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Purpose For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. Methods In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. Results Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians’ choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). Conclusion CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

To obtain reliable 3D stacking, a void-free bonding interface should be obtained during wafer-to-wafer direct bonding. Historically, SiO2 is the most studied dielectric layer for direct bonding applications, and it is reported to form voids at the interface. Recently, SiCN has raised as a new candidate for bonding layer. Further understanding of the mechanism behind void formation at the interface would allow to avoid bonding voids on different dielectrics. In this study, the void formation at the bonding interface was studied for a wafer pair of SiO2 and SiCN deposited by plasma enhanced chemical vapor deposition (PECVD). The presence of voids for SiO2 was confirmed after the post-bond anneal (PBA) at 350 °C by Scanning Acoustic Microscopy. Alternatively, SiCN deposited by PECVD has demonstrated a void-free interface after post bond annealing. To better understand the mechanism of void formation at the SiO2 bonding interface, we used Positron Annihilation Spectroscopy (PAS) to inspect the atomic-level open spaces and Electron Spin Resonance (ESR) to evaluate the dangling bond formation by N2 plasma activation. By correlating these results with previous results, a model for void formation mechanism at the SiO2 and the absence of for SiCN bonding interface is proposed.

Patterns of reproduction, such as size-fecundity relationships used in models to assess fish populations, are generally treated as static through time and invariant to environmental change. However, growing evidence suggests that changes in ocean conditions, such as warming water temperatures and reduced primary productivity, affect life history traits, including reproduction. Under controlled experimental conditions, we documented reproductive plasticity in the live-bearing rosy rockfish Sebastes rosaceus in response to different temperature and feeding regimes, with maternal size as a covariate. Rosy rockfish occur throughout the California Current, a highly dynamic ecosystem for which increased environmental variability is predicted with climate change. Females produced 0-5 larval broods annually. Larger females had disproportionately higher fecundity than smaller females by producing larger-sized broods and a greater number of annual broods. Warmer water temperature decreased the time interval between brood releases, likely reflecting faster egg and larval development. However, warmer temperature did not increase the total number of broods, potentially reflecting a tradeoff with increased metabolic demand. Well-fed females had better body condition and higher annual fecundity compared to poorly fed females, primarily due to a greater number of broods. Conversely, females with poor body condition at the start of the reproductive season did not reproduce, providing possible evidence of delayed maturation at smaller sizes or skipped spawning at larger sizes. Reproductive plasticity (in terms of whether and how many broods are produced per year) in response to the environment likely contributes to high inter-annual variation in population larval production. Understanding the causes and consequences of reproductive plasticity is critical to developing sustainable management strategies and predicting population response to changing climate conditions.

Acute pancreatitis is a primary sterile inflammation of the pancreas, which is characterized by an unphysiological enzyme activation. This leads to an inflammatory reaction with edema, vascular damage and cell decay. The first German interdisciplinary S3 guidelines on chronic pancreatitis were published in 2012. Under the auspices of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and with the participation of various societies and patient representatives, the guidelines were recently revised and extended, Comprehensive S3 guidelines on acute and chronic pancreatitis were compiled and agreed by consensus. This article presents the important clinical aspects on acute pancreatitis from these guidelines in a compact form and the recommendations are justified.Die akute Pankreatitis ist eine primär sterile Entzündung der Bauchspeicheldrüse, die durch eine unphysiologische Enzymaktivierung gekennzeichnet ist. Diese führt zu einer Entzündungsreaktion mit Ödem, Gefäßschädigung und Zelluntergang. Im Jahr 2012 wurde die erste deutsche interdisziplinäre S3-Leitlinie zur chronischen Pankreatitis publiziert. Unter Federführung der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und unter Beteiligung verschiedener Gesellschaften sowie von Patientenvertretungen wurde die Leitlinie aktuell überarbeitet und erweitert. Es wurde eine umfassende S3-Leitlinie zur akuten und chronischen Pankreatitis erstellt und konsentiert. In diesem Beitrag werden wichtige klinische Aspekte zur akuten Pankreatitis aus dieser Leitlinie in kompakter Form dargestellt und Empfehlungen begründet.

Fishes caught from depth often suffer from barotrauma, which can result in high mortality rates (close to 100% for some species) when released at the surface. To mitigate for this, the recreational fishing community pro-actively developed several different types of descending devices designed to assist unwanted or prohibited fish back toward the bottom for release. Post-release survival using recompression techniques has been documented for some species, which has allowed fisheries managers to begin revising estimates of total fishing mortality in some cases, but the effectiveness of the different commercially-available descending device types has not been quantified. We conducted 24 Commercial Passenger Fishing Vessel charters at 11 sites along the coast of California, and invited volunteer recreational anglers aboard the charters to test the effectiveness of five different commercially available device types, and respond to a survey of their device preferences. During release, all fish were descended either to 46 m (150 ft) depth or directly to the bottom, whichever depth was shallower. While there were some significant differences between device types, all devices were effective for releasing rockfishes back to depth. Initial post-release mortality (defined as all mortality events observable from the vessel while fishing) across all devices was relatively low (7.5%) in capture depths less than 100 m, but increased significantly to 16.4% at capture depths from 100 to 135 m. Our results suggest that rockfishes should be released at least half-way to the bottom (preferably directly to the bottom) for the device to be effective in minimizing post-release mortality. The time required to use the devices averaged under three minutes regardless of device type, meaning that all device types could be used efficiently on deck, but anglers showed a clear preference for the SeaQualizer™. This device produced some of the lowest release error rates and lowest initial post-release mortality of rockfishes aboard the charters, so angler preference coincided with device effectiveness. Collaborating with the recreational fishing community was an extremely important aspect to this study, provided more robust results, and fostered working relationships that can be built upon in future research projects.

Achieving a void-free bonding interface is an important requirement for the wafer-to-wafer direct bonding process. The two main potential mechanisms for void formation at the interface are (i) void formation induced by gas, such as condensation by-products caused by the bonding process or outgassing of trapped precursors, and (ii) void formation induced by physical obstacles, such as particles. In this work, emphasis is on the latter process. Particles were intentionally deposited on the wafer prior to bonding to study the kinetics of the physical void formation process. Void formations induced by particles deposited on different dielectrics bonding materials were analyzed using scanning acoustic microscopy and image software. The void formation mechanism is then discussed along with the wafer bonding dynamics at room temperature.

We present fundamental exploration of inorganic dielectric wafer-to-wafer (W2W) bonding by electron spin resonance (ESR) to assess the function of dangling bond-type interface defects. As compared to a standard PECVD SiO2 which contains negligible dangling bonds (DBs), it is found that a substantial amount of silicon and carbon types of DBs, as high as 1014 cm-2, are present in the pre-bonding layer of SiCN and SiCO, mainly as a result of surface modification by means of low energy plasma activation prior to bonding. It is inferred that the evolution of DBs has a positive influence on improving the wafer bonding energy during post-bond anneal, in that the results suggest that a decrease of DBs translates into the formation of chemical bonds at the bonding interface.

Silicon carbon nitride (SiCN) compounds have aroused great interest as dielectric materials for direct bonding because of the high thermal stability and high bond strength, as well as its Cu diffusion barrier properties. While wafer-to-wafer direct bonding, including the dielectric deposition step, is generally performed at high temperature (>350 °C), applications such as heterogeneous chips and DRAMs would require wafer-to-wafer direct bonding at lower temperature (

In this paper the role of electroless NiB as capping layer for the microbumps in preventing oxidation and improving the solder wetting and wirebonding is discussed. Surface properties of such a layer is analyzed by XPS analysis technique and the mechanical properties such as modulus and hardness are studied using nanoindentation tool. Deposition quality of NiB is investigated using TEM and EDX mapping and at the end the electrical data and cross section SEM images of the stacked samples are discussed when using H 2 plasma cleaning and capping layers for both pre-applied under fill and wafer level UF.

Current roadblocks within the collective die-to-wafer bonding flow, limiting die-transfer yield and throughput, are identified and discussed. Based on the obtained assessment a new carrier system is introduced. The use of the ultra-soft and highly-UV-transparent BrewerBOND® C1301 material and its compatibility with BrewerBOND® 701 laser release material, which is coated on top of ultra-thin dies, allows for a room temperature, ultra-low force collective bonding with laser-assisted die transfer sequence.

Readability of infant formula preparation instructions is universally poor, which may result in inaccurate infant feeding. Given that inaccurate formula dispensing can lead to altered infant growth and increased adiposity, there is an increased need for easy to follow instructions for formula preparation. We hypothesize that altering infant formula instruction labels using feedback from iterative focus groups will improve the preparation accuracy of powdered infant formula in a randomized controlled trial. Participants were recruited from the community, 18 years of age or older, willing to disclose demographic information for focus group matching, and willing to participate freely in the first (n = 21) or second (n = 150) phase of the study. In the second phase, participants were randomized to use the standard manufacturer instructions or to use the modified instructions created in the first phase. Accuracy was defined as the percent error between manufacturer-intended powder formula quantity and the amount dispensed by the participant. Participants who were assigned to the modified instructions were able to dispense the powdered formula more accurately than participants who used the standard manufacturer instructions (&minus, 0.67 &plusmn, 0.76 vs. &minus, 4.66 &plusmn, 0.74% error, p &lt, 0.0001). Accuracy in powdered formula dispensing was influenced by bottle size (p = 0.02) but not by body mass index (p = 0.17), education level (p = 0.75), income (p = 0.7), age (p = 0.89) or caregiver status (p = 0.18). Percent error of water measurement was not different between the groups (standard: &minus, 1.4 &plusmn, 0.6 vs. modified: 0.7 &plusmn, 0.6%, p = 0.38). Thus, caloric density was more accurate in the modified instructions group compared to the standard manufacturer instructions group (&minus, 0.3 &plusmn, 0.6 vs.&minus, 2.9 &plusmn, 0.9%, p = 0.03). Infant formula label modifications using focus group feedback increased infant formula preparation accuracy.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide affecting upwards of one third the global population. For reasons not fully understood, individuals with NAFLD and its more severe variant, nonalcoholic steatohepatitis (NASH), are at increased risk for venous thromboembolism which significantly increases morbidity and mortality. Lifestyle changes centering around exercise training are the mainstay of treatment for NAFLD/NASH. While exercise training can lessen venous thromboembolic risk in healthy persons and those with cardiovascular disease, whether or not this benefit is seen in patients with NAFLD/NASH remains unknown. In order to better understand how exercise training impacts thrombosis risk in NAFLD, we present the design of a thirty-two week randomized controlled clinical trial of 42 sedentary subjects age 18–69 with biopsy proven NASH. The main aim is to determine the impact of an aerobic exercise training program on the abnormal hemostatic system unique to NAFLD/NASH. The main outcome is change in plasminogen activator inhibitor one level, an established marker for venous thromboembolism. Secondary outcomes include body composition, cardiorespiratory fitness, control of comorbid metabolic conditions (e.g., obesity, hypertension, hyperlipidemia, diabetes), dietary composition, health related quality of life, liver enzymes and histology, NAFLD/NASH disease activity (e.g., biomarkers, clinical decision aids), microbiome, other markers of hemostasis, and PNPLA3 gene expression. The study represents the first clinical trial of an exercise training program to reduce elevated clotting risk in subjects with NAFLD/NASH.

An understanding of the reproductive biology of a species is fundamental to successful management of fish stocks. Rockfish (Sebastes spp.) have complex reproduction, being viviparous and generally late to mature, often with extended adolescent periods characterized by abortive maturation events. Furthermore, whereas the majority of Sebastes species in the California Current region produce one brood of larvae annually, several are known to produce more than one, though no stock assessments have yet considered the impact multiple brooding may have on population spawning potential for these species. We documented abortive maturation and examined the prevalence and size-dependent and regional patterns of multiple brooding using macroscopic evaluation and detailed histological analysis of ovaries from a model species, chilipepper (S. goodei), collected off Central and Southern California. We modeled the size-related maternal effect on the probability of multiple brooding, and quantified size-dependent fecundity relationships. Our results indicate that the most robust estimation of reproductive output, as a function of the fecundity-length relationship, is improved for chilipepper when multiple brooding is incorporated, due to the greater probability of additional broods, and thus greater spawning potential, in larger females.

The article analyzes the most common mistakes in the observation and management of patients with acute pancreatitis. Analysis of mistakes is based on modern international guidelines and results of research. In particular, suitable amount of infusion therapy is considered, as well as terms of and indications for endoscopic retrograde cholangiopancreatography and computed tomography, indications for endoscopic and surgical invasions, the benefits of antibiotic prophylaxis and creation of rest for digestive tract are counted.

Estimates of fecundity at size are a key component of age-structured population dynamics models such as those used for stock assessment purposes. Fecundity-length relationships for many exploited fish stocks are often poorly understood due to small sample sizes and high levels of intrinsic variability among individuals. Several species in the genus Sebastes match this description, and are important components of commercial and recreational fisheries off the U.S. West Coast. We used a hierarchical Bayesian modeling framework for simultaneous estimation of parameters in the fecundity-length relationships for 29 species of rockfish while accounting for variability within and among subgenera. Hierarchical models that account for subgeneric phylogenetic structure and variability among species outperformed models that treat all species in the genus as exchangeable or ignored variation among species within a subgenus, based on a predictive information criterion. Our results confirm that weight-specific fecundity increases with size in nearly all Sebastes species, and that the assumption of proportionality between mature female biomass and total egg production is inappropriate for most Sebastes stock assessments. Benefits of the hierarchical framework include prediction of fecundity-length parameters at the genus, subgenus, and species level, as well as predictive distributions for unobserved Sebastes species.

The recent developments of wafer-to-wafer bonding technology based on direct assembly of inorganic dielectric materials is offering a path for the continuous need for higher integration density and lower interconnect pitches. However, numerous applications could benefit of a higher degree of design flexibility offered by a die-to-wafer approach. The achievement of high yielding die-to-wafer bonding with micron range die overlay is an essential element to unlock the potential of heterogeneous integration.

Nowadays, the direct bonding process is embedded in a BEOL manufacturing process where the maximum temperature is 400C. For certain applications there is the need to lower such thermal budget. One of the first process steps which will be modified will be the bonding layer deposition step as well as the densification step. It is known that by lowering the deposition temperature the quality of the dielectric will be decreased as well. This change will have a direct consequence on the bonding process which relies on the quality of the dielectric. It is found that if we use a post bond anneal temperature which exceeds the densification temperature voids originate at the bonding interface. By means of FTIR studies and ERD analysis the origin of the voids is tentatively ascribed to H or H related species. These findings provide a basic understanding on how to tune the deposition condition to select a proper low temperature dielectric which will enable us to obtain a good bonding uniformity and a good bond strength for the described application.

As the need for higher degrees of function integration on chips continues to rise, chip-to-chip connection density exponentially increases. The continuous push for denser interconnects has brought conventional FO-WLP to its limit. A novel FO-WLP concept has been proposed to enable 20-µm pitch interconnect chip-to-chip. To achieve this density and to further scale it down, a critical element is ultra-precise die-to-die positioning in the micron range. Advances in temporary bonding materials and carrier systems are required to enable such applications.

This paper demonstrates the fabrication of a reliable 0.7µm diameter and 5µm deep (0.7x5µm) via-last module, fitting a 1.4µm TSV pitch. Enabling sub-micron TSV diameters requires a thinner photo resist, however still withstanding the top passivation dielectric etch, the deep silicon etch and the bottom dielectric etch. The actual TSV silicon diameter is 0.8µm just below the top dielectric hard mask, but reduces to 0.7µm in the middle and to 0.65µm at the bottom of the via. The bottom dielectric tri-layer, consisting of an STI oxide, a thin SiN and a PMD oxide layer, is etched using a dedicated three step selective etch recipe. A thin ALD TiN embedded barrier is implemented, assuring good TSV reliability. An alternative and scalable protection of the oxide liner at the top of the TSV during bottom liner etch is worked out. It makes use of an APF strippable amorphous carbon film. Despite the sub-micron TSV diameter, a conventional PVD Ta barrier and PVD Cu seed is still maintained. Discontinuities in the PVD Cu seed are repaired by using a 30nm thin alkaline ECD seed layer enhancement (SLE), resulting in a conformal copper seed all over the TSV and ensuring void less ECD copper fill. Electrical results prove the maturity of this 0.7µm diameter, 1.4µm pitch via-last module. The connectivity of the TSV, from wafer front to back side, has been checked by means of kelvin and daisy chain structures, showing 100% yield and low spread on the measured resistance values. High breakdown voltage of the TSVs is obtained. The integrity of the oxide liner all over the TSV sidewall is proven by means of IV-controlled reliability measurements (IVCTRL). The breakdown voltage Vbd has very little dependence on the applied stress voltage ramp rate, resulting in high field accelerating factor γ, confirming the high TSV liner/barrier reliability.

Results are presented of recent studies in material exploration for W2W bonding and advanced W2W alignment carried out as a holistic approach to enable a robust ultra-fine pitch interconnect for 3Dsystem-on-chip (SoC) technology. Various characterization methods have been employed, including electron-spin-resonance (ESR) monitoring of dangling-bond-type defects, invoked to compare SiCN-SiCN and SiO 2 -SiO 2 bonding bonding strength in terms of the the evolution of chemical bond densities at the interface. Furthermore, sub-200 nm W2W overlay performance has been demonstrated to cope with 3D interconnect scaling and stringent contact requirements. State-of-the-art overlay performance is achieved by the enabling features of the W2W aligner while the incoming wafer characteristics are monitored. The study provides a positive outlook to 3D SoC technological realization and sub-µm pitch scaling solutions.

a b s t r a c t A comprehensive understanding of reproductive biology is fundamental to the accurate assessment of a given stock's spawning potential relative to the unfished level. Such an understanding is particularly important given the growing recognition of size, age or weight dependent relative fecundity (Фrel, eggs per kg of female weight), or other maternal effects that may demonstrate a relatively greater contribu- tion of specific demographic components of a population toward reproduction. However, size-specific data on Фrel, or other data on maternal effects on reproductive output, are not always available for many stock assessments because intensive efforts are required to collect such data. In the absence of data, the assumption of no size-specific Фrel relationship is typically made, which can lead to bias in esti- mating stock status and related management parameters. We examined effects of misspecifications of size-specific Фrel functions on estimated stock assessment parameters and related management quan- tities using two stocks as case studies and three sets of simulation models, chosen to represent wide ranges of life and fishing histories. The results showed that misspecification effects were relatively small when stocks were less depleted (e.g. 75% of virgin spawning output), but could lead to more substantive misspecifications in more depleted stocks with slower growth and lower mortality rates. For example, we found that stock was estimated to be as much as 20% less depleted if a strong size-specific Фrel exists in a population, but no size-specific Фrel is used in the model. This represents a non-trivial shift in the perception of status for most stocks. The results also showed that overestimating the strength of the size-specific Фrel function in stock assessment models led to smaller estimation errors in assessment outputs compared to underestimating the size-specific Фrel. The results are insightful with respect to the importance of gathering data on size-dependent Фrel and other aspects of reproductive ecology, as well as with respect to the nature of assumptions that are made with regards to reproductive ecology in data limited situations. Published by Elsevier B.V.

Over 60 species of rockfish (Sebastes spp.) reside off the coast of California, many of which are economically important to both recreational and commercial fisheries. Rockfish are live-bearers with a diverse array of reproductive strategies. Understanding the reproductive potential of an exploited stock is critical to assessing the health and status of a fishery. We investigated the reproductive ecology of four rockfish species to examine species contrasts and to determine spatial and maternal-size effects on reproductive potential. Females were sampled during the winter parturition season (November through March) of 2009 through 2012. Maternal length and somatic weight were positively correlated with relative fecundity (larvae per g somatic weight) in all four species, indicating a disproportionately greater reproductive output by larger, older females. Fecundity estimates in Chilipepper, S. goodei, and Yellowtail rockfish, S. flavidus, varied regionally, but did not significantly differ over time within the years sampled (sample sizes for Speckled, S. ovalis, and Blackgill rockfish, S. melanostomus, were too small to allow spatiotemporal comparisons). Two reproductive strategies were evident as Yellowtail and Blackgill rockfish produced a relatively highly fecund, single brood of smaller-sized larvae annually, in contrast to Chilipepper and Speckled rockfish, which produced larger-sized larvae with lower fecundity. In some regions multiple broods were common, complicating estimates of annual fecundity for these two species. There was some evidence that egg production was positively correlated with female condition, indicating that environmental variability in oceanographic conditions and productivity may drive changes in fecundity and reproductive strategy (i.e., single versus multiple broods).

The atrioventricular heart valve (AHV) leaflets have a complex microstructure composed of four distinct layers: atrialis, ventricularis, fibrosa and spongiosa. Specifically, the spongiosa layer is primarily proteoglycans and glycosaminoglycans (GAGs). Quantification of the GAGs' mechanical contribution to the overall leaflet function has been of recent focus for aortic valve leaflets, but this characterization has not been reported for the AHV leaflets. This study seeks to expand current GAG literature through novel mechanical characterizations of GAGs in AHV leaflets. For this characterization, mitral and tricuspid valve anterior leaflets (MVAL and TVAL, respectively) were: (i) tested by biaxial mechanical loading at varying loading ratios and by stress-relaxation procedures, (ii) enzymatically treated for removal of the GAGs and (iii) biaxially mechanically tested again under the same protocols as in step (i). Removal of the GAG contents from the leaflet was conducted using a 100 min enzyme treatment to achieve approximate 74.87% and 61.24% reductions of all GAGs from the MVAL and TVAL, respectively. Our main findings demonstrated that biaxial mechanical testing yielded a statistically significant difference in tissue extensibility after GAG removal and that stress-relaxation testing revealed a statistically significant smaller stress decay of the enzyme-treated tissue than untreated tissues. These novel findings illustrate the importance of GAGs in AHV leaflet behaviour, which can be employed to better inform heart valve therapeutics and computational models.

3D stacked IC (3D-SIC) is one of the main approaches within 3D technologies as it is the most mature and economically viable technology and provides the highest through silicon via density. Enabling 3D SIC requires the modification of standard IC process flows by adding several process modules, such as through silicon via (TSV), wafer bonding and thinning, prior backside processing (e.g. Cu nails exposure), micro bumps formation for the front side and/or the backside and finally stacking to another chips [. Within the 3D-SIC technology developed at IMEC, surface control and preparation by means of wet clean and wet etch are essential steps notably in two key process modules: wafer thinning and micro bump formation.

This paper describes ultra-fine pitch 3D integration development using wafer level Cu/insulator hybrid bonding approach on 300mm substrate. Via-middle process with TSV dimension of 5×50μm is utilized to demonstrate and characterize vertical interconnects formed via face-to-face wafer-to-wafer (W2W) bonding. Key process steps are introduced with specific requirements and challenges. A non-SiO 2 insulator is studied and chosen to enable a high mechanical bond strength with a low temperature anneal (≤250 °C). High alignment accuracy (< 400nm) is achieved with an advanced bonding system, which allows comprehensive characterizations of interconnect pitch scaling through various test structures. Finally, a high repeatability of the electrical performance of 3.6 μm pitch bonded structures is demonstrated statistically across numerous wafer pairs thanks to the precise Cu-Cu contacts established during bonding.