Fiber-coupled 2 mL vacuum-gap Fabry-Perot reference cavity for portable laser stabilization.

Vacuum-gap Fabry-Perot cavities are indispensable for the realization of frequency-stable lasers, with applications across a diverse range of scientific and industrial pursuits. However, making these cavity-based laser stabilization systems compact, portable, and rugged enough for use outside of controlled laboratory conditions has proven difficult. Here, we present a fiber-coupled 1396 nm laser stabilization system requiring no free-space optics or alignment, built for a portable strontium optical lattice clock. Based on a 2 mL vacuum-gap Fabry-Perot cavity, this system demonstrates thermal noise-limited performance and 1 × 10-14 fractional frequency instability. Fiber-integrated optical components have been instrumental in both advancing the field of optics and leveraging those advances across disciplines to facilitate other fields of study. This portable system represents a major step toward making the frequency stability of cavity-based systems broadly accessible.

Measurement-based quantum control of mechanical motion.

Controlling a quantum system by using observations of its dynamics is complicated by the backaction of the measurement process-that is, the unavoidable quantum disturbance caused by coupling the system to a measurement apparatus. An efficient measurement is one that maximizes the amount of information gained per disturbance incurred. Real-time feedback can then be used to cancel the backaction of the measurement and to control the evolution of the quantum state. Such measurement-based quantum control has been demonstrated in the clean settings of cavity and circuit quantum electrodynamics, but its application to motional degrees of freedom has remained elusive. Here we demonstrate measurement-based quantum control of the motion of a millimetre-sized membrane resonator. An optomechanical transducer resolves the zero-point motion of the resonator in a fraction of its millisecond-scale coherence time, with an overall measurement efficiency close to unity. An electronic feedback loop converts this position record to a force that cools the resonator mode to its quantum ground state (residual thermal occupation of about 0.29). This occupation is nine decibels below the quantum-backaction limit of sideband cooling and six orders of magnitude below the equilibrium occupation of the thermal environment. We thus realize a long-standing goal in the field, adding position and momentum to the degrees of freedom that are amenable to measurement-based quantum control, with potential applications in quantum information processing and gravitational-wave detectors.

A blood screening tool for detecting mild cognitive impairment and Alzheimer's disease among community-dwelling Mexican Americans and non-Hispanic Whites: A method for increasing representation of diverse populations in clinical research.

INTRODUCTION: Representation of Mexican Americans in Alzheimer's disease (AD) clinical research has been extremely poor. METHODS: Data were examined from the ongoing community-based, multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models. RESULTS: Data were examined from n = 1649 participants (Mexican American n = 866; non-Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups. DISCUSSION: A blood-based screening tool can serve as a method for increasing access to state-of-the-art AD clinical research by bridging between community-based and clinic-based settings.

Using Fractional Anisotropy Imaging to Detect Mild Cognitive Impairment and Alzheimer's Disease among Mexican Americans and Non-Hispanic Whites: A HABLE Study.

INTRODUCTION: Alzheimer's disease (AD) is the most frequently occurring neurodegenerative disease; however, little work has been conducted examining biomarkers of AD among Mexican Americans. Here, we examined diffusion tensor MRI marker profiles for detecting mild cognitive impairment (MCI) and dementia in a multi-ethnic cohort. METHODS: 3T MRI measures of fractional anisotropy (FA) were examined among 1,636 participants of the ongoing community-based Health & Aging Brain among Latino Elders (HABLE) community-based study (Mexican American n = 851; non-Hispanic white n = 785). RESULTS: The FA profile was highly accurate in detecting both MCI (area under the receiver operating characteristic curve [AUC] = 0.99) and dementia (AUC = 0.98). However, the FA profile varied significantly not only between diagnostic groups but also between Mexican Americans and non-Hispanic whites. CONCLUSION: Findings suggest that diffusion tensor imaging markers may have a role in the neurodiagnostic process for detecting MCI and dementia among diverse populations.

Artificial Intelligence in Toxicologic Pathology: Quantitative Evaluation of Compound-Induced Hepatocellular Hypertrophy in Rats.

Digital pathology evolved rapidly, enabling more systematic usage of image analysis and development of artificial intelligence (AI) applications. Here, combined AI models were developed to evaluate hepatocellular hypertrophy in rat liver, using commercial AI-based software on hematoxylin and eosin-stained whole slide images. In a first approach, deep learning-based identification of critical tissue zones (centrilobular, midzonal, and periportal) enabled evaluation of region-specific cell size. Mean cytoplasmic area of hepatocytes was calculated via several sequential algorithms including segmentation in microanatomical structures (separation of sinusoids and vessels from hepatocytes), nuclear detection, and area measurements. An increase in mean cytoplasmic area could be shown in groups given phenobarbital, known to induce hepatocellular hypertrophy when compared to control groups, in multiple studies. Quantitative results correlated with the gold standard: observation and grading performed by board-certified veterinary pathologists, liver weights, and gene expression. Furthermore, as a second approach, we introduce for the first time deep learning-based direct detection of hepatocellular hypertrophy with similar results. Cell hypertrophy is challenging to pick up, particularly in milder cases. Additional evaluation of mean cytoplasmic area or direct detection of hypertrophy, combined with histopathological observations and liver weights, is expected to increase accuracy and repeatability of diagnoses and grading by pathologists.

Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signalling networks using SILAC-based phosphoproteomics.

Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which rapidly induces inhibitory effects on PLK4 and leads to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and PLK4 signalling outside centriolar networks remains poorly characterised. We report an unbiased mass spectrometry (MS)-based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing U2OS human cells exposed to centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to the compound, resulting in PLK4 stabilisation. Analysing asynchronous cell populations, we report hundreds of centrinone-regulated cellular phosphoproteins, including centrosomal and cell cycle proteins and a variety of likely 'non-canonical' substrates. Surprisingly, sequence interrogation of ∼300 significantly down-regulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm that NMYC and PTPN12 are PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Pro-directed targets that are likely to be important in PLK4-mediated cell signalling.

Obesity, transplantation, and bariatric surgery: An evolving solution for a growing epidemic.

The increasing obesity epidemic has major implications in the realm of transplantation. Patients with obesity face barriers in access to transplant and unique challenges in perioperative and postoperative outcomes. Because of comorbidities associated with obesity, along with the underlying end-stage organ disease leading to transplant candidacy, these patients may not even be referred for transplant evaluation, much less be waitlisted or actually undergo transplant. However, the use of bariatric surgery in this population can help optimize the transplant candidacy of patients with obesity and end-stage organ disease and improve perioperative and postoperative outcomes. We review the impact of obesity on kidney, liver, and cardiothoracic transplant candidates and recipients and explore potential interventions to address obesity in these populations.

Differentiated thyroid cancer mortality by disease stage in northern England.

OBJECTIVE: Mortality from thyroid cancer is reported to be higher in the UK compared with several other European countries, though UK data on mortality by disease stage have not been published. The aim of this study was to ascertain disease-specific mortality by stage in our centre. DESIGN, PATIENTS AND MEASUREMENTS: This was a cohort study of all patients presenting to a single centre. Four hundred and twenty patients treated between 2000 and 2010 were identified. The medical records and causes of deaths were reviewed and analysed. RESULTS: Overall disease-specific mortality at 5 and 10 years was 1.4% and 5.8%, respectively. The observed mortality was 58 against 66.3 expected deaths (CI 43.8-75.4) thus yielding an age-standardized mortality rate of 0.87. There were no deaths due to thyroid cancer in patients with stage I disease at 5 or 10 years. The 10-year disease-specific mortality rose with stage (stage II 3.1%, stage III 28.6%, stage IV 30%). CONCLUSIONS: Thyroid cancer mortality of patients treated at our centre was lower than the official national UK registry and most European figures.

Observing and Verifying the Quantum Trajectory of a Mechanical Resonator.

Continuous weak measurement allows localizing open quantum systems in state space and tracing out their quantum trajectory as they evolve in time. Efficient quantum measurement schemes have previously enabled recording quantum trajectories of microwave photon and qubit states. We apply these concepts to a macroscopic mechanical resonator, and we follow the quantum trajectory of its motional state conditioned on a continuous optical measurement record. Starting with a thermal mixture, we eventually obtain coherent states of 78% purity-comparable to a displaced thermal state of occupation 0.14. We introduce a retrodictive measurement protocol to directly verify state purity along the trajectory, and we furthermore observe state collapse and decoherence. This opens the door to measurement-based creation of advanced quantum states, as well as potential tests of gravitational decoherence models.

Timing of ECMO Initiation Impacts Survival in Influenza-Associated ARDS.

In the past decade, extracorporeal membrane oxygenation (ECMO) has emerged as an innovative therapy for influenza-associated acute respiratory distress syndrome (ARDS). Despite its promising results, the ideal timing of ECMO initiation for these patients remains unclear. Retrospective analysis of a single institution experience with venovenous ECMO for influenza-induced ARDS was performed. Twenty-one patients were identified and categorized into early (0-2 days), standard (3-6 days), or late (more than 7 days) cannulation cohorts. Patients cannulated within 48 hours of admission had 80% survival rate at 90 days. Comparatively, the standard and late cannulation cohorts had an observed 90-day survival rate of 60 and 16.7%, respectively.

Bilateral sympathectomy for treatment of refractory ventricular tachycardia.

Ventricular tachycardia (VT) commonly occurs in patients with ischemic or nonischemic cardiomyopathy and requires antiarrhythmic drugs, ablation, or advanced circulatory support. However, life-threatening VT may be refractory to these therapies, and may cause frequent implantable cardioverter defibrillator (ICD) discharges. Left cardiac sympathetic denervation reduces the occurrence of these fatal arrhythmias by inhibiting the sympathetic outflow to the cardiac tissue. We present a 69-year-old man with nonischemic cardiomyopathy, life-threatening VT, and hemodynamic instability with numerous ICD discharges, who remained refractory to antiarrhythmic drug therapy and ablation attempts. He was effectively treated with bilateral cardiac sympathectomy. Six months later, he remained free of VT with no ICD discharges.

Fifteen-minute consultation: Pain relief for children made simple-a pragmatic approach to prescribing oral analgesia in the postcodeine era.

What are the most effective doses of simple oral analgesics such as paracetamol and ibuprofen for pain relief in children? Why can't I prescribe codeine phosphate for children anymore? Is oral morphine really a safe alternative to codeine phosphate, and if so what dose should I prescribe? These questions are frequently asked by clinicians who wish to give analgesics to children for pain relief. In this article I will address these questions and describe a pragmatic approach for pain relief using oral analgesics based on the best evidence available and my experience as a consultant paediatric anaesthetist.

Live Imaging of Cell Invasion Using a Multicellular Spheroid Model and Light-Sheet Microscopy.

Three-dimensional cellular assays are becoming increasingly popular as a fundamental tool to bridge the gap between tissue culture systems and in vivo tissue. In particular, spheroids are recognised today as a necessary intermediate model between testing in monolayer cultures and testing in animals. This chapter describes a straightforward protocol, from sample preparation to image acquisition and initial post-processing, based on one of most widely used commercial light-sheet fluorescence microscopy platform, the Zeiss Lightsheet Z.1.

Effects of intermittent pressure imitating rolling manipulation on calcium ion homeostasis in human skeletal muscle cells.

BACKGROUND: Homeostasis imbalance of intracellular Ca(2+) is one of the key pathophysiological factors in skeletal muscle injuries. Such imbalance can cause significant change in the metabolism of Ca(2+)-related biomarkers in skeletal muscle, such as superoxide dismutase (SOD), malondialdehyde (MDA) and creatine kinase (CK). Measurements of these biomarkers can be used to evaluate the degree of damage to human skeletal muscle cells (HSKMCs) injury. Rolling manipulation is the most popular myofascial release technique in Traditional Chinese Medicine. The mechanism of how this technique works in ameliorating muscle injury is unknown. This study aimed to investigate the possible Ca(2+) mediated effects of intermittent pressure imitating rolling manipulation (IPIRM) of Traditional Chinese Medicine in the injured HSKMCs. METHODS: The normal HSKMCs was used as control normal group (CNG), while the injured HSKMCs were further divided into five different groups: control injured group (CIG), Rolling manipulation group (RMG), Rolling manipulation-Verapamil group (RMVG), static pressure group (SPG) and static pressure-Verapamil group (SPVG). RMG and RMVG cells were cyclically exposed to 9.5-12.5 N/cm(2) of IPIRM at a frequency of 1.0 Hz for 10 min. SPG and SPVG were loaded to a continuous pressure of 12.5 N/cm(2) for 10 min. Verapamil, a calcium antagonist, was added into the culture mediums of both RMVG and SPVG groups to block the influx of calcium ion. RESULT: Compared with the CNG (normal cells), SOD activity was remarkably decreased while both MDA content and CK activity were significantly increased in the CIG (injured cells). When the injured cells were treated with the intermittent rolling manipulation pressure (RMG), the SOD activity was significantly increased and MDA content and CK activity were remarkably decreased. These effects were suppressed by adding the calcium antagonist Verapamil into the culture medium in RMVG. On the other hand, exposure to static pressure in SPG and SPVG affected neither the SOD activity nor the MDA content and CK activity in the injured muscle cells regardless of the presence of verapamil or not in the culture medium. CONCLUSION: These data suggest that the intermittent rolling pressure with the manipulation could ameliorate HSKMCs injury through a Ca(2+) dependent pathway. Static pressure did not lead to the same results.

Hemodynamic response to exercise and head-up tilt of patients implanted with a rotary blood pump: a computational modeling study.

The present study investigates the response of implantable rotary blood pump (IRBP)-assisted patients to exercise and head-up tilt (HUT), as well as the effect of alterations in the model parameter values on this response, using validated numerical models. Furthermore, we comparatively evaluate the performance of a number of previously proposed physiologically responsive controllers, including constant speed, constant flow pulsatility index (PI), constant average pressure difference between the aorta and the left atrium, constant average differential pump pressure, constant ratio between mean pump flow and pump flow pulsatility (ratioP I or linear Starling-like control), as well as constant left atrial pressure ( P l a ¯ ) control, with regard to their ability to increase cardiac output during exercise while maintaining circulatory stability upon HUT. Although native cardiac output increases automatically during exercise, increasing pump speed was able to further improve total cardiac output and reduce elevated filling pressures. At the same time, reduced venous return associated with upright posture was not shown to induce left ventricular (LV) suction. Although P l a ¯ control outperformed other control modes in its ability to increase cardiac output during exercise, it caused a fall in the mean arterial pressure upon HUT, which may cause postural hypotension or patient discomfort. To the contrary, maintaining constant average pressure difference between the aorta and the left atrium demonstrated superior performance in both exercise and HUT scenarios. Due to their strong dependence on the pump operating point, PI and ratioPI control performed poorly during exercise and HUT. Our simulation results also highlighted the importance of the baroreflex mechanism in determining the response of the IRBP-assisted patients to exercise and postural changes, where desensitized reflex response attenuated the percentage increase in cardiac output during exercise and substantially reduced the arterial pressure upon HUT.

Intralobar Pulmonary Sequestration Presenting as Chronic Non-productive Cough.

We report a case of a 60-year-old female who was known to have intralobar pulmonary sequestration and her only symptom was chronic cough. She had no history of infections and surgical resection led to complete resolution of her chronic cough.

Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease.

OBJECTIVE: The aim of the study was to prospectively evaluate clinical and mucosal responses to the specific carbohydrate diet (SCD) in children with Crohn disease (CD). METHODS: Eligible patients with active CD (Pediatric Crohn's Disease Activity Index [PCDAI] ≥ 15) underwent a patency capsule and, if passed intact, capsule endoscopy (CE) was performed. Patients taking SCD were monitored for 52 weeks while maintaining all prescribed medications. Demographic, dietary, and clinical information, PCDAI, Harvey-Bradshaw Index (HBI), and Lewis score (LS) were collected at 0, 12, and 52 weeks. CEs were evaluated by an experienced reader blinded to patient clinical information and timing. RESULTS: Sixteen patients were screened; 10 enrolled; and 9 completed the initial 12-week trial-receiving 85% of estimated caloric needs before, and 101% on the SCD. HB significantly decreased from 3.3 ± 2.0 to 0.6 ± 1.3 (P = 0.007) as did PCDAI (21.1 ± 5.9 to 7.8 ± 7.1, P = 0.011). LS declined significantly from 2153 ± 732 to 960  ± 433 (P = 0.012). Seven patients continued the SCD up to 52 weeks; HB (0.1 ± 0.4) and PCDAI (5.4 ± 5.5) remained improved (P = 0.016 and 0.027 compared to baseline), with mean LS at 1046 ± 372 and 2 patients showed sustained mucosal healing. CONCLUSIONS: Clinical and mucosal improvements were seen in children with CD, who used SCD for 12 and 52 weeks. In addition, CE can monitor mucosal improvement in treatment trials for pediatric CD. Further studies are critically needed to understand the mechanisms underlying SCD's effectiveness in children with CD.

Robotic surgery for primary hyperparathyroidism.

BACKGROUND: Open cervical parathyroidectomy is the standard of care for the treatment of primary hyperparathyroidism (PHP). However, in patients with a history of keloid or hypertrophic scar formation, the cosmetic result may sometimes be unsatisfactory. Furthermore, in the presence of mediastinal glands, a more morbid approach is sometimes necessary, involving a sternal split or thoracotomy. Robotic parathyroidectomy, either transaxillary or transthoracic, could be an alternative in both settings. METHODS: Between 2008 and 2013, 14 patients with PHP and a well-localized single adenoma underwent robotic transaxillary cervical (TAC) (n = 8) or transthoracic mediastinal (TTM) (n = 6) parathyroidectomy at an academic tertiary medical center and their outcomes were analyzed. RESULTS: All 14 operations were completed successfully as planned. For TAC and TTM parathyroidectomies, mean operative time was 184 and 168 min, respectively. With the exception of one TTM patient, intraoperative PTH determination indicated a >50 % drop in all patients 10 min after excision and no patients presented with recurrent disease on follow-up. Average length of hospital stay was 1 day after TAC parathyroidectomy and 2.2 days after TTM. On a visual analog pain scale (0-10), average pain scores after TAC were 6/10 on postoperative day 1 and 1/10 on day 14, compared to 7.7/10 and 1.5/10, respectively, after TTM. Complications included development of seroma in 1 patient in the TAC group and pericardial and pleural effusion in 1 patient in the TTM cohort. CONCLUSIONS: This initial study shows that robotic TAC and TTM parathyroidectomy are feasible in selected PHP patients with preoperatively well-localized disease. Although the TAC approach offers a potential cosmetic benefit in patients with a history of keloid or hypertrophic scar formation, a more generalized use cannot be recommended based on current evidence. The robotic TTM approach presents a minimally invasive alternative to resections previously performed through thoracotomy and sternotomy.