和代谢物高维度测量的医疗应用也在增加。为了适应这些分子“大数据”的数量、速度和多样性，分析工具也得到了改进。机器学习的出现被证明特别有价值。在这些方法中，计算机系统使用大量数据构建预测性统计模型，并通过整合新数据进行迭代改进。深度学习是机器学习的一个强大子集，其中包括使用深度神经网络，已在图像对象识别、语音识别、自动驾驶和虚拟助理等领域具有高知名度的应用。现在，这些方法正在医学领域应用，以提供临床指导性的医疗信息。在这篇综述文章中，作者简要描述了生成高维分子数据的方法，然后重点介绍了机器学习在这些数据的临床应用中扮演的关键角色。 大规模分子数据生成 在大规模测量分子的能力方面发生了重大变化，推动了当前个体化医学的时代（图1）。几十年来，基于Sanger技术的基因测序主要集中在长度最多达几百个碱基的DNA或RNA片段上。在21世纪初，像Illumina的合成测序方法开始流行，允许同时合成和读取数百甚至数十亿个短DNA模板。更近期的方法（来自Pacific Biosciences和Oxford Nanopore）专注于连续测序长的核酸分子，具有额外的优势。而人类基因组计划花费了10年时间以数十亿美元的成本测序了一个不完整的单倍体基因组，到了2022年，一个更完整的人类基因组只需5小时的时间和几百美元的成本就能测序完成。这种基因组数据可用性的快速提高引发了对这些数据的快速处理和准确解读的需求。 基因组测序的过程会生成一个计算机文本文件，其中每一行代表一个单独“读取”的DNA或RNA分子。对于基因组测序，通常的目标是生成足够的重叠数据来覆盖基因组的每个部分40倍。某些技术可以捕获基因组的一个子集，并对其进行更多次的覆盖。这个输出的文本文件大小为100到200千兆字节（类似于现在入门级笔记本电脑的硬盘容量）。这些读取数据的长度从几百个碱基到几百万个碱基不等，通过Burrows-Wheeler变换，一种从数据压缩信息理论导出的方法，将这些读取数据映射到人类基因组计划生成的参考基因组上。然后，使用机器学习或算法方法确定正在分析的基因组与参考序列之间的差异。这样就得到了一个变异调用文件，通常有300万到400万行，几兆字节的大小。为了按照例如在患者中可能导致罕见疾病的概率对文件中的变异进行优先级排序，可以使用过滤或机器学习方法。对于RNA测序，映射后，大多数应用会侧重于基因或同工型表达的定量，而不是序列识别，将每个基因或同工型的读取计数转换为标准化的定量测量。 机器学习在基因组学（细胞内一组基因，即基因组的研究）中的应用中，最重要的进展出现在变异检测领域：即确定分析物序列（例如来自患者的样本）与参考序列的差异位置。当将个体读取映射到参考基因组中的相应位置时，它们可以被可视化为"堆积"，其中与参考不同的碱基被突出显示（图1）。这种可视化表示有助于在基因组的复杂区域进行快速的手动审核，这一发现促使了深度学习方法用于变异识别，借鉴了计算机视觉和图像识别方面的进展。其他变异检测方法则在更狭窄的应用领域中使用机器学习，例如用于特定变异或基因组区域的技术校准误差模型。 深度神经网络是复杂的非线性函数，适用于大规模数据集。多层次的交替"神经元"权重和非线性变换将数据转化为对分类有用的抽象和低维表示。层次之间通过激活函数连接，激活函数作为输出的进一步传播的门控。在图像任务中，池化函数用于在特定区域对输入进行下采样。然后通过反向传播过程对神经元权重进行细化，并最终以对几个输出选项的置信度估计形式进行分类。卷积神经网络是一种特定形式的深度神经网络，通常用于图像识别，其特点是在图像输入上滑动滤波器的过程（图2和3）。 图3 凭借神经网络的强大能力和读取更长的DNA分子的能力，可能会出现一种新的单倍型分析时代（将DNA链映射到原始亲本染色体）。单倍型分析方法通过更好地表示起源的DNA分子来提高变异检测的质量，并可以在临床管理中发挥作用，例如在复合杂合性的情况下，同一位点上两个变异体的起源父本的识别可以影响患者的护理。最近，通过将单倍型分析与针对连续数据优化的模型结合起来，然后再采用上述的卷积神经网络方法，取得了前所未有的准确性。 通过国家标准与技术研究所（National Institute of Standards and Technology）的“基因组在瓶中”联盟（Genome in a Bottle Consortium）以及美国食品药品监督管理局（FDA）的precisionFDA计划，这些进展使变异检测的改进成为可能。这两个组织共同开展了开放的“真实性挑战”比赛，使用标准化样本进行竞争。结果显示，在全基因组范围内以及染色体上编码主要组织相容性复合体等基因组中具有挑战性的区域，变异检测的准确性不断提高。机器学习（图2）在罕见疾病变异的优先级排序中也被证明非常有用。例如，一种方法使用基于逻辑回归的机器学习在一个大型的基于文献的数据集中，将表型与候选基因匹配，以帮助确定可能是门德尔遗传疾病的潜在致病基因。 读取转录组（生物体中所有RNA转录本的总和）被用作识别罕见疾病中的致病基因的一种额外工具。最初的努力揭示了通过将每个基因的表达谱与参考范围进行比较，识别表达异常可以指向未被怀疑的致病基因。为了获得额外的益处，这种方法后来与预测罕见变异的调节效应的贝叶斯模型相结合。在一大批患有未诊断罕见疾病的患者中，血液转录组测序识别出8%的患者的致病变异。随后，使用包括基因表达、等位基因特异表达和可选择剪接数据的分层贝叶斯模型来识别遗传驱动的转录组异常。 尽管取得了一些进展，但预测剪切位点仍然是一个具有挑战性的问题。使用一个32层深度神经网络的深度学习模型在改善罕见疾病的诊断方面显示出了希望。使用自编码器，它可以有效地学习如何将输入数据编码为压缩表示，然后解码回原始输入的表示，已经被证明可以改善从RNA测序数据中的异常剪接预测（图2）。 这些方法被应用于一个12岁女孩的案例中，该女孩出现了发育退化、震颤和癫痫。通过短读长度的基因组测序，鉴定了96个候选基因变异，但没有一个看起来与患者的病情有关。通过对患者血液进行RNA测序并应用剪切异常算法，发现了KCTD7中的一个剪切增益变异，该变异并不在最初的候选基因列表中，从而确立了进行性肌阵挛癫痫的诊断。 表观基因组学被定义为影响基因表达的一系列修饰。虽然已知表观遗传机制在某些罕见病和常见疾病的表现中起作用，但在临床医学中，对DNA化学修饰的大规模表征才刚刚开始产生影响。长读测序方法提供了令人兴奋的机会，因为它们在核苷酸通过蛋白质纳米孔时产生信号，或者在DNA聚合酶嵌入碱基时产生信号。这些信号可以通过机器学习方法解读，不仅可以确定该位点的核苷酸，还可以确定该核苷酸的一系列化学修饰。这些方法不需要之前的标准中的亚硫酸盐转化，该转化已被证明会引起DNA断裂。由于在组织特异性转录中扮演关键角色，大部分关注集中在将甲基基团加到顺序CG二核苷酸序列中称为CpG位点的C5位点。采用各种神经网络方法，包括卷积神经网络、双向循环神经网络（图3），以及两种类型的组合，已经在甲基化检测方面达到了超过0.95的C统计量，优于以前的基准模型。 深度学习在蛋白质组学的几乎所有环节中取得了重大进展。通过对已知化学实体的光谱图模式进行训练，深度学习方法改善了候选肽段的光谱预测能力，这是基于串联质谱的蛋白质组学的关键步骤之一。利用基于卷积神经网络的工具，还能准确预测肽段的保留时间，即肽段从液相色谱柱中洗脱的时间点。除了质谱法外，深度学习应用还集中在新生肽序列和蛋白质鉴定上，采用了卷积神经网络和长短时记忆方法。此外，最近还将大型语言模型应用于蛋白质功能预测，以加速药物发现。 蛋白质的翻译后修饰，如磷酸化等过程对于蛋白质的功能、调节和降解至关重要，但其定量仍然是一个尚未解决的挑战。通过仅从蛋白质序列预测翻译后修饰位点的深度学习已经取得了成功，其中的例子包括乙酰化和泛素化等修饰。近期，通过隐藏马尔可夫模型和卷积神经网络的组合，预测蛋白质功能的能力也得到了改进。这种综合方法为360个以前未注释的人类参考蛋白质提供了功能预测，使标准蛋白质家族数据库的覆盖率提高了9%以上。 在蛋白质组学领域，基于神经网络的AlphaFold（图3）是一项备受关注的深度学习应用。它在第13届和第14届关键蛋白质结构预测评估竞赛中获得了胜利。这些是每两年举办一次的盲测竞赛，旨在评估蛋白质结构预测的进展。在第13届竞赛中，AlphaFold1为43个自由建模结构中的24个结构提供了高准确性的预测结果，大大超过了以往的方法和排名第二的方法，后者只在43个结构中的14个结构上达到了类似的准确性。在CASP14竞赛中，AlphaFold2在这一基础上取得了进一步的进展，优于许多竞争模型。 近年来，蛋白质组学在生物标志物的预测上成为临床研究的主要焦点。研究主要集中在单一标志物和多标志物的发现上。在一项研究中，利用一组配体（与蛋白质结合的寡核苷酸）实现了蛋白质定量，利用一系列机器学习模型，包括基于逻辑回归和随机森林的模型（图2和图3），对约17,000名无重大疾病的个体进行训练，预测了11个常用于预防医学的健康指标，这些个体来自五个独立的队列研究。 多组学应用

STEVENAGE, England--( BUSINESS WIRE )--Autifony Therapeutics Limited (“Autifony”), which is pioneering the development of novel pharmaceutical treatments for rare CNS disorders and other serious brain diseases, today announced that a Phase Ib trial of AUT00201, a potent and selective modulator of Kv3 ion channels, is enrolling patients with Myoclonus Epilepsy and Ataxia due to Potassium (K+) Channel Mutation or MEAK (also known as EPM7) at the Hospital of the University of Pennsylvania. Epilepsy is a brain disorder that causes recurring, unprovoked seizures. It is the fourth most common neurological disorder worldwide. Patients with EPM7 have a very rare form of epilepsy, caused by reduced function of Kv3.1 ion channels, which gives rise to myoclonic seizures (brief shock-like jerks of a muscle or a group of muscles), action-induced myoclonus and a progressive ataxia (impairing co-ordination, balance and speech). EPM7 symptoms typically emerge between the ages of 3 and 15, with progressively severe myoclonus, ataxia, and occasional tonic-clonic seizures. Patients are typically wheel-chair bound by the time they are in their late teens. Current anti-seizure drugs can help to reduce the incidence of tonic-clonic seizures, but these drugs do not improve the myoclonus or ataxia. AUT00201 is a potent positive modulator of Kv3.1 ion channels. In a genetic mouse model of EPM7 conducted by Dr. Ethan Goldberg at the Children’s Hospital of Philadelphia, AUT00201 completely reversed the seizure and ataxia phenotype. The Phase Ib study in patients with EPM7 is a randomized, double-blind, placebo-controlled, crossover study in 8-10 patients aged 18 or over in which effects both on clinical symptoms and biomarkers related to dysfunction of Kv3.1 channels are evaluated. Separately, the US FDA has designated AUT00201 for treatment of EPM7 as a drug for a ‘rare pediatric disease’ as defined in section 529(a)(3) of the Federal Food, Drug, and Cosmetic Act. The Office of Orphan Products Development has also granted orphan drug designation for AUT00201 for the treatment of EPM7. Dr. Charles Large, Chief Executive Officer of Autifony Therapeutics, commented: “This is a unique opportunity for precision medicine, in which we aim to reverse the impact of a genetic mutation that causes a highly debilitating disorder. We are hopeful that this will offer benefit to patients with EPM7 where there are currently no effective treatments, and might one day also bring benefits to patients suffering from other forms of myoclonic epilepsy, which we will be looking to investigate in future.” Notes to Editors About Autifony Therapeutics Ltd Autifony Therapeutics is an independent UK-based biotechnology company formed in 2011 as a spin-out from GSK, which retains equity in the company. The Company is focused on the development of high value, novel medicines to treat serious diseases of the central nervous system. It is funded by SV Health Investors, IP Group, Pfizer Ventures, International Biotechnology Trust PLC, and UCL Business plc. For more information, please visit www.autifony.com . About AUT00201 AUT00201 is a novel, orally active small molecule designed to selectively modulate Kv3 potassium channels. Safety and toxicology studies support the clinical development of AUT00201.