The impact of musculoskeletal ill health on quality of life and function after critical care: a multicentre prospective cohort study.

Physical disability is a common component of post-intensive care syndrome, but the importance of musculoskeletal health in this population is currently unknown. We aimed to determine the musculoskeletal health state of intensive care unit survivors and assess its relationship with health-related quality of life; employment; and psychological and physical function. We conducted a multicentre prospective cohort study of adults admitted to intensive care for > 48 h without musculoskeletal trauma or neurological insult. Patients were followed up 6 months after admission where musculoskeletal health state was measured using the validated Musculoskeletal Health Questionnaire score. Of the 254 participants, 150 (59%) had a musculoskeletal problem and only 60 (24%) had received physiotherapy after discharge. Functional Comorbidity Index, Clinical Frailty Scale, duration of intensive care unit stay and prone positioning were all independently associated with worse musculoskeletal health. Musculoskeletal health state moderately correlated with quality of life, rs = 0.499 (95%CI 0.392-0.589); anxiety, rs = -0.433 (95%CI -0.538 to -0.315); and depression, rs = -0.537 (95%CI -0.631 to -0.434) (all p < 0.001). Patients with a musculoskeletal problem were less physically active than those without a problem (median (IQR [range]) number of 30 min physical activity sessions per week 1 (0-3.25 [0-7]) vs. 4 (1-7 [0-7]), p < 0.001, respectively). This study found that musculoskeletal health problems were common after intensive care unit stay. However, we observed that < 25% of patients received physical rehabilitation after discharge home. Our work has identified potential high-risk groups to target in future interventional studies.

Return to Activities of Daily Living after Breast Cancer Surgery: An Observational Prospective Questionnaire-Based Study of Patients Undergoing Mastectomy with or without Immediate Reconstruction.

Background: Patients often ask about the time taken to return to activities of daily living (ADLs) after breast surgery, but there is a lack of data to give accurate guidance. We aimed to assess the feasibility of a study to determine the time taken to return to ADLs after mastectomy with or without breast reconstruction. Materials and Methods: A prospective multicentre, self-reported questionnaire-based feasibility study of women who had undergone mastectomy ± reconstruction was performed, between Jan 2017 and Dec 2019. Women were asked to self-report when they returned to 15 ADLs with a 5-option time scale for "return to activity." Results: The questionnaire was returned by 42 patients (median [range] age: 64 [31-84]). Of these, 22 had simple mastectomy, seven mastectomy and implant reconstruction, seven mastectomy and autologous reconstruction (DIEP), and six did not specify. Overall, over 90% could manage stairs and brush hair by two weeks and 84% could get in and out of the bath by four weeks. By 1-2 months, 92% could do their own shopping and 86% could drive. 68% of women employed returned to work within four months. Compared to simple mastectomy, patients undergoing reconstruction took a longer time to return to getting in/out of bath (<2 vs. 2-4 weeks), vacuuming (2-4 weeks vs. 1-2 months), and fitness (1-2 vs. 3-4 months). There was a slower return to shopping (1-2 months vs. 2-4 weeks), driving and work (both 3-4 vs. 1-2 months), and sports (3-4 vs. 1-2 months) in autologous reconstruction compared to implant reconstruction. Conclusion: This study is feasible. It highlights slower return to specific activities (particularly strength-based) in reconstruction patients, slower in autologous compared with implant reconstruction. The impact on return to ADLs should be discussed as part of the preoperative counselling as it will inform patients and help guide their decision making. A larger study is required to confirm these results.

Sugar or salt ("SOS"): A protocol for a UK multicentre randomised trial of mannitol and hypertonic saline in severe traumatic brain injury and intracranial hypertension.

Hyperosmolar solutions are widely used to treat raised intracranial pressure following severe traumatic brain injury. Although mannitol has historically been the most frequently administered, hypertonic saline solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline compared with mannitol in the management of patients with severe traumatic brain injury. Patients requiring intensive care unit admission and intracranial pressure monitoring post-traumatic brain injury will be allocated at random to receive equi-osmolar boluses of either mannitol or hypertonic saline following failure of routine first-line measures to control intracranial pressure. The primary outcome for the study will be the Extended Glasgow Outcome Scale assessed at six months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments.

Assessing the impact of a gynaecomastia assessment and treatment infographic in primary care in Greater Manchester.

INTRODUCTION: Men with gynaecomastia are routinely referred to breast clinics, yet most do not require breast surgical intervention. The aim of this study was to assess the impact of a novel point-of-care gynaecomastia decision infographic in primary care on the assessment, management and referral practices to tertiary breast surgical services. METHODS: A study was carried out of male patient referrals from primary care in Greater Manchester to a tertiary breast centre between January and March in 2018-2020. Referral patterns were compared before and after the infographic went live in general practices in Greater Manchester in January 2020. Data were collected for gynaecomastia referrals, including aetiology, investigation and management. RESULTS: In total, 394 men were referred to a tertiary breast centre from 163 general practices, of which 271 (68.8%) had a diagnosis of gynaecomastia. Use of the decision infographic by primary healthcare providers was associated with a decrease in male breast referrals with gynaecomastia (79.6% to 62.0%). Fewer gynaecomastia patients were referred with a benign physiological or drug-related cause after implementation of the infographic (52.2% vs 41.8%). Only 10 (3.7%) patients with gynaecomastia underwent breast surgery during the study period. CONCLUSION: Implementation of a gynaecomastia infographic in primary care in Manchester was associated with a reduction in gynaecomastia referrals to secondary care. We hypothesise that implementation of the infographic into primary care nationally may potentially translate to hundreds of patients receiving more specialty-appropriate referrals, improving overall management of gynaecomastia. Further study is warranted to test this hypothesis.

Quality attributes of breads from high-quality cassava flour improved with wet gluten.

This study investigated the physical, chemical, and sensory attributes of breads produced from preheated high-quality cassava flour (PCF) and its composite with wheat flour (CWF). Wet gluten was added to the PCF and CWF for production of bread, while bread from wheat served as the control. Flour functionality was determined prior to bread production. The moisture contents of the flour samples were in the range of 12.80 to 14.21%, and PCF exhibited water absorption capacity (1.12 mL/g) comparable to that of wheat flour (WF) (1.10 mL/g). There were significant (P < 0.05) differences in color characteristics, except in L* values and breads produced from WF and CWF were similar in specific volume (3.85 to 4.21 mL/g) and firmness (2.04 to 2.64 N). Breads from WF and CWF exhibited similar crumb microstructure, though gas bubbles in the sample from PCF appeared less developed. Wheat bread had significantly (P < 0.05) higher calorie, crude protein and crude fat, but lower crude fiber, ash, and carbohydrate compared to other bread samples. Sensory evaluation showed that bread from PCF was not significantly different from 100% wheat bread in crust color, texture, and overall acceptability but was impaired in flavor. The study revealed the feasibility of bread baking from preheated cassava flour with added gluten extract. The bread produced had some quality attributes comparable to that of wheat bread. PRACTICAL APPLICATION: Bread from wheat-cassava composite flour with added gluten was similar to wheat bread in specific volume and firmness while sample from cassava flour with added gluten compared favorably well with wheat bread in crust color, texture, and overall acceptability. Findings from the study present wheat gluten extract as a viable component to be used in nonwheat flours for bread making. This could be a basis to further add value to the gluten churned out as a by-product in the wheat starch industry.

The millipede genus Globanus Attems, 1914, endemic to São Tomé and Príncipe, with the description of a new species (Diplopoda, Spirostreptida, Spirostreptidae).

During a soil zoological expedition to São Tomé and Príncipe in 2010 by the California Academy of Sciences, millipedes of the genus Globanus were collected. Samples of G. marginescaber (Karsch, 1884) and G. integer (Karsch, 1884) were recovered in addition to those containing a new species. Globanus drewesi sp. nov. is described and additional records, illustrations, and descriptive notes are given for the other two species. A key to all three species of the genus is provided, and a distribution map is presented. The monotypic genus Lobogonus Demange, 1971, which includes L. trilobatus Demange, 1971, from Sierra Leone, mainland western Africa, is revalidated and removed from synonymy under Globanus. Lobogonus is illustrated from a type specimen.

Decoding collective communications using information theory tools.

Organisms have evolved sensory mechanisms to extract pertinent information from their environment, enabling them to assess their situation and act accordingly. For social organisms travelling in groups, like the fish in a school or the birds in a flock, sharing information can further improve their situational awareness and reaction times. Data on the benefits and costs of social coordination, however, have largely allowed our understanding of why collective behaviours have evolved to outpace our mechanistic knowledge of how they arise. Recent studies have begun to correct this imbalance through fine-scale analyses of group movement data. One approach that has received renewed attention is the use of information theoretic (IT) tools like mutual information, transfer entropy and causation entropy, which can help identify causal interactions in the type of complex, dynamical patterns often on display when organisms act collectively. Yet, there is a communications gap between studies focused on the ecological constraints and solutions of collective action with those demonstrating the promise of IT tools in this arena. We attempt to bridge this divide through a series of ecologically motivated examples designed to illustrate the benefits and challenges of using IT tools to extract deeper insights into the interaction patterns governing group-level dynamics. We summarize some of the approaches taken thus far to circumvent existing challenges in this area and we conclude with an optimistic, yet cautionary perspective.

Solved after 140 years: the identity of the millipede Polydesmus cavicola Packard, 1877, and proposal of Packardesmus n. gen. (Diplopoda: Polydesmida: Macrosternodesmidae).

The identity of Polyesmus cavicola Packard, 1877, described from a cave in Utah, is clarified through examination of a female lectotype and a newly collected adult male. The species is placed in the family Macrosternodesmidae and is designated as the type species of Packardesmus, n. gen.

Image-plate sensitivity to x rays at 2 to 60 keV.

The sensitivity of Fuji SR and MS image plates (IPs) used in x-ray spectrometers on OMEGA and the National Ignition Facility has been measured using two techniques. A set of radioisotopes has been used to constrain image-plate sensitivity between 6 and 60 keV, while a Manson source has been used to expose image plates to x rays at energies between 1.5 and 8 keV. These data have shown variation in sensitivity on the order of 5% for a given IP type and scanner settings. The radioisotope technique has also been used to assess IP fading properties for MS-type plates over long times. IP sensitivity as a function of scanner settings and pixel size has been systematically examined, showing variations of up to a factor of 2 depending on the IP type. Cross-calibration of IP scanners at different facilities is necessary to produce a consistent absolute sensitivity curve spanning the energy range of 2-60 keV.

Xanthotropis, a new genus in the Neotropical millipede subfamily Aphelidesminae (Diplopoda, Polydesmida, Aphelidesmidae).

The monotypic taxon Xanthotropis n. gen. is established to accommodate Haematotropis media Golovatch, Hoffman Spelda, 2004, known only from the vicinity of Manaus, Brazil, as it is incompatible with both its originally assigned genus and Aphelidesmus Brölemann, 1898, a suggested alternative. Xanthotropis is defined primarily by minute teeth on paranota 2-4, a sublinear posterior margin of the telson, and an elongated, distally expanded/laminate acropodite. The Aphelidesmidae Brölemann, 1916, range from northeastern Mexico and Tobago to northern Brazil and southwestern Peru; a questionable more-northerly record, from Monterey, Mexico, requires verification with fresh material. One of two families of the polydesmidan superfamily Platyrhacoidea (Leptodesmidea), Aphelidesmidae comprises two subfamilies, the nominate and Amplininae Hoffman, 1954. The latter has been addressed by several authors, and we here review Aphelidesminae by providing full synonymies, a literature review, and a key to its four genera: Aphelidesmus Brölemann, 1898; Haematotropis and Ochrotropis, both by Jeekel, 2000; and Xanthotropis n. gen.

Studies on the resting behaviour and host choice of Anopheles gambiae and An. arabiensis from Muleba, Tanzania.

The relative efficacy of a mechanical (Prokopack) collection method vs. manual aspiration in the collection of resting mosquitoes was evaluated in northern Tanzania before and after an intervention using indoor residual spraying and longlasting insecticide-treated nets. In smoke-free houses mosquitoes were collected from the roof and walls, but in smoky houses mosquitoes were found predominantly on the walls. Anopheles gambiae (Diptera: Culicidae) constituted 97.7% of the 312 An. gambiae complex specimens identified before but only 19.3% of the 183 identified after the intervention. A single sampling with the Prokopack collected a third of the available insects. Anopheles gambiae completed its gonotrophic development indoors, whereas Anopheles arabiensis did so outdoors. In both species gonotrophic development took 2 days. Most unfed resting An. arabiensis collected outdoors were virgins, whereas the majority of engorged insects were parous (with well-contracted sacs). Daily survival was estimated to be 80.0%. Only 9.4% of the engorged An. arabiensis collected outdoors and 47.1% of those collected indoors had fed on humans. Using the Prokopack sampler is more efficient than manual methods for the collection of resting mosquitoes. Malaria transmission may have been affected by a change in vector composition resulting from a change in feeding, rather than reduced survival. Monitoring the proportions of members of the An. gambiae complex may provide signals of an impending breakdown in control.

Whole body physiologically based modelling of ß-blockers in the rat: events in tissues and plasma following an i.v. bolus dose.

BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Previous PBPK model development of enantiomers of a series of seven racemic ß-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design. KEY RESULTS: Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments. CONCLUSIONS AND IMPLICATIONS: PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.

Long-term follow-up of the incidence of Helicobacter pylori.

OBJECTIVES: Helicobacter pylori causes peptic ulcer disease and gastric cancer. Understanding the incidence of H. pylori could help guide research on potential infection prevention strategies. Previous studies indicate infection occurs in young children, but the risk of infection in older children and adolescents is unclear. Our hypothesis was that H. pylori infection is rare in adolescence or adulthood. Our aim was to determine the incidence of H. pylori over a prolonged follow-up in a cohort of 626 noninfected individuals. METHODS: Participants, including index children, mothers, fathers and siblings, from a previous study (1997-2002) were traced, and 883 of 946 participated in this extended follow-up. We used the 13C urea breath test (13C-UBT) to determine the incidence of H. pylori among 626 family members not infected in 2002, including 75 younger siblings who were not born or too young for testing in 2002. RESULTS: Eight (3.8%) of 210 index participants (mean ± standard deviation age 17.92 ± 0.77 years) became infected during 11.07 ± 0.56 years of follow-up (incidence, 3.42 per 1000 person-years; 95% confidence interval (CI), 1.48-6.74). Only one (0.6%) of 165 older siblings became infected (incidence, 0.57 per 1000 person-years; 95% CI, 0.007-3.16) and one of 176 parents became infected (incidence, 0.63 per 1000 person-years; 95% CI, 0.01-3.5). Of 75 younger siblings (age 10.9 ± 2.85 years) who were too young for testing or not yet born in 2002, nine (12%) became infected (incidence, 11.32 per 1000 person-years; 95% CI, 5.27-21.49). The highest incidence of H. pylori infection was in those born after 2005. CONCLUSIONS: The incidence of H. pylori was extremely low in older children and adults in developed countries. Spontaneous clearance of infection was uncommon in our study population.

Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans.

Intra-Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18 F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.

Evaluation of the efficacy and toxicity profile associated with intraperitoneal chemotherapy use in older women.

OBJECTIVE: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70. METHODS: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated. RESULTS: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups. CONCLUSIONS: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials.

Joint ESPGHAN/NASPGHAN guidelines for the management of helicobacter pylori in children and adolescents (Update 2016)

BACKGROUND: Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required. METHODS: A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting. RESULTS: The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests. CONCLUSIONS: The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.

Coronostoma claireae n. sp. (Nematoda: Rhabditida: Oxyuridomorpha: Coronostomatidae) from the Indigenous Milliped Narceus gordanus (Chamberlain, 1943) (Diplopoda: Spirobolida) in Ocala National Forest, Florida.

Twenty-four individuals of Narceus gordanus (Diplopoda: Spirobolidae) were collected in Ocala National Forest, FL, between November 2013 and July 2014. Each specimen was dissected to extract the intestine, which was removed and examined for parasitic nematodes. Coronostoma claireae n. sp. was collected from the hindgut and midgut of 10 specimens, and its morphology was examined with brightfield, differential interference contrast, phase contrast, and scanning electron microscopy. This species is separated from other Coronostoma spp. by the following characteristics: body length less than 3 mm; head sense organs pit-like; first annule long, extending past middle of corpus, width similar to that of second annule; basal bulb pyriform; eggs larger than 60 × 50 µm. This species is the first North American record for the genus Coronostoma, which is removed from Thelastomatoidea: Thelastomatidae and reassigned to Coronostomatidae on the basis of presumed apomorphies. A key is provided for known Coronostoma spp. The superfamily Coronostomatoidea is re-established for Coronostomatidae and Traklosiidae.

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development.

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.