NIR Fluorescence lifetime macroscopic imaging with a novel time-gated SPAD camera.

SwissSPAD3 is the latest of a family of widefield time-gated SPAD imagers developed for fluorescence lifetime imaging (FLI) applications. Its distinctive features are (i) the ability to define shorter gates than its predecessors (width W < 1 ns), (ii) support for laser repetition rates up to at least 80 MHz and (iii) a dual-gate architecture providing an effective duty cycle of 100%. We present widefield macroscopic FLI measurements of short lifetime NIR dyes, analyzed using the phasor approach. The results are compared with those previously obtained with SwissSPAD2 and to theoretical predictions.

Massively parallel, real-time multispeckle diffuse correlation spectroscopy using a 500 × 500 SPAD camera.

Diffuse correlation spectroscopy (DCS) is a promising noninvasive technique for monitoring cerebral blood flow and measuring cortex functional activation tasks. Taking multiple parallel measurements has been shown to increase sensitivity, but is not easily scalable with discrete optical detectors. Here we show that with a large 500 × 500 SPAD array and an advanced FPGA design, we achieve an SNR gain of almost 500 over single-pixel mDCS performance. The system can also be reconfigured to sacrifice SNR to decrease correlation bin width, with 400 ns resolution being demonstrated over 8000 pixels.

Blueprint for safe transition from a low- to high-volume pancreatic surgery center.

We describe a straightforward model to implement a high volume specialty surgery program at a community hospital. Using pancreatic surgery as an example, we employed published processes in three arenas. First, mandatory multidisciplinary tumor board presentations captured all the patients considered for surgery. Then, perioperative protocols using tools such as enhanced recovery and teamwork in the perioperative arena created a reproducible and safe environment for complex surgery. We critically reviewed all complications using the Clavien-Dindo methodology, and confirmed our favorable outcomes via the targeted NSQIP program. These standard steps can be used for implementation of a new complex surgical procedure.

Gas chromatograph calibration of gas mixtures using a versatile precision volumetric apparatus.

A compact, volumetric apparatus was developed for accurate automated preparation of standard gas and gas-liquid mixtures for gas chromatograph detector calibration, with accuracies comparable to those from gravimetric or Coriolis flow methods. The method developed by the principal author is not an adaptation or extension of any other apparatus or technology, and measurements involve only stepper motor steps, temperature, and pressure ratios. Mixture preparation is accomplished via the displacement of gas between chambers in a highly uniform cylinder, separated by a movable piston. Piston movement, with piston end rods of exactly equal diameter, ensures that there is no change in interior volume, and the volume of gas displaced from the bottom into the top compartment is exactly proportional to the piston travel measured to within 10 µm. The apparatus, operation, and previously unpublished measurements on common refinery gas mixtures over large concentration ranges are described in detail. These confirmed the accuracy and versatility of the apparatus and also the principle of no pressure change during mixture preparation, from sensitive pressure measurements. Conservative expanded uncertainties in prepared mixture mole fraction ranged from 0.001 to 0.002 over extended composition ranges. Absolute average deviations for the detector response factor for the mixtures ranged from 0.001 to 0.002. An exact new mathematical solution procedure permits the use of impure "pure" gases without loss of accuracy and can be applied to other procedures for standard gas mixture preparation. An exact expression is listed for determining "pure" gas purity.

Experimental Shot-by-Shot Estimation of Quantum Measurement Confidence.

We demonstrate the single-shot confidence estimation for individual quantum measurement outcomes using the continuous measurement theory of the quantum counting process applied to the quantum state identification problem. We experimentally obtain single-shot and average confidences for quantum measurements and show that they favorably compare to that of the idealized classical measurement. Finally, we demonstrate that single-shot confidence estimations correctly represent observed experimental outcomes for a large ensemble of measurements.

Low-noise photon counting above 100 million counts per second with a high-efficiency reach-through single-photon avalanche diode system.

We demonstrate a method that allows a high-efficiency single-photon-avalanche diode (SPAD) with a thick absorption region (> 10 µm) to count single photons at rates significantly higher than previously demonstrated. We apply large (> 30 V) AC bias gates to the SPAD at 1 GHz and detect minute avalanches with a discrimination threshold of 5(1) mV by means of radio-frequency (RF) interferometry. We measure a reduction by a factor of ≈ 500 in the average charge per avalanche when compared to operation in its traditional active-quenching module, and a relative increase of >19 % in detection efficiency at 850 nm. The reduction in charge strongly suppresses self-heating effects in the diode that can degrade performance at high avalanche rates. We show that the single-photon detection system maintains high efficiency at count rates exceeding 108s-1.

Author Correction: Structure and Distribution of an Unrecognized Interstitium in Human Tissues.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Structure and Distribution of an Unrecognized Interstitium in Human Tissues.

Confocal laser endomicroscopy (pCLE) provides real-time histologic imaging of human tissues at a depth of 60-70 µm during endoscopy. pCLE of the extrahepatic bile duct after fluorescein injection demonstrated a reticular pattern within fluorescein-filled sinuses that had no known anatomical correlate. Freezing biopsy tissue before fixation preserved the anatomy of this structure, demonstrating that it is part of the submucosa and a previously unappreciated fluid-filled interstitial space, draining to lymph nodes and supported by a complex network of thick collagen bundles. These bundles are intermittently lined on one side by fibroblast-like cells that stain with endothelial markers and vimentin, although there is a highly unusual and extensive unlined interface between the matrix proteins of the bundles and the surrounding fluid. We observed similar structures in numerous tissues that are subject to intermittent or rhythmic compression, including the submucosae of the entire gastrointestinal tract and urinary bladder, the dermis, the peri-bronchial and peri-arterial soft tissues, and fascia. These anatomic structures may be important in cancer metastasis, edema, fibrosis, and mechanical functioning of many or all tissues and organs. In sum, we describe the anatomy and histology of a previously unrecognized, though widespread, macroscopic, fluid-filled space within and between tissues, a novel expansion and specification of the concept of the human interstitium.

Prevention and Early Detection of Pancreatic Cancer.

Preventing cancer has much to offer. Aside from plummeting health care costs, we might enjoy a healthier life free of cancer and chronic disease. Prevention requires the adoption of healthier choices and a moderate amount of exercise. The supporting evidence is observational, clinical, and partly common sense. Further investigations reveal several substances in a whole-food plant-based diet that have protective effects and an inhibitory effect on tumor development. For pancreatic cancer, the basis of cure remains a century old operation that rarely cures. With little to lose, prevention deserves center stage and additional studies.

A Tale of 2 Techniques: Preoperative Biliary Drainage and Routine Surgical Drainage with Pancreaticoduodenectomy.

Preoperative drainage of an obstructed biliary tree before pancreaticoduodenal resection (PDR) and placement of intraabdominal drains following pancreatic resection have been suggested to be both unnecessary and associated with a higher complication rate. The evidence for and against that practice is presented and analyzed to highlight its risks and benefits. A selective approach on an individual basis for preoperative biliary decompression is advocated, based on multiple factors. Additionally, the evidence for routine use of surgical drains after PDR is critically reviewed and the rationale for routine drainage is made.

Cancer of the Pancreas-Actual 5, 10, and 20+Year Survival: The Lucky and Fortunate Few.

Cancer of the pancreas (CaP) is a dismal, uncommon, systemic malignancy. This article updates an earlier experience of actual long-term survival of CaP in patients treated between 1991 to 2000, and reviews the literature. Survival is expressed as actual, not projected, survival.

Rare, Uncommon, and Unusual Complications After Pancreaticoduodenal Resection.

Complications after pancreaticoduodenal resection occur in at least 30% of patients. Most are a direct result of an intraoperative event, dissection, or anastomoses which account for the most serious morbidities, sepsis, pseudoaneurysms, and hemorrhage. Rarely, complications are due to the systemic impact of the procedure even if the procedure itself was unremarkable. Rare systemic complications after PDR (Transfusion transmitted Babesiosis, pituitary apoplexy, and TRALI) and a number of uncommon and unusual other complications are discussed. Pancreaticoduodenal resection is a significant operation with serious consequences. Decisions on selection of candidates and safe operations should be thoughtful and always in surgeons' minds.

Restricted feeding for 9h in the active period partially abrogates the detrimental metabolic effects of a Western diet with liquid sugar consumption in mice.

BACKGROUND: Obesity is a major public health concern that can result from diets high in fat and sugar, including sugar sweetened beverages. A proposed treatment for dietary-induced obesity is time-restricted feeding (TRF), which restricts consumption of food to specific times of the 24-hour cycle. Although TRF shows great promise to prevent obesity and the development of chronic disease, the effects of TRF to reverse metabolic changes and the development of NAFLD in animal models of a Western diet with sugary water consumption is not known. OBJECTIVE: The objective of the current study was to evaluate the role of TRF in the treatment of obesity and NAFLD through examination of changes in metabolic and histopathologic parameters. METHODS: To better understand the role of TRF in the treatment of obesity and NAFLD, we investigated the metabolic phenotype and NAFLD parameters in a mouse model of NAFLD in which obesity and liver steatosis are induced by a Western Diet (WD): a high-fat diet of lard, milkfat and Crisco with sugary drinking water. Mice were subjected to a short-term (4-weeks) and long-term (10-weeks) TRF in which food was restricted to 9h at night. RESULTS: Prior to TRF treatment, the WD mice had increased body mass, and exhibited less activity, and higher average daytime energy expenditure (EE) than chow fed mice. Approximately 4- and 10-weeks following TFR treatment, WD-TRF had moderate but not statistically significant weight loss compared to WD-ad libitum (WD-AL) mice. There was a modest but significant reduction in the inguinal adipose tissue weight in both WD-TRF groups compared to the WD-AL groups; however, there was no difference in epididymal and retroperitoneal adipose tissue mass or adipocyte size distribution. In contrast, the diet-induced increase in normalized liver tissue weight, hepatic triglyceride, and NAFLD score was partially abrogated in the 4-week WD-TRF mice, while systemic insulin resistance was partially abrogated and glucose intolerance was completely abrogated in the 10-week WD-TRF mice. Importantly, WD-induced metabolic dysfunction (substrate utilization, energy expenditure, and activity) was partially abrogated by 4- and 10-week TRF. CONCLUSIONS: Our results support the hypothesis that TRF aids in reducing the detrimental metabolic effects of consuming a WD with sugary drinking water but does not ameliorate obesity.

A post-processing-free single-photon random number generator with ultra-low latency.

The low-latency requirements of a practical loophole-free Bell test preclude time-consuming post-processing steps that are often used to improve the statistical quality of a physical random number generator (RNG). Here we demonstrate a post-processing-free RNG that produces a random bit within 2.4(2) ns of an input trigger. We use weak feedback to eliminate long-term drift, resulting in 24 hour operation with output that is statistically indistinguishable from a Bernoulli process. We quantify the impact of the feedback on the predictability of the output as less than 6.4×10-7 and demonstrate the utility of the Allan variance as a tool for characterizing non-idealities in RNGs.

Simple autocorrelation method for thoroughly characterizing single-photon detectors.

We introduce and demonstrate a simple and highly sensitive method for characterizing single-photon detectors. This method is based on analyzing multi-order correlations among time-tagged detection events from a device under calibrated continuous-wave illumination. First- and second-order properties such as detection efficiency, dark count rate, afterpulse probability, dead time, and reset behavior are measured with high accuracy from a single data set, as well as higher-order properties such as higher-order afterpulse effects. While the technique is applicable to any type of click/no-click detector, we apply it to two different single-photon avalanche diodes, and we find that it reveals a heretofore unreported afterpulse effect due to detection events that occur during the device reset.

Strong Loophole-Free Test of Local Realism.

We present a loophole-free violation of local realism using entangled photon pairs. We ensure that all relevant events in our Bell test are spacelike separated by placing the parties far enough apart and by using fast random number generators and high-speed polarization measurements. A high-quality polarization-entangled source of photons, combined with high-efficiency, low-noise, single-photon detectors, allows us to make measurements without requiring any fair-sampling assumptions. Using a hypothesis test, we compute p values as small as 5.9×10^{-9} for our Bell violation while maintaining the spacelike separation of our events. We estimate the degree to which a local realistic system could predict our measurement choices. Accounting for this predictability, our smallest adjusted p value is 2.3×10^{-7}. We therefore reject the hypothesis that local realism governs our experiment.

What is the incidence of biliary carcinoma in choledochal cysts, when do they develop, and how should it affect management?

The incidence of cancer in choledochal cysts (CCs) in adults was calculated to determine the timing and need for surgery. In 78 publications (1996-2010), 434 of 5780 reported CCs patients had cancer. Cholangiocarcinoma (70.4 %) and gallbladder cancer (23.5 %) were the most common malignancies. Only nine malignancies were reported before age 18 (0.42 %). In contrast, the incidence of malignancy in adults was 11.4 %. The median age for diagnosis of cancer was 42 years, and the incidence increased with each decade.

Three synchronous, sporadic and separate periampullary and pancreatic tumors: more than a coincidence?

Three sporadic, synchronous, and separate lesions in the ampulla of Vater and the head of the pancreas presented in an 81-year-old male. One was symptomatic and two were incidental. One was detected preoperatively (the ampullary lesion) and two by examination of the resected specimen (the neuroendocrine and pancreatic carcinomas). The case is summarized and the literature and the issue of commonality are reviewed.

Familial pancreatic cancer: the case for prophylactic pancreatectomy in lieu of serial screening and shared decision making.

At-risk family members with familial pancreatic cancer (FCaP) face uncertainty regarding the individual risk of developing pancreatic cancer (CaP) and whether to choose serial screening or prophylactic pancreatectomy to avoid CaP. We treated 2 at-risk siblings with a history of FCaP, congenital hepatic fibrosis (CHF), and jaundice secondary to a bile duct stricture. In one, a pancreaticoduodenal resection was done and in the second a total pancreatectomy. Malignancy was not present, but extensive pancreatic intraepithelial neoplasia (PanIn) 2 was present throughout both pancreata. The clinical course and literature review are presented along with the previously unreported association of CHF and CaP.

Biliary pain, no gallstones--remove the gallbladder, anyway?

As these 2 cases show, cholecystectomy may be helpful for such patients, even those with a high ejection fraction.