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Background: Acid-fast bacilli(AFB) and fungi are generally slow-growing, difficult to culture, and rarely the cause of infection. The goal of this study was to evaluate the value of routinely obtaining AFB and fungal cultures in foot and ankle surgery at a US hospital.Methods: A retrospective review was conducted to determine the number of positive AFB and fungal cultures out of the total number of foot and ankle samples tested. Between 2014 and 2019, patients who underwent surgery for a foot and ankle infection for soft tissue infection, septic arthritis, infectious postoperative complications were identified. Charts were reviewed to identify the results of the microbiological tests performed. To determine the value of running AFB and fungal cultures, the costs of each were provided by the microbiology lab at our institution.Results: Of the 322 patient charts reviewed, there were 434 AFB and 525 fungal cultures performed. None of these cultures were indicated to be positive for AFB (0%), and 22 (4.19%) were positive for fungi. The total labor and material costs were calculated to be $38 767. The AFB cultures cost $23 967, the positive fungal cultures cost $2371, and the negative fungal cultures cost $36 395.36.Conclusion: This 322-case series of surgically managed foot and ankle infections showed 0% and 4.1% positivity rates of AFB and fungal cultures, respectively. Additionally, only 20% of cases with positive cultures were identified as pathologic requiring antifungal treatment. Further analysis is needed to determine best practices for obtaining vs declining to culture for AFB or fungal species, including assessing patient outcomes in the series of culture-positive(fungal-only) cases. Our results suggest that in our clinical setting of a US hospital system, routine fungal and AFB cultures may not be necessary but should be considered for chronic/recalcitrant infections, immunocompromised patients, and those with high surgeon suspicion.Level of Evidence: Level IV, case series.

Everyone has a chronological age. Because survivorship declines relentlessly in populations with age-specific death rates greater than zero, everyone also has a survivorship age (“s-age”), the age at which a proportion s of the population is still alive. S-ages can be estimated for both periods and cohorts. While trajectories of mortality over chronological ages differ (e.g., across populations, over time, by sex, or by any subpopulation), mortality trajectories over s-ages are similar, a sign that populations experience similar mortality dynamics at specific levels of survivorship. We show that this important demographic regularity holds for 23 sex-specific populations analyzed during a period comprising more than 100 years.

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12Cinhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12Cinhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12CC12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.

AbstractThe effect of filtering face piece grade 2 (FFP2) masks for infection prevention is essential in health care systems; however, it depends on supply chains. Efficient methods to reprocess FFP2 masks may be needed in disasters. Therefore, different UV-C irradiation schemes for bacterial decontamination of used FFP2 masks were investigated.Seventy-eight masks were irradiated with UV light for durations between 3 and 120 seconds and subsequently analyzed for the presence of viable bacteria on the inside. Ten masks served as the control group. Irradiation on the inside of the masks reduced bacteria in proportion to the dose, with an almost complete decontamination after 30 seconds. Outside irradiation reduced the quantity of colonies without time-dependent effects. Both sides of irradiation for a cumulated 30 seconds or more showed almost complete decontamination.Overall, this study suggests that standardized UV irradiation schemes with treatment to both sides might be an efficient and effective method for FFP2 mask decontamination in times of insufficient supplies.

ABSTRACTIntroduction: Lung cancer is a devastating disease with poor overall survival. Despite significant advances in the treatment of lung cancers using radiochemotherapy, targeted therapies and/or immune therapies prognosis remains poor. The capacity of natural killer (NK) cells to provide a first line of defense that can bridge and orchestrate innate and ‘downstream’ adaptive immune responses renders them to be an ideal platform on which to base new cancer therapeutics.Areas covered: We provide an overview of the mechanisms controlling the effector functions of NK cells, tumor-directed immune escape, the impact and influence of NK cells on the development of effective, protective anti-tumor immunity and the therapeutic potential of combined cytokine-, complement-dependent- and antibody-dependent cellular cytotoxicity (CDC/ADCC), NK-92-, KIR mismatch- and CAR-NK cell-based therapies.Expert opinion: Despite promising results of immuno-oncological approaches, a relevant proportion of patients do not profit from these therapies, partly due to an ineffective NK cell activation, a lack of tumor-specific NK cells, an upregulated expression of checkpoint pathways, and a low mutational burden, which hinders the development of long-term adaptive immunity. Strategies that re-activate NK cells in combination with other therapies are therefore likely to be beneficial for the clinical outcome of patients with lung cancer.Abbreviations:ADCC: antibody-dependent cell-mediated cytotoxicity; ALK: anaplastic lymphoma kinase; CAR: chimeric antigen receptor; CDC: complement-dependent cytotoxicity; CEACAM-1: carcinoembryonic antigen-related cell adhesion molecule 1; DC: dendritic cell; DNAM: activating, maturation receptor; EGFR, epidermal growth factor receptor; EMT: epithelial-to-mesenchymal transition; EpCAM: epithelial cell adhesion molecule; GM-CSF: granulocyte monocyte colony stimulating factor; HIF: hypoxia inducible factor; IDO, indoleamine 2,3-dioxygenase; IFN: interferon; IL: interleukin; ITIM/ITAM: immune tyrosine-based inhibitory/activatory motif; KIR: killer cell immunoglobulin-like receptor; LAG-3: lymphocyte activation gene 3; MDSC: myeloid derived suppressor cells; MICA/B: MHC class I-related proteins A/B; MHC: major histocompatibility complex; mTOR: mechanistic target of rapamycin; NCAM: neuronal adhesion molecule; NCR: natural cytotoxicity receptor; NK: natural killer; NSCLC: non-small cell lung cancer; PD-1: programmed cell death 1; PS: phosphatidylserine; SCLC: small cell lung cancer; STAT: signal transducer and activator of transcription; TAM: tumor-associated M2 macrophages; TCR: T cell receptor; TIGIT: T cell immunoglobulin and ITIM domain; Tim-3: T cell immunoglobulin- and mucin domain-containing 3; TNF: tumor necrosis factor; ULBP: UL16-binding protein

Nonlinear model predictive control requires the solution of nonlinear programs with potentially multiple local solutions. Here, deterministic global optimization can guarantee to find a global optimum. However, its application is currently severely limited by computational cost and requires further developments in problem formulation, optimization solvers, and computing architectures. In this work, we propose a reduced-space formulation for the global optimization of problems with recurrent neural networks (RNN) embedded, based on our recent work on feed-forward artificial neural networks embedded. The method reduces the dimensionality of the optimization problem significantly, lowering the computational cost. We implement the NMPC problem in our open-source solver MAiNGO and solve it using parallel computing on 40 cores. We demonstrate real-time capability for the illustrative van de Vusse CSTR case study. We further propose two alternatives to reduce computational time: i) reformulate the RNN model by exposing a selected state variable to the optimizer; ii) replace the RNN with a neural multi-model. In our numerical case studies each proposal results in a reduction of computational time by an order of magnitude.

Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition.

Programmed cell death protein 1/programmed cell death protein ligand1 (PD-1/PD-L1) interaction is an important immune checkpoint targeted by anti-PD-1/PD-L1 immunotherapies. However, the observed prognostic significance of PD-1/PD-L1 expression in diffuse large B-cell lymphoma treated with the standard of care has been inconsistent and even contradictory. To clarify the prognostic role of PD-1/PD-L1 expression and interaction in diffuse large B-cell lymphoma, in this study we used 3-marker fluorescent multiplex immunohistochemistry and Automated Quantitative Analysis Technology to assess the CD3+, PD-L1+, and PD-1+CD3+expression in diagnostic samples and PD-1/PD-L1 interaction as indicated by presence of PD-1+CD3+cells in the vicinity of PD-L1+cells, analyzed their prognostic effects in 414 patients with de novo diffuse large B-cell lymphoma, and examined whether PD-1/PD-L1 interaction is required for the prognostic role of PD-1+/PD-L1+expression. We found that low T-cell tissue cellularity, tissue PD-L1+expression (irrespective of cell types), PD-1+CD3+expression, and PD-1/PD-L1 interaction showed hierarchical adverse prognostic effects in the study cohort. PD-1/PD-L1 interaction showed higher sensitivity and specificity than PD-1+and PD-L1+expression in predicting inferior prognosis in patients with high CD3+tissue cellularity (“hot”/inflammatory tumors). However, both PD-1+and PD-L1+expression showed adverse prognostic effects independent of PD-1/PD-L1 interaction, and PD-1/PD-L1 interaction showed favorable prognostic effect in PD-L1+patients without high CD3+tissue cellularity. Macrophage function and tumor-cell MYC expression may contribute to the PD-1-independent adverse prognostic effect of PD-L1+expression. In summary, low T-cell tissue cellularity has unfavorable prognostic impact in diffuse large B-cell lymphoma, and tissue PD-L1+expression and T-cell-derived PD-1+expression have significant adverse impact only in patients with high T-cell infiltration. PD-1/PD-L1 interaction in tissue is essential but not always responsible for the inhibitory effect of PD-L1+/PD-1+expression. These results suggest the benefit of PD-1/PD-L1 blockade therapies only in patients with sufficient T-cell infiltration, and the potential of immunofluorescent assays and Automated Quantitative Analysis in the clinical assessment of PD-1/PD-L1 expression and interaction.

Injuries to the tarsometatarsal joint complex are known as Lisfranc injuries. Although relatively rare when considered with all other injuries about the foot and ankle, they are frequently seen in the orthopedic clinic. These injuries are often missed and can lead to long-standing pain and disability. Therefore, a high index of suspicion must be maintained by the evaluating orthopedic surgeon. Studies have shown that anatomic reduction is critical to obtain a good result. Transarticular screw fixation has the ability to obtain and maintain an anatomic reduction. This technique has historically been the most common method of treatment. But, follow-up studies have shown a high rate of posttraumatic arthritis and reoperation. This has led to the consideration of other means of treatment such as primary arthrodesis, extra-articular plating, and suture button fixation. Regardless of the chosen method, the goal of treatment is a stable, pain-free, plantigrade foot.Level of Evidence:Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background:A relative cardiovascular risk reduction of 25% to 35% has been reported in patients starting a statin for elevated cholesterol; yet many patients fail to consistently take these medications as directed. Objective:To evaluate factors affecting adherence and persistence with statin therapy. Methods:This retrospective study analyzed data from a Veterans Affairs database of facilities west of the Rocky Mountains. Patient demographics, co-morbidities, and prescription information was collected for individuals newly prescribed a statin between July 1, 2007, and December 31, 2012. Adherence was determined using the medication possession ratio (MPR). Persistence was defined as the time from initiation of therapy until a refill gap of 135 days or greater occurred. Results:Of 164 687 unique patients, overall adherence to statins a mean MPR of 0.843. Approximately 63% of patients were persistent with statin therapy 675 days after statin initiation. Patients prescribed pravastatin, atorvastatin, lovastatin, and rosuvastatin and those who took more than 1 different statin during the follow-up period had statistically significantly higher rates of adherence than those prescribed simvastatin. Older patients and those with a greater number of active prescriptions were found to be more adherent to statin medications. Patients with hypertension were more adherent to a statin, and those with diabetes mellitus and/or posttraumatic stress disorder (PTSD) were less adherent. Conclusion and Relevance:In veterans, overall statin adherence was excellent. Certain populations may benefit from interventions targeted at improving statin adherence, including younger veterans, those prescribed fewer medications, those taking simvastatin, and veterans with PTSD or diabetes mellitus.

Fresh allograft transplantation of osteochondral defects restores functional articular cartilage and subchondral bone; however, rapid loss of chondrocyte viability during storage and osteoclast-mediated bone resorption at the graft–host interface after transplantation negatively impact outcomes. The authors present a pilot study evaluating the in vitro and in vivo impact of augmenting storage media with bisphosphonates. Forty cylindrical osteochondral cores were harvested from femoral condyles of human cadaveric specimens and immersed in either standard storage media or storage media supplemented with nitrogenated or non-nitrogenated bisphosphonates. Maintenance of graft structure and chondrocyte viability were assessed at 3 time points. A miniature swine trochlear defect model was used to evaluate the influence of bisphosphonate-augmented storage media on in vivo incorporation of fresh osteochondral tissue, which was quantified via μCT and decalcified histology. In the in vitro study, Safranin-O/Fast Green staining showed that both low- and high-dose nitrogenated-treated grafts retained chondrocyte viability and cartilage matrix for up to 43 days of storage. Allografts stored in nitrogenated-augmented storage media showed both μCT and histologic evidence of enhanced in vivo bony and cartilaginous incorporation in the miniature swine trochlear defect model. Several preclinical studies have shown the potential for enhanced storage of fresh osteochondral allografts via additions of relatively common drugs and biomolecules. This study showed that supplementing standard storage media with nitrogenated bisphosphonates may improve maintenance of chondrocyte viability and graft structure during cold storage as well as enhance in vivo osseous and cartilaginous incorporation of the graft. [Fresh allograft transplantation of osteochondral defects restores functional articular cartilage and subchondral bone; however, rapid loss of chondrocyte viability during storage and osteoclast-mediated bone resorption at the graft–host interface after transplantation negatively impact outcomes. The authors present a pilot study evaluating the in vitro and in vivo impact of augmenting storage media with bisphosphonates. Forty cylindrical osteochondral cores were harvested from femoral condyles of human cadaveric specimens and immersed in either standard storage media or storage media supplemented with nitrogenated or non-nitrogenated bisphosphonates. Maintenance of graft structure and chondrocyte viability were assessed at 3 time points. A miniature swine trochlear defect model was used to evaluate the influence of bisphosphonate-augmented storage media on in vivo incorporation of fresh osteochondral tissue, which was quantified via μCT and decalcified histology. In the in vitro study, Safranin-O/Fast Green staining showed that both low- and high-dose nitrogenated-treated grafts retained chondrocyte viability and cartilage matrix for up to 43 days of storage. Allografts stored in nitrogenated-augmented storage media showed both μCT and histologic evidence of enhanced in vivo bony and cartilaginous incorporation in the miniature swine trochlear defect model. Several preclinical studies have shown the potential for enhanced storage of fresh osteochondral allografts via additions of relatively common drugs and biomolecules. This study showed that supplementing standard storage media with nitrogenated bisphosphonates may improve maintenance of chondrocyte viability and graft structure during cold storage as well as enhance in vivo osseous and cartilaginous incorporation of the graft. [Orthopedics: 2018; 41(3):e376–e382.]

Osteochondral lesions of the talus (OLTs) are an increasingly implicated cause of ankle pain and instability. Several treatment methods exist with varying clinical outcomes. Due in part to successful osteochondral allografting (OCA) in other joints, such as the knee and shoulder, OCA has gained popularity as a treatment option, especially in the setting of large lesions. The clinical outcomes of talar OCA have been inconsistent relative to the positive results observed in other joints. Current literature regarding OCA failure focuses mainly on 3 factors: the effect of graft storage conditions on chondrocyte viability, graft/lesion size, and operative technique. Several preclinical studies have demonstrated the ability for bone and cartilage tissue to invoke an immune response, and a limited number of clinical studies have suggested that this response may have the potential to influence outcomes after transplantation. Further research is warranted to investigate the role of immunological mechanisms as an etiology of OCA failure.Level of Evidence:Level V, expert opinion.

The oldest-old (those aged ≥80 years) are the most rapidly growing age group globally, and are most in need of health care and assistance. We aimed to assess changes in mortality, disability in activities of daily living, and physical and cognitive functioning among oldest-old individuals between 1998 and 2008.

Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2VAF predicted for monocytosis (P=0.003), RUNX1VAF with thrombocytopenia (P=0.01) and SF3B1with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood.

PURPOSE: To evaluate the routine clinical value of attenuation-corrected whole-body fluorodeoxyglucose positron emission tomography in colorectal cancer, a total of 59 patients who were referred for evaluation of suspected or proven colorectal cancers were studied. METHODS: Positron emission tomography scans were recorded using a Siemens ECAT Exact 921/47. RESULTS: Median follow-up after the positron emission tomography study was 11 (mean, 12.3; range, 1–21) months. According to computed tomography, coloscopy, and ultrasound, we recorded eight apparently false-positive results. During later follow-up, however, three of those cases, which were negative with computed tomography, magnetic resonance imaging, sonography, or laparoscopy, turned out to be true-positive instead. In 3 patients, a primary colorectal cancer was suspected; in 26 patients, a recurrence of colorectal cancer was suspected. Eight patients were studied for follow-up after the history of colorectal cancer with no suspicion of recurrence. In 12 patients, the rise of serum tumor marker concentrations was the reason for the positron emission tomography study; 12 patients with known metastatic disease were also included (“restaging”). With regard to the entire patient population, we found an overall sensitivity of 100 percent, a specificity of 67 percent, and positive and negative predictive values of 92 and 100 percent, respectively. Being merely confirmative with respect to tumor recurrence or distant metastases in the majority of patients, positron emission tomography revealed a primary tumor in one patient and confirmed metastatic foci in several patients that had not been delineated by other imaging modalities. CONCLUSION: A whole-body positron emission tomography scan provides optimum conditions to locate metastatic lesions that might not be seen otherwise. There is a trend showing that positron emission tomography diagnostics as a consequence of early increased tumor markers is a highly sensitive combination, because computed tomography and magnetic resonance imaging were not as sensitive in early recurrences. Positron emission tomography, as performed in daily clinical practice, proved to be a powerful diagnostic tool in our subset of colorectal cancer patients.

YBa2Cu3O7step-edge junctions are fabricated on SrTiO3-substrates. The steps of 300nm height are milled by argon-ion-beam-etching (IBE). The films are deposited by high-pressure on-axis magnetron sputter technique patterned to microbridges with widths down to 0.5µm by electron beam lithography and argon ion etching. For ratios of film thickness to step height of t/h≈1/2 the current-voltage characteristics show Shapiro steps under microwave irradiation and RSJ-(resistively shunted junction)-like behavior. The periodic dependence of the critical current upon the magnetic field resembles a Fraunhofer-pattern. The period of the variation ΔB0follows a 1/w2-dependence in agreement with the theoretical prediction for planar thin Josephson junctions : ΔB0=1.84Φ0/W2. Junctions with widths of 0.7µm possess a large magnetic field stability with ΔB0≈100G. Small junctions (w<1µm) exhibit voltage jumps in the Fraunhofer pattern, which are explained by flux penetration of single vortices into the superconducting electrodes. The developed preparation technique for "field-stable" Josephson junctions will be used for wafer scaling on 2-inch substrates and for the production of magnetically stable rf-SQUIDs.

Summary A 64-year-old man with high malignant B-cell lymphoma in both adrenal glands was investigated. Adrenal insufficiency was his predominant symptom at presentation. Despite surgical resection of the malignancy and cytostatic chemotherapy leptomeningeal involvement occurred and the patient died nine month after the diagnosis. Nine so far reported cases with primary adrenal lymphoma were reviewed. One of these also developed lymphomatous leptomeningitis. Suggestions of a pathogenetic contribution of adrenal lymphoma to leptomeningeal involvement and arising therapeutic consequences in the treatment of primary adrenal lymphoma are discussed.

Supplemental Digital Content is available in the text.

The primary purpose of this study was to determine whether the Sanders computed tomography (CT) scan classification was still prognostic for outcome when long-term (10–20 years) radiographic and functional data of patients after open reduction and internal fixation for Sanders type II versus type III displaced intra-articular calcaneal fractures (DIACFs) were compared. The secondary purpose was to assess whether a bone graft or a locked plate was needed to maintain a reduction over time.

AbstractPrevious preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence.

Several letters to the editor are presented in response to articles in previous issues, including "25 Years After the Japanese Onslaught, Germany Is Still Winning," in the May 2014 issue, "How're Ya Dying" in the May 2014 issue and "Power: Chevrolet Corvette Stingray vs. 1990 Ferrari Testarossa" in the May 2014 issue.

We present a high-energy, high-average-power picosecond laser system based on a hybrid chain in a master oscillator power amplifier configuration. The chain is seeded by a Ti:sapphire oscillator, followed by a Yb-doped fiber preamplifier, a Nd:YAG-based regenerate amplifier, and a Nd:YVO_4-based single-pass amplifier. The final diode-pumped, solid-state amplifier is detailed and produces pulses with more than 10 mJ energy at 32 W average power with 207 ps duration, corresponding to 50 MW peak power. The picosecond pulse output is seeded and optically synchronized with the sub-5-fs oscillator for optical parametric chirped-pulse amplification pumping.

A rapidly increasing proportion of people in high-income countries are surviving into their tenth decade. Concern is widespread that the basis for this development is the survival of frail and disabled elderly people into very old age. To investigate this issue, we compared the cognitive and physical functioning of two cohorts of Danish nonagenarians, born 10 years apart.

Studies examining predictors of survival among the oldest-old have primarily focused on objective measures, such as physical function and health status. Only a few studies have examined the effect of personality traits on survival, such as optimism. The aim of this study was to examine whether an optimistic outlook predicts survival among the oldest-old. The Danish 1905 Cohort Surveyis a nationwide, longitudinal survey comprising all individuals born in Denmark in 1905. At baseline in 1998, a total of 2,262 persons aged 92 or 93 agreed to participate in the intake survey. The baseline in-person interview consisted of a comprehensive questionnaire including physical functioning and health, and a question about whether the respondent had an optimistic, neutral or pessimistic outlook on his or her own future. During the follow-up period of 12 years (1998–2010) there were 2,239 deaths (99 %) in the 1905 Cohort Survey. Univariable analyses revealed that optimistic women and men were at lower risk of death compared to their neutral counterparts [HR 0.82, 95 % CI (0.73–0.93) and 0.81, 95 % CI (0.66–0.99), respectively]. When confounding factors such as baseline physical and cognitive functioning and disease were taken into account the association between optimism and survival weakened in both sexes, but the general pattern persisted. Optimistic women were still at lower risk of death compared to neutral women [HR 0.85, 95 % CI (0.74–0.97)]. The risk of death was also decreased for optimistic men compared to their neutral counterparts, but the effect was non-significant [HR 0.91, 95 % CI (0.73–1.13)]. An optimistic outlook appears to be a significant predictor of survival among the oldest-old women. It may also be a significant predictor for men but the sample size is small.

Backgroud:Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently. Methods:Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF-1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified. Results:Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only. Conclusions:WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

A Joule-class, narrow-linewidth amplifier line delivering 20 ns pulses with a TEM00 spatial profile is presented. A Q-switched Nd:YAG oscillator with an intra-cavity volume Bragg grating (VBG) is used to seed the amplifier line. A series of flashlamp-pumped Nd:YAG amplifiers consisting of a double-pass and two single-pass amplifiers boost the energy of the 21 ns pulses to 480 mJ. The presented amplifier line will be used for fundamental studies including remote Raman spectroscopy and ns filamentation.

Als während des Ersten Weltkrieges der Pfeffer, das beliebteste Scharfstoffgewürz der Deutschen, knapp wurde, synthetisierte Hermann Staudinger, der Chemie‐Nobelpreisträger des Jahres 1953, in Zusammenarbeit mit Paul Immerwahr einen Piperin‐ähnlichen Scharfstoff. Auf indifferente Füllstoffe aufgetragen, kam er zwischen 1917–1923 und abermals zwischen 1940–1948 als “Kunstpfeffer” in den Handel. Als nach Kriegsende wieder Naturpfeffer zur Verfügung stand, wurde die Herstellung des qualitativ schlechten, teuren Ersatzpfeffers eingestellt. Trotz der auf die Kriegs‐ und frühen Nachkriegsjahre beschränkten Produktion verschiedener Ersatzgewürze hatte die Suche nach entsprechenden Synthesen zur Herstellung einzelner Duftstoffe einen entscheidenden Einfluss auf die sich allmählich entwickelnde Aromastoffindustrie.

If the pace of increase in life expectancy in developed countries over the past two centuries continues through the 21st century, most babies born since 2000 in France, Germany, Italy, the UK, the USA, Canada, Japan, and other countries with long life expectancies will celebrate their 100th birthdays. Although trends differ between countries, populations of nearly all such countries are ageing as a result of low fertility, low immigration, and long lives. A key question is: are increases in life expectancy accompanied by a concurrent postponement of functional limitations and disability? The answer is still open, but research suggests that ageing processes are modifiable and that people are living longer without severe disability. This finding, together with technological and medical development and redistribution of work, will be important for our chances to meet the challenges of ageing populations.

Next generation THz applications require specially tailored THz pulses. Systems that use optical rectification in crystals as their THz source are susceptible to changes in the pulse envelope. Our feedback-loop system designed around a pulse shaper with a liquid crystal mask can shape the phase and amplitude of the excitation pulse and optimize the shape of the emitted THz waveform. This is demonstrated using as an example the creation of single-cycle THz pulses.

In the quest to address the ageing population, labour shortages and demographic decline, this article advocates the redistribution of work over the course of individuals’ lives. Work hours must be spread more evenly over a longer life span. In this way, individuals will have the time necessary to bear and rear children and will be able to offer their expertise later in life. With such a policy, the elderly population would be occupied and supportive of society and youth would have the opportunity to conceive and care for children during those years in which they are physically able to do so.

The dispersion functions for the refractive index and the extinction coefficient of single- and multiple-layer graphene oxide samples were measured by imaging spectroscopic ellipsometry in the wavelength range of 350−1000 nm and were compared to previously reported results measured by confocal microscopy. The dispersion functions for thin platelets were also compared to those obtained by standard spectroscopic ellipsometry on a deposit consisting of many overlapping graphene oxide layers. Changes were observed in both the thickness of the deposits and the values of the dispersion parameters following heating. A model is proposed to explain these observations, based on the removal of water between the graphene-oxide layers upon thermal treatment.

The method of imaging spectroscopic ellipsometry is applied on magnetic read/write heads of hard disks. By means of spectroscopic ellipsometry, an optical model of the TiC/Al2O3substrate including surface roughness and concentration gradient of TiC in the alumina substrate is generated. Surface roughness is measured with both ellipsometry and atomic force microscopy (AFM). The granular structure of TiC/Al2O3is investigated in micrographs of nand k. It is discussed how Delta mapping of the magnetic pole area of the head can be used to measure DLC coating thickness and the variation of chemical constitution of the metal substrate. Repeatability of measurements of Delta is optimized in a one µm2region of interest (ROI) on a metal stripe of the magnetic pole. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

This review examines sex differences in health and survival, with a focus on the Nordic countries. There is a remarkable discrepancy between the health and survival of the sexes: men are physically stronger and have fewer disabilities, but have substantially higher mortality at all ages compared with women: the so-called male-female health-survival paradox. A number of proposed explanations for this paradox are rooted in biological, social, and psychological interpretations. It is likely to be due to multiple causes that include fundamental biological differences between the sexes such as genetic factors, immune system responses, hormones, and disease patterns. Behavioral differences such as risk-taking and reluctance to seek and comply with medical treatment may also play a role. Another consideration is that part of the difference may be due to methodological challenges, such as selective non-participation and under-reporting of health problems, and delayed seeking of treatment by men. The Nordic countries provide a unique opportunity for such studies, as they have good-quality data in their national health registers, which cover the whole population, and a long tradition of high participation rates in surveys.

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Im Gegensatz zur Rolle der Chemie in den Weltkriegen wurde die Rolle der Chemie im deutsch-französischen Krieg 1870/71 bisher noch wenig untersucht. In diesem nur 190 Tage dauernden Waffengang, der so viele Tote und Verletzte forderte wie kein anderer neuzeitlicher Krieg, wurden die Aktivitäten der Chemiker auf deutscher wie auf französischer Seite von den jeweiligen chemischen Gesellschaften beider Länder koordiniert. Auf deutscher Seite stand die Beschaffung von Desinfektionsmitteln, insbesondere Carbolsäure, im Vordergrund, während sich die französischen Chemiker bemühten, den Munitions- und Nahrungsmittelmangel im belagerten Paris zu beheben.

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