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We have found that vinculin is localized at the sarcolemma of skeletal muscle cells in a two-dimensional orthogonal lattice. Perpendicular to the longitudinal axis of the cell, bands of vinculin encircle the muscle cell and repeat along its length with a periodicity corresponding to the subjacent sarcomeres. Because of their appearance and probable function, we call the transverse elements of the lattice ``costameres'' (Latin costa, rib; Greek meros, part). Costameres have a substructure consisting of densely clustered patches of vinculin; the patches are segregated into two rows which flank the Z line and overlie the I band of the underlying sarcomere. It is likely that the costameres are physically coupled to the underlying myofibrils because: (i) the costameres broaden and narrow in concert with the underlying I band in stretched and contracted muscle, and (ii) adjacent but misaligned myofibrils are mirrored by corresponding discontinuities in the overlying costameres. We hypothesize that the sarcolemmal lattice, detected because vinculin is one of its molecular components, integrates the contractile apparatus with the sarcolemma during lengthening and shortening of the muscle cells.

Molecular recognition between proteins and their interacting partners underlies the biochemistry of living organisms. Specificity in this recognition is thought to be essential, whereas promiscuity is often associated with unwanted side effects, poor catalytic properties and errors in biological function. Recent experimental evidence suggests that promiscuity, not only in interactions but also in the actual function of proteins, is not as rare as was previously thought. This has implications not only for our fundamental understanding of molecular recognition and how protein function has evolved over time but also in the realm of biotechnology. Understanding protein promiscuity is becoming increasingly important not only to optimize protein engineering applications in areas as diverse as synthetic biology and metagenomics but also to lower attrition rates in drug discovery programs, identify drug interaction surfaces less susceptible to escape mutations and potentiate the power of polypharmacology.

In Tanzania, inadequate access to comprehensive emergency obstetric and newborn care (CEmONC) services is the major bottleneck for perinatal care and results in high maternal and perinatal mortality. From 2015 to 2019, the Accessing Safe Deliveries in Tanzania project was implemented to study how to improve access to CEmONC services in underserved rural areas. A five-year longitudinal cohort study was implemented in seven health centres (HCs) and 21 satellite dispensaries in Morogoro region. Five of the health centres received CEmONC interventions and two served as controls. Forty-two associate clinicians from the intervention HCs were trained in teams for three months in CEmONC and anaesthesia. Managers of 20 intervention facilities, members of the district and regional health management teams were trained in leadership and management. Regular supportive supervision was conducted. Integration of leadership and managerial capacity building, with CEmONC-specific interventions was associated with health systems strengthening and improved quality of services.

The U.S. was at war for nearly two decades, supporting unprecedented survival on the battlefield. As the nation pivots to a relative peace, it is critical that U.S. Army certified registered nurse anesthetist (CRNA) leaders mitigate the loss of lessons learned and prepare future Army CRNAs for war. This article describes the U.S. Army CRNA Readiness Model that incorporates the knowledge, skills, and abilities required to sustain readiness. This model will provide U.S. Army nursing leaders with the framework to implement and evaluate solider readiness to provide anesthesia in operational environments.

Background The Cancer Center Cessation Initiative (C3I) was launched in 2017 as a part of the NCI Cancer Moonshot program to assist NCI-designated cancer centers in developing tobacco treatment programs for oncology patients. Participating centers have implemented varied evidence-based programs that fit their institutional resources and needs, offering a wide range of services including in-person and telephone-based counseling, point of care, interactive voice response systems, referral to the quitline, text- and web-based services, and medications. Methods We used a mixed methods comparative case study design to evaluate system-level implementation costs across 15 C3I-funded cancer centers that reported for at least one 6-month period between July 2018 and June 2020. We analyzed operating costs by resource category (e.g., personnel, medications) concurrently with transcripts from semi-structured key-informant interviews conducted during site visits. Personnel salary costs were estimated using Bureau of Labor Statistics wage data adjusted for area and occupation, and non-wage benefits. Qualitative findings provided additional information on intangible resources and contextual factors related to implementation costs. Results Median total monthly operating costs across funded centers were $11,045 (range: $5129–$20,751). The largest median operating cost category was personnel ($10,307; range: $4122–$19,794), with the highest personnel costs attributable to the provision of in-person program services. Monthly (non-zero) cost ranges for other categories were medications ($17–$573), materials ($6–$435), training ($96–$516), technology ($171–$2759), and equipment ($10–$620). Median cost-per-participant was $466 (range: $70–$2093) and cost-per-quit was $2688 (range: $330–$9628), with sites offering different combinations of program components, ranging from individually-delivered in-person counseling only to one program that offered all components. Site interviews provided context for understanding variations in program components and their cost implications. Conclusions Among most centers that have progressed in tobacco treatment program implementation, cost-per-quit was modest relative to other prevention interventions. Although select centers have achieved similar average costs by offering program components of various levels of intensity, they have varied widely in program reach and effectiveness. Evaluating implementation costs of such programs alongside reach and effectiveness is necessary to provide decision makers in oncology settings with the important additional information needed to optimize resource allocation when establishing tobacco treatment programs.

Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference −1·91 h [95% CI −3·05 to −0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. AbbVie.

Abstract Rationale Studies have shown that reducing sedation of critically ill patients shortens time on the ventilator and in the intensive care unit (ICU). Little is known, however, of how such strategies affect long-term cognitive, psychological, and functional outcomes. Objectives To determine the long-term effects of a wake up and breathe protocol that interrupts and reduces sedative exposure in the ICU. Methods In this a priori planned substudy conducted at one tertiary care hospital during the Awakening and Breathing Controlled Trial, a multicenter randomized controlled trial, we assessed cognitive, psychological, and functional/quality-of-life outcomes 3 and 12 months postdischarge among 180 medical ICU patients randomized to paired daily spontaneous awakening trials with spontaneous breathing trials (SBTs) or to sedation per usual care plus daily SBTs. Measurements and Main Results Cognitive impairment was less common in the intervention group at 3-month follow-up (absolute risk reduction, 20.2%; 95% confidence interval, 1.5–36.1%; P = 0.03) but not at 12-month follow-up (absolute risk reduction, −1.9%; 95% CI, −21.3 to 27.1%; P = 0.89). Composite cognitive scores, alternatively, were similar in the two groups at 3-month and 12-month follow-up (P = 0.80 and 0.61, respectively), as were symptoms of depression (P = 0.59 and 0.82) and posttraumatic stress disorder (P = 0.59 and 0.97). Activities of daily living, functional status, and mental and physical quality of life were similar between groups throughout follow-up. Conclusions In this trial, management of mechanically ventilated medical ICU patients with a wake up and breathe protocol resulted in similar cognitive, psychological, and functional outcomes among patients tested 3 and 12 months post-ICU. The proven benefits of this protocol, including improved 1-year survival, were not offset by adverse long-term outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT00097630).

Italian has a length contrast in its series of voiced and voiceless obstruents while also presenting phonetic differences across regional varieties. Northern varieties of the language, including Veneto Italian (VI), are described as maintaining the voicing contrast but, in some cases, not the length contrast. In central and southern varieties, the opposite trend may occur. For instance, Roman Italian (RI) is reported to optionally pre-voice intervocalic voiceless singleton obstruents whilst also maintaining the length contrast for this consonant class. This study looks at the acoustic realization of selected obstruents in VI and RI and investigates (a) prevoicing patterns and (b) the effects and interactions of regional variety, gemination, and (phonological and phonetic) voicing on consonant (C) and preceding-vowel (V) durations, as well as the ratio between the two (C/V), with a focus on that particular measure. An acoustic phonetic analysis is conducted on 3703 tokens from six speakers from each variety, producing eight repetitions of 40 real CV́C(C)V and CVC(C)V́CV words embedded in carrier sentences, with /p, pp, t, tt, k, kk, b, bb, d, dd, ɡ, ɡɡ, f, ff, v, vv, t∫, tt∫, dʒ, ddʒ/ as the target intervocalic consonants. The results show that both VI and RI speakers produce geminates, yielding high C/V ratios in both varieties, although there are cross-regional differences in the realization of singletons. On the one hand, RI speakers tend to pre-voice voiceless singletons and produce overall shorter C durations and lower C/V ratios for these consonants. On the other hand, VI speakers produce longer C durations and higher C/V ratios for all voiceless singletons, triggering some overlap between the C length categories, which results in partial degemination through singleton lengthening, although only for voiceless obstruents. The implications of a trading relationship between phonetic voicing and duration of obstruents in Italian gemination are discussed.

The aim was to determine whether commercial baby foods marketed within Europe (up to 36 months of age) have inappropriate formulation and high sugar content and to provide suggestions to update European regulations and recommendations as part of a nutrient profile model developed for this age group. The latter was produced following recommended World Health Organization (WHO) steps, including undertaking a rapid literature review. Packaging information from countries across the WHO European region was used to determine mean energy from total sugar by food category. The percentage of products containing added sugar and the percentage of savoury meal‐type products containing pureed fruit were also calculated. A total of 2,634 baby foods from 10 countries were summarised: 768 sold in the United Kingdom, over 200 each from Denmark (319), Spain (241), Italy (430) and Malta (243) and between 99–200 from Hungary, Norway, Portugal, Estonia and Slovenia. On average, approximately a third of energy in baby foods in these European countries came from total sugar, and for most food categories, energy from sugar was higher than 10%. Use of added sugars was widespread across product categories, with concentrated fruit juice most commonly used. Savoury meal‐type purees did not contain added sugars except in United Kingdom and Malta; however, fruit as an ingredient was found in 7% of savoury meals, most frequently seen in UK products. Clear proposals for reducing the high sugar content seen in commercial baby foods were produced. These suggestions, relating to both content and labelling, should be used to update regulations and promote product reformulation.