Mutation of CD2AP and SH3KBP1 binding motif in alphavirus nsP3 hypervariable domain results in attenuated virus

Infection by Chikungunya virus (CHIKV) of the Old World alphaviruses (family Togaviridae) in humans can cause arthritis and arthralgia. The virus encodes four non-structural proteins (nsP) (nsP1, nsp2, nsP3 and nsP4) that act as subunits of the virus replicase. These proteins also interact with numerous host proteins and some crucial interactions are mediated by the unstructured C-terminal hypervariable domain (HVD) of nsP3. In this study, a human cell line expressing EGFP tagged with CHIKV nsP3 HVD was established. Using quantitative proteomics, it was found that CHIKV nsP3 HVD can bind cytoskeletal proteins, including CD2AP, SH3KBP1, CAPZA1, CAPZA2 and CAPZB. The interaction with CD2AP was found to be most evident; its binding site was mapped to the second SH3 ligand-like element in nsP3 HVD. Further assessment indicated that CD2AP can bind to nsP3 HVDs of many different New and Old World alphaviruses. Mutation of the short binding element hampered the ability of the virus to establish infection. The mutation also abolished ability of CD2AP to co-localise with nsP3 and replication complexes of CHIKV; the same was observed for Semliki Forest virus (SFV) harbouring a similar mutation. Similar to CD2AP, its homolog SH3KBP1 also bound the identified motif in CHIKV and SFV nsP3

Landscape elements and river chemistry as affected by river regulation – a 3-D perspective

We tested the hypothesis whether individual land classes within a river catchment contribute equally to river loading with dissolved constituents or whether some land classes act as "hot spots" to river loading and if so, are these land classes especially affected by hydrological alterations. The amount of land covered by forests and wetlands and the average soil depth (throughout this paper soil refers to everything overlying bedrock i.e. regolith) of a river catchment explain 58–93% of the variability in total organic carbon (TOC) and dissolved silicate (DSi) concentrations for 22 river catchments in Northern Sweden. For the heavily regulated Luleälven, with 7 studied sub-catchments, only 3% of the headwater areas have been inundated by reservoirs, some 10% of the soils and aggregated forest and wetland areas have been lost due to damming and further hydrological alteration such as bypassing entire sub-catchments by headrace tunnels. However, looking at individual forest classes, our estimates indicate that some 37% of the deciduous forests have been inundated by the four major reservoirs built in the Luleälven headwaters. These deciduous forest and wetlands formerly growing on top of alluvial deposits along the river corridors forming the riparian zone play a vital role in loading river water with dissolved constituents, especially DSi. A digital elevation model draped with land classes and soil depths which highlights that topography of various land classes acting as hot spots is critical in determining water residence time in soils and biogeochemical fluxes. Thus, headwater areas of the Luleälven appear to be most sensitive to hydrological alterations due to the thin soil cover (on average 2.7–4.5 m) and only patchy appearance of forest and wetlands that were significantly perturbed. Hydrological alterations of these relatively small headwater areas significantly impacts downstream flux of dissolved constituents and their delivery to receiving water bodies

Electromagnetic dissociation of relativistic 8^8B nuclei in nuclear track emulsion

Experimental data on fragmentation channels in peripheral interactions of $^8$B nuclei in nuclear track emulsions are presented. A detailed analysis made it possible to justify selections of events of the electromagnetic-dissociation process $^8$B $\to^7$Be + \emph{p} and to estimate its cross section. Events of $^{10}$C peripheral dissociation that were observed in the same exposure are described.Comment: 12 pages, 10 figures, 4 tables, Published in Phys.Atom.Nucl.72:690-701,200

Fine Structure in the β\beta-Delayed Proton Decay of 33^{33}Ar

Low energy beta-delayed protons from $^{33}$Ar have been measured for the first time. The data reveal states, which, despite unfavourable barrier penetrability values, strongly decay to the first excited 2$^+$ state in $^{32}$S. The observation is discussed in terms of the standard shell model. A natural explanation is provided by the large spectroscopic amplitudes, involving $s_{1/2}$ and $d_{3/2}$ orbitals, as well as the $l$=0 barrier penetrability, favouring the decay to the 2$^+$ state

Initial State Dependence of the Breakup of Weakly Bound Carbon Isotopes

The one-neutron nuclear breakup from the Carbon isotopes $^{19}$C and $^{17}$C, is calculated as an example of application of the theory of transfer to the continuum reactions in the formulation which includes spin coupling. The effect of the energy sharing between the parallel and transverse neutron momentum distributions is taken into account thus resulting in a theory which is more general than sudden eikonal approaches. Both effects are necessary to understand properly the breakup from not too weakly bound $l_i>1$ orbitals. Breakup which leaves the core into an excited state below particle threshold is also considered. The core-target interaction is treated in the smooth cut-off approximation. By comparing to presently available experimental data we show how to make some hypothesis on the quantum numbers and occupancy of the neutron initial state. Possible ambiguities in the interpretation of inclusive cross sections are discussed.Comment: 22 RevTeX pages,3 ps figures. Phys. Rev. C, accepte

COVID-19 symptoms at time of testing and association with positivity among outpatients tested for SARS-CoV-2

Introduction Symptoms associated with SARS-CoV-2 infection remain incompletely understood, especially among ambulatory, non-hospitalized individuals. With host factors, symptoms predictive of SARS-CoV-2 could be used to guide testing and intervention strategies. Methods Between March 16 and September 3, 2020, we examined the characteristics and symptoms reported by individuals presenting to a large outpatient testing program in the Southeastern US for nasopharyngeal SARS-CoV-2 RNA RT-PCR testing. Using self-reported symptoms, demographic characteristics, and exposure and travel histories, we identified the variables associated with testing positive using modified Poisson regression. Results Among 20,177 tested individuals, the proportion positive was 9.4% (95% CI, 9.0–9.8) and was higher for men, younger individuals, and racial/ethnic minorities (all P<0.05); the positivity proportion was higher for Hispanics (26.9%; 95% CI. 24.9–29.0) compared to Blacks (8.6%; 95% CI, 7.6–9.7) or Whites (5.8%; 95% CI, 5.4–6.3). Individuals reporting contact with a COVID-19 case had the highest positivity proportion (22.8%; 95% CI, 21.5–24.1). Among the subset of 8,522 symptomatic adults who presented for testing after May 1, when complete symptom assessments were performed, SARS-CoV-2 RNA PCR was detected in 1,116 (13.1%). Of the reported symptoms, loss of taste or smell was most strongly associated with SARS-CoV-2 RNA detection with an adjusted risk ratio of 3.88 (95% CI, 3.46–4.35). The presence of chills, fever, cough, aches, headache, fatigue and nasal congestion also significantly increased the risk of detecting SARS-CoV-2 RNA, while diarrhea or nausea/vomiting, although not uncommon, were significantly more common in those with a negative test result. Symptom combinations were frequent with 67.9% experiencing ≥4 symptoms, including 19.8% with ≥8 symptoms; report of greater than three symptoms increased the risk of SARS-CoV-2 RNA detection. Conclusions In a large outpatient population in the Southeastern US, several symptoms, most notably loss of taste or smell, and greater symptom burden were associated with detection of SARS-CoV-2 RNA. Persons of color and those with who were a contact of a COVID-19 case were also more likely to test positive. These findings suggest that, given limited SARS-CoV-2 testing capacity, symptom presentation and host characteristics can be used to guide testing and intervention prioritization

International guidelines for groin hernia management

Worldwide, more than 20 million patients undergo groin hernia repair annually. The many different approaches, treatment indications and a significant array of techniques for groin hernia repair warrant guidelines to standardize care, minimize complications, and improve results. The main goal of these guidelines is to improve patient outcomes, specifically to decrease recurrence rates and reduce chronic pain, the most frequent problems following groin hernia repair. They have been endorsed by all five continental hernia societies, the International Endo Hernia Society and the European Association for Endoscopic Surgery. An expert group of international surgeons (the HerniaSurge Group) and one anesthesiologist pain expert was formed. The group consisted of members from all continents with specific experience in hernia-related research. Care was taken to include surgeons who perform different types of repair and had preferably performed research on groin hernia surgery. During the Group's first meeting, evidence-based medicine (EBM) training occurred and 166 key questions (KQ) were formulated. EBM rules were followed in complete literature searches (including a complete search by The Dutch Cochrane database) to January 1, 2015 and to July 1, 2015 for level 1 publications. The articles were scored by teams of two or three according to Oxford, SIGN and Grade methodologies. During five 2-day meetings, results were discussed with the working group members leading to 136 statements and 88 recommendations. Recommendations were graded as "strong" (recommendations) or "weak" (suggestions) and by consensus in some cases upgraded. In the Results and summary section below, the term "should" refers to a recommendation. The AGREE II instrument was used to validate the guidelines. An external review was performed by three international experts. They recommended the guidelines with high scores. The risk factors for inguinal hernia (IH) include: family history, previous contra-lateral hernia, male gender, age, abnormal collagen metabolism, prostatectomy, and low body mass index. Peri-operative risk factors for recurrence include poor surgical techniques, low surgical volumes, surgical inexperience and local anesthesia. These should be considered when treating IH patients. IH diagnosis can be confirmed by physical examination alone in the vast majority of patients with appropriate signs and symptoms. Rarely, ultrasound is necessary. Less commonly still, a dynamic MRI or CT scan or herniography may be needed. The EHS classification system is suggested to stratify IH patients for tailored treatment, research and audit. Symptomatic groin hernias should be treated surgically. Asymptomatic or minimally symptomatic male IH patients may be managed with "watchful waiting" since their risk of hernia-related emergencies is low. The majority of these individuals will eventually require surgery; therefore, surgical risks and the watchful waiting strategy should be discussed with patients. Surgical treatment should be tailored to the surgeon's expertise, patient- and hernia-related characteristics and local/national resources. Furthermore, patient health-related, life style and social factors should all influence the shared decision-making process leading up to hernia management. Mesh repair is recommended as first choice, either by an open procedure or a laparo-endoscopic repair technique. One standard repair technique for all groin hernias does not exist. It is recommended that surgeons/surgical services provide both anterior and posterior approach options. Lichtenstein and laparo-endoscopic repair are best evaluated. Many other techniques need further evaluation. Provided that resources and expertise are available, laparo-endoscopic techniques have faster recovery times, lower chronic pain risk and are cost effective. There is discussion concerning laparo-endoscopic management of potential bilateral hernias (occult hernia issue). After patient consent, during TAPP, the contra-lateral side should be inspected. This is not suggested during unilateral TEP repair. After appropriate discussions with patients concerning results tissue repair (first choice is the Shouldice technique) can be offered. Day surgery is recommended for the majority of groin hernia repair provided aftercare is organized. Surgeons should be aware of the intrinsic characteristics of the meshes they use. Use of so-called low-weight mesh may have slight short-term benefits like reduced postoperative pain and shorter convalescence, but are not associated with better longer-term outcomes like recurrence and chronic pain. Mesh selection on weight alone is not recommended. The incidence of erosion seems higher with plug versus flat mesh. It is suggested not to use plug repair techniques. The use of other implants to replace the standard flat mesh in the Lichtenstein technique is currently not recommended. In almost all cases, mesh fixation in TEP is unnecessary. In both TEP and TAPP it is recommended to fix mesh in M3 hernias (large medial) to reduce recurrence risk. Antibiotic prophylaxis in average-risk patients in low-risk environments is not recommended in open surgery. In laparo-endoscopic repair it is never recommended. Local anesthesia in open repair has many advantages, and its use is recommended provided the surgeon is experienced in this technique. General anesthesia is suggested over regional in patients aged 65 and older as it might be associated with fewer complications like myocardial infarction, pneumonia and thromboembolism. Perioperative field blocks and/or subfascial/subcutaneous infiltrations are recommended in all cases of open repair. Patients are recommended to resume normal activities without restrictions as soon as they feel comfortable. Provided expertise is available, it is suggested that women with groin hernias undergo laparo-endoscopic repair in order to decrease the risk of chronic pain and avoid missing a femoral hernia. Watchful waiting is suggested in pregnant women as groin swelling most often consists of self-limited round ligament varicosities. Timely mesh repair by a laparo-endoscopic approach is suggested for femoral hernias provided expertise is available. All complications of groin hernia management are discussed in an extensive chapter on the topic. Overall, the incidence of clinically significant chronic pain is in the 10-12% range, decreasing over time. Debilitating chronic pain affecting normal daily activities or work ranges from 0.5 to 6%. Chronic postoperative inguinal pain (CPIP) is defined as bothersome moderate pain impacting daily activities lasting at least 3 months postoperatively and decreasing over time. CPIP risk factors include: young age, female gender, high preoperative pain, early high postoperative pain, recurrent hernia and open repair. For CPIP the focus should be on nerve recognition in open surgery and, in selected cases, prophylactic pragmatic nerve resection (planned resection is not suggested). It is suggested that CPIP management be performed by multi-disciplinary teams. It is also suggested that CPIP be managed by a combination of pharmacological and interventional measures and, if this is unsuccessful, followed by, in selected cases (triple) neurectomy and (in selected cases) mesh removal. For recurrent hernia after anterior repair, posterior repair is recommended. If recurrence occurs after a posterior repair, an anterior repair is recommended. After a failed anterior and posterior approach, management by a specialist hernia surgeon is recommended. Risk factors for hernia incarceration/strangulation include: female gender, femoral hernia and a history of hospitalization related to groin hernia. It is suggested that treatment of emergencies be tailored according to patient- and hernia-related factors, local expertise and resources. Learning curves vary between different techniques. Probably about 100 supervised laparo-endoscopic repairs are needed to achieve the same results as open mesh surgery like Lichtenstein. It is suggested that case load per surgeon is more important than center volume. It is recommended that minimum requirements be developed to certify individuals as expert hernia surgeon. The same is true for the designation "Hernia Center". From a cost-effectiveness perspective, day-case laparoscopic IH repair with minimal use of disposables is recommended. The development and implementation of national groin hernia registries in every country (or region, in the case of small country populations) is suggested. They should include patient follow-up data and account for local healthcare structures. A dissemination and implementation plan of the guidelines will be developed by global (HerniaSurge), regional (international societies) and local (national chapters) initiatives through internet websites, social media and smartphone apps. An overarching plan to improve access to safe IH surgery in low-resource settings (LRSs) is needed. It is suggested that this plan contains simple guidelines and a sustainability strategy, independent of international aid. It is suggested that in LRSs the focus be on performing high-volume Lichtenstein repair under local anesthesia using low-cost mesh. Three chapters discuss future research, guidelines for general practitioners and guidelines for patients. The HerniaSurge Group has developed these extensive and inclusive guidelines for the management of adult groin hernia patients. It is hoped that they will lead to better outcomes for groin hernia patients wherever they live. More knowledge, better training, national audit and specialization in groin hernia management will standardize care for these patients, lead to more effective and efficient healthcare and provide direction for future research

Women’s beliefs about medicines and adherence to pharmacotherapy in pregnancy: Opportunities for community pharmacists?

Background During pregnancy women might weigh benefits of treatment against potential risks to the unborn child. However, non-adherence to necessary treatment can adversely affect both mother and child. To optimize pregnant women’s beliefs and medication adherence, community pharmacists are ideally positioned to play an important role in primary care. Objective This narrative review aimed to summarize the evidence on 1) pregnant women’s beliefs, 2) medication adherence in pregnancy, and 3) community pharmacists’ counselling during pregnancy. Method Three search strategies were used in Medline and Embase to find original studies evaluating women’s beliefs, medication adherence and community pharmacists’ counselling during pregnancy. All original descriptive and analytic epidemiological studies performed in Europe, North America and Australia, written in English and published from 2000 onwards were included. Results We included 14 studies reporting on women’s beliefs, 11 studies on medication adherence and 9 on community pharmacists’ counselling during pregnancy. Women are more reluctant to use medicines during pregnancy and tend to overestimate the teratogenic risk of medicines. Risk perception varies with type of medicine, level of health literacy, education level and occupation. Furthermore, low medication adherence during pregnancy is common. Finally, limited evidence showed current community pharmacists’ counselling is insufficient. Barriers hindering pharmacists are insufficient knowledge and limited access to reliable information. Conclusion Concerns about medication use and non-adherence are widespread among pregnant women. Community pharmacists’ counselling during pregnancy is insufficient. Further education, training and research are required to support community pharmacists in fulfilling all the opportunities they have when counselling pregnant women