Reversible computation has been recognized as a potential solution to the technological bottleneck in the future of computing machinery. Rolf Landauer determined the lower limit for power dissipation in computation and noted that dissipation happens when information is lost, that is, when a bit is erased. This meant that with reversible computation, conserving information conserves energy as well, and as such can operate on arbitrarily small power. There were only a few applications and use cases of reversible computing hardware. Here, we present a novel reversible computation architecture for time reversal of waves, with an application to sound wave communications. This energy-efficient design is also a natural one, and it allows the use of the same hardware for transmission and reception at the time reversal mirror.

Immune checkpoint inhibitors (ICI), monoclonal antibodies enhancing T cell responses against tumour cells, have revolutionised the treatment of cancers such as advanced melanoma, leading to enhanced survival. Their action, however, is not tumour-specific, and patients can develop multisystem immune related adverse events (irAE). Neurological irAEs have been reported in 1–14% of patients, depending upon the ICI used, and can affect any part of the neuro-axis. A recent case series from the Royal Marsden Hospital (RMH) identified 10 patients with neurotoxicity following ICI for advanced melanoma between 2010–15, specifically neuropathy (6), plexopathy (1) and aseptic meningitis (3). Exactly how neurological injury occurs, whether cell-, cytokine- or antibody-mediated, is unknown. We present early data from a newly established collaboration with RMH, aiming to clinically characterize these patients, and identify the cause of neurological injury. To date, we have advised on patients (age range 53–80) with myositis, Guillain-Barré (GBS)-like neuropathy, plexopathy, aseptic meningitis, and encephalitis following ICI (ipilimumab and/or nivolumab) for advanced melanoma. Features common to these patients include their subacute onset, time from ICI administration, and steroid responsiveness (including in GBS-like cases). The incidence of neurological irAEs following ICI will rise with increasing use, and is therefore of concern to practicing neurologists.

The finite element method and the DEFORM software were used for the plastic metal flow prediction of ring shaped parts. Various parameters that affect the forging operation are the material characteristics like material strength, ductility, deformation rate, temperature sensitivity and frictional characteristics of the workpiece, preform design, die design and die material. Numerical simulation has been done for axisymmetric automobile parts. The procedure of numerical modeling contains all simulations phases like the movement of preform from inductor to the tool, placement and setting of preform piece inside the tool before the blow in order to get as good result as possible. These techniques are used to reduce the amount of input material for forgings, extend the lifetime of forging dies, and prevent defects in forged components.

The North American oak lace bug feeds on leaves of ‘white oaks” in its native range. In Europe, it was first discovered in northern Italy in 2000. In recent years, it has subsequently spread rapidly and population outbreaks have been observed in several European countries. In the present study, we summarize the steps of its expansion. To predict its potential host range, we checked 48 oak species in 20 sentinel gardens in seven countries between 2013 and 2018. In total, 27 oak species were recorded as suitable hosts; 13 of them are globally new ones, 23 out of the 29 in section Quercus (∼ white oaks, an intrageneric taxonomic unit within genus Quercus), including Asian oaks, native to Japan, Korea and China, and four out of five in section Cerris (another intrageneric unit of the same genus), were accepted as hosts. None of the species in section Lobatae (red oaks) or in the Ilex group was accepted. Host records were also collected in forest stands of 10 countries. We found 11 oak species that were infested. Outbreak populations were most commonly found on Quercus robur, Quercus frainetto, Quercus petraea and Quercus cerris, comprising widespread and outstandingly important oaks species in Europe. Based on our findings, we conclude that suitable hosts for oak lace bug are present in most of Europe and Asia. This means that a lack of hosts will likely not restrict further range expansion.

Abstract The paper presents the development of the mathematical model of joint parameters impact, during solid wood lengthening with a mini tooth, on the joint strength. Impact parameters are wood density (ρ), ratio of wood element width and thickness (b/h) and geometrical size of mini tooth expressed as ratio of length and distance between width of the tooth (l/p). This paper presents an example of how the process of joining solid wood can be optimized prior to the production process to avoid exploitation testing and increased costs of the process. Based on the obtained model (F), force optimization was performed as a function of the maximum tensile force. The results of the conducted research indicate that mathematical modelling and optimization can be successfully used to define the tensile break force and technological parameters of solid wood elements lengthened by finger joint.

BackgroundThe wars that ravaged the former Socialist Federal Republic of Yugoslavia in the 1990’s resulted in the near destruction of the healthcare system, including education of medical students and the training of specialist physicians. In the latter stages of the war, inspired by Family Medicine programs in countries such as Canada, plans to rebuild a new system founded on a strong primary care model emerged. Over the next fifteen years, the Queen’s University Family Medicine Development Program in Bosnia and Herzegovina played an instrumental role in rebuilding the primary care system through educational initiatives at the undergraduate, residency, Masters, PhD, and continuing professional development levels. Changes were supported by new laws and regulations to insure sustainability. This study revisited Bosnia and Herzegovina (B-H) 8-years after the end of the program to explore the impact of initiatives through understanding the perspectives and experiences of individuals at all levels of the primary care system from students, deans of medical schools, Family Medicine residents, practicing physicians, Health Center Directors and Association Leaders.MethodsQualitative exploratory design using purposeful sampling. Semi-structured interviews and focus groups with key informants were conducted in English or with an interpreter as needed and audiotaped. Transcripts and field notes were analyzed using an interpretative phenomenological approach to identify major themes and subthemes.ResultsOverall, 118 participants were interviewed. Three major themes and 9 subthemes were identified including (1) The Development of Family Medicine Education, (subthemes: establishment of departments of family medicine, undergraduate medical curriculum change), (2) Family Medicine as a Discipline (Family Medicine specialization, academic development, and Family Medicine Associations), and (3) Health Care System Issues (continuity of care, comprehensiveness of care, practice organization and health human resources).ConclusionsDespite the impact of years of war and the challenges of a complex and unstable postwar environment, initiatives introduced by the Queen’s Program succeeded in establishing sustainable changes, allowing Family Medicine in B-H to continue to adapt without abandoning its strong foundations. Despite the success of the program, the undervaluing of Primary Care from a human resource and health finance perspective presents ongoing threats to the system.

Background Human herpes-virus 8-negative/idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder involving multicentric lymphadenopathy with characteristic histopathology. Clinical presentation is heterogenous and includes cytokine-driven constitutional symptoms, cytopenias, systemic inflammation, and multi-organ dysfunction. International consensus treatment guidelines are based on a large cohort of case studies and a few clinical trials, but the available evidence is limited. Siltuximab, an anti-IL-6 therapy, is the only FDA-approved treatment for iMCD; 34% of patients achieved durable symptomatic and tumor response in the phase II trial. Tocilizumab, an anti-IL-6 receptor therapy, is frequently used off label and demonstrated promising results in an open-label study in Japan. The treatment guidelines recommend siltuximab ± corticosteroids (CS) as first-line therapy for all iMCD patients and tocilizumab as a substitute when siltuximab is not available. Rituximab, a CD20 antibody, is recommended as an alternate first-line therapy in patients who are non-severe and do not exhibit marked cytokine-driven symptoms. In all other patients, rituximab is recommended second-line; however, it has never been systematically evaluated in iMCD. Chemotherapies, immunosuppressants, and immunomodulators are recommended second- or third-line, but again, effectiveness is not well described. Better understanding of treatment effectiveness is urgently needed. Herein, we describe treatment and response in a real-world cohort of iMCD patients. Methods Data were collected and abstracted for 68 patients enrolled in an on-going IRB-approved natural history study of Castleman disease. Diagnosis is graded by an expert panel of clinicians and pathologists on an on-going basis; patients unlikely to have iMCD were excluded from analysis (N=12). Of the 56 patients included, 37 (66%) are expert panel-confirmed and 19 (34%) are awaiting confirmation. Durable response is defined as achieving ≥50% improvement in the proportion of abnormal iMCD minor clinical and laboratory diagnostic criteria sustained for ≥1 year. Small sample size prevented statistical comparisons. Results Median age at diagnosis is 33 years (range: 1-65 years). The cohort is 52.9% female, 63% white, and 4 (7%) patients died. Thirty-three unique drugs, including anti-IL-6 therapies, CS, chemotherapies, immunosuppressants, and others have been administered across the 56 patients. Rituximab is the most frequently used drug, administered to 39 (70%) patients. Siltuximab (29 patients, 52%) and tocilizumab (19 patients, 34%) are the next two most frequently used targeted therapies. There was a 52% response (15/29) to regimens inclusive of siltuximab, 50% response (9/18) to those inclusive of tocilizumab, and 25% response (9/26) to those inclusive of rituximab. Siltuximab±CS induced response in 15/24 (63%) patients, tocilizumab±CS in 4/7 (57%), and rituximab±CS in 2/13 (15%). Among the 37 expert-confirmed iMCD patients, we found a 58% response (11/19) to regimens inclusive of siltuximab, 47% (8/17) to those inclusive of tocilizumab, and 27% (7/26) to those inclusive of rituximab. Further, in these patients, siltuximab±CS induced response in 11/16 (69%), tocilizumab±CS in 3/6 (50%), and rituximab±CS in 1/6 (17%) patients. Of note, 3 of 4 deceased patients received both anti-IL-6 therapy and rituximab and all 4 received chemotherapies and immunosuppressants but did not respond to any drug. Discussion These data reveal that despite there being one FDA-approved treatment, iMCD is treated with a variety of agents. Among the full cohort, siltuximab±CS demonstrated a 63% durable response, which was higher than the response reported in the clinical trial (not statistically compared). This may reflect differences in response criteria and/or disease activity of patients in clinical trials versus real world settings. Siltuximab and tocilizumab have never been systematically compared; in this cohort they demonstrated similar response. Considering the morbidity and mortality of iMCD, these data suggest that current therapies demonstrate important activity. However, additional agents are needed for refractory patients, who have few options and are at risk of death due to disease progression. Further data are needed to compare groups and identify optimal treatment protocols. Liu: BridgeBio Pharma: Employment, Equity Ownership. Gibson:EUSA Pharma: Employment. Kanhai:EUSA Pharma: Employment. Martin:EUSA Pharma: Employment. Srkalovic:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Foundation Medicine: Speakers Bureau; EUSA Pharma: Speakers Bureau. Uldrick:Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled ; Celgene: Other: research support from Celgene through a CRADA at the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Karyopharm Therapeutics: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Castleman Disease Collaborative Network: Consultancy. Fajgenbaum:Janssen Pharmaceuticals: Research Funding. Tocilizumab, a monoclonal antibody directed against IL-6-receptor, is approved for use in rheumatoid arthritis in the US. It is frequently used off-label in idiopathic multicentric Castleman disease (iMCD) and is recommended as a substitute first-line therapy in the International Consensus iMCD treatment guidelines. Rituximab, a monoclonal antibody directed against CD20, is used in rheumatoid arthritis and other autoimmune and cancerous disorders. It is frequently used off-label in iMCD and is recommended as an alternate first-line or a second-line therapy in the International Consensus iMCD treatment guidelines. Corticosteroids are used broadly in iMCD and are recommended as needed as useful adjunctive therapy in the International Consensus iMCD treatment guidelines.

We have developed a precise dictionary between the spectrum of primordial density fluctuations and the parameters of the effective field theory (EFT) of inflation that determine the primordial power spectrum (PPS). At lowest order the EFT contains two parameters: the slow-roll parameter $\epsilon$, which acts as an order parameter, and the speed of sound $c_s$. Applying second-order perturbation theory, we provide maps from the PPS to the EFT parameters that are precise up to the cube of the fractional change in the PPS $(\Delta \mathcal{P}/\mathcal{P})^3$, or less than $1\%$ for spectral features that modulate the PPS by $20\%$. While such features are not required when the underlying cosmological model is assumed to be $\Lambda$CDM they are necessary for alternative models that have no cosmological constant/dark energy. We verify the dictionary numerically and find those excursions in the slow-roll parameter that reproduce the PPS needed to fit Planck data for both $\Lambda$ and no-$\Lambda$ cosmological models.

O câncer é uma doença caracterizada pelo crescimento exacerbado das células podendo alastrar-se para outros órgãos e tecidos (metástase). O câncer de pele não melanoma é o tipo de câncer mais comum no Brasil contendo como uns dos fatores de risco a idade e a exposição prolongada ao sol. Os idosos, mediante a longevidade, apresentam maior suscetibilidade para adquirir o câncer de pele. Em face dessa realidade, faz-se necessário a intervenção da enfermagem direcionada a prevenção, com a disseminação da informação, atuação na detecção precoce de sinais indicativos da doença, bem como proceder pela orientação adequada. Trata-se de uma revisão narrativa da literatura por meio de abordagem qualitativa tendo como principais resultados: os idosos possuem sistema imune e tegumentar diferente, além de sofrerem consequências de fatores ambientais como exposição ao sol; a enfermagem deve intervir por meio da educação em saúde na Atenção Básica, além de oferecer uma assistência humanizada; possuir conhecimento de lesões pré-malignas para obtenção de prevenção considerável e utilização da regra ABCDE por intermédio do exame físico.

Abstract Despite the great progress made in neonatal and perinatal medicine over the last couple of decades, sepsis remains one of the main causes of morbidity and mortality. Sepsis in pediatric population was defined at the Pediatric Sepsis Consensus Conference in 2005. There is still no consensus on the definition of neonatal sepsis. Neonatal sepsis is a sepsis that occurs in the neonatal period. According to the time of occurrence, neonatal sepsis can be of early onset, when it occurs within the first 72 hours of birth and results from vertical transmission, and of late onset, in which the source of infection is found most often in the environment and occurs after the third day of life. The most common causes of early-onset sepsis are Group B Streptococcus (GBS) and E. coli. Risk factors can be mother-related and newborn-related. Clinical symptoms and signs of sepsis are quite unspecific. The dysfunction of different organs may imitate sepsis. On the other hand, infectious and non-infectious factors may exist simultaneously. The start of the antimicrobial therapy in any newborn with suspected sepsis should not be delayed. Pentoxifylline may have potential benefits in preterm newborns with sepsis. The only proven intervention that has been shown to reduce the risk of early-onset neonatal sepsis is intrapartum intravenous antibiotic administration to prevent GBS infection. It is still a great challenge to discontinue antibiotic treatment in non-infected newborns as soon as possible, because any extended antibiotic use may later be associated with other pathological conditions.

Pozegaca’ is the most important native plum genotype in southeast Europe. In this study, the phytochemical fruit composition of the ‘Pozegaca’ ecotype from four different growing regions was evaluated over three growing years. HPLC was used for identification and quantification of sugars, organic acids and phenolic compounds in the fruits. The total effects of growing years and regions on different phytochemical characteristics of ‘Pozegaca’ fruit were analysed using principal component analysis (PCA). Glucose, fructose, sucrose and sorbitol were detected as major sugars in ‘Pozegaca’ fruit. Malic, citric, fumaric and shikimic acids were identified in the studied plum ecotype. Glucose was the predominant sugar and malic acid was the predominant organic acid. A range of phenol compounds was identified, including hydroxycinnamic acids, flavonols, anthocyanins and flavan3-ols. The main factor affecting the fruit quality and phenol composition of the ‘Pozegaca’ plum ecotype in skin and pulp was the growing year. The geographical origin of the ‘Pozegaca’ ecotype appears to have no major influence on the phenol profile of ‘Pozegaca’ fruit. The results showed that air temperature has a strong correlation with sugar compounds (particularly with fructose and sucrose) and with some organic acids (fumaric, shikimic and citric). Related to the accumulation of phenol compounds, air temperature strongly correlated with flavanols (particularly with quercetin 3-rutinoside) and anthocyanins in pulp. Precipitation and altitude were strongly correlated with total phenols in pulp, chlorogenic acid in skin and pulp, neochlorogenic acid in pulp, and all three identified flavanols in pulp. The results showed that specific seasonal and geographic environmental conditions could significantly affect the content of secondary metabolites in ‘Pozegaca’ fruit.