Differential response in downstream processing of CHO cells grown under mild hypothermic conditions.

The manufacture of complex therapeutic proteins using mammalian cells is well established, with several strategies developed to improve productivity. The application of sustained mild hypothermic conditions during culture has been associated with increases in product titer and improved product quality. However, despite associated cell physiological effects, very few studies have investigated the impact on downstream processing (DSP). Characterization of cells grown under mild hypothermic conditions demonstrated that the stationary phase was prolonged by delaying the onset of apoptosis. This enabled cells to maintain viability for extended periods and increase volumetric productivity from 0.74 to 1.02 g L(-1) . However, host cell proteins, measured by ELISA, increased by ∼50%, attributed to the extended time course and higher peak and harvest cell densities. The individual components making up this impurity, as determined by SELDI-TOF MS and 2D-PAGE, were shown to be largely comparable. Under mild hypothermic conditions, cells were less shear sensitive than those maintained at 37°C, enhancing the preliminary primary recovery step. Adaptive changes in membrane fluidity were further investigated by adopting a pronounced temperature shift immediately prior to primary recovery and the improvement observed suggests that such a strategy may be implementable when shear sensitivity is of concern. Early and late apoptotic cells were particularly susceptible to shear, at either temperature, even under the lowest shear rate investigated. These findings demonstrate the importance of considering the impact of cell culture strategies and cell physiology on DSP, by implementing a range of experimental methods for process characterization. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 2013

Population genetics of trypanosoma brucei rhodesiense: clonality and diversity within and between foci

African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda) and Southern (Malawi) Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics

A composite axion from a supersymmetric product group

A global $U(1)_\text{PQ}$ symmetry is protected from gravitational effects in the s-confining $SU(N)^k$ product group theory with $A+4Q +N\overline{Q}$ matter. If the $SU(4)$ family symmetry is gauged and an appropriate tree-level superpotential is added, then the dynamically generated superpotential spontaneously breaks $SU(4)\times U(1)_\text{PQ} \rightarrow SU(3)_c$ and produces a QCD axion. Small values of the $CP$-violating $\theta$ parameter are then possible without any fine-tuning, as long as the product group is suitably large. By introducing a second copy of the s-confining $SU(N)$ product group also coupled to the gauged $SU(4)$, we find that values as small as $N=7$ are consistent with $\bar\theta<10^{-10}$, even under the pessimistic assumption that the dominant contribution to the axion quality is at tree level.Comment: 16 pages, 3 figures, 4 tables, 2 appendice

Sociocultural Determinants of Teenage Childbearing Among Latinas in California

Objectives U.S. Latinas have a persistently high rate of teenage childbearing, which is associated with adverse outcomes for both mother and child. This study was designed to investigate the roles of socioeconomic factors and acculturation in teenage childbearing in this population. Methods Logistic regression was used to analyze the association of measures of acculturation (language spoken at home, nativity, and age at immigration) and respondents’ parents’ education with age at first birth in a stratified sample of post-partum women in California. Results The unadjusted odds ratio for teenage birth for Latinas versus non-Latina Whites was 5.2 (95% CI 4.1–6.6). Nativity was not significantly associated with teen birth, but speaking Spanish at home was positively associated and immigrating at a later age was negatively associated with teen birth. Overall, these measures of acculturation accounted for 17% (95% CI 8–28%) of the difference in odds of teen birth between Latinas and non-Latina Whites. Higher levels of education among respondents’ parents had differentially protective effects across the racial/ethnic groups. Controlling for disparities in respondents’ parents’ education without changing its differential effects across racial/ethnic groups reduced the odds ratio for Latinas compared to non-Latina Whites by 30% (95% CI 14–60%). Conclusion These findings call into question common assumptions about the protective effect of acculturation on teen fertility and suggest that improving childhood socioeconomic factors among Latinas may decrease teen childbearing

Low adherence with antihypertensives in actual practice: the association with social participation – a multilevel analysis

BACKGROUND: Low adherence is a key factor in explaining impaired effectiveness and efficiency in the pharmacological treatment of hypertension. However, little is known about which factors determine low adherence in actual practice. The purpose of this study is to examine whether low social participation is associated with low adherence with antihypertensive medication, and if this association is modified by the municipality of residence. METHODS: 1288 users of antihypertensive medication were identified from The Health Survey in Scania 2000, Sweden. The outcome was low adherence with antihypertensives during the last two weeks. Multilevel logistic regression with participants at the first level and municipalities at the second level was used for analyses of the data. RESULTS: Low social participation was associated with low adherence with antihypertensives during the last two weeks (OR = 2.05, 95% CI: 1.05–3.99), independently of low educational level. However, after additional adjustment for poor self-rated health and poor psychological health, the association between low social participation and low adherence with antihypertensives during the last two weeks remained but was not conclusive (OR = 1.80, 95% CI: 0.90–3.61). Furthermore, the association between low social participation and low adherence with antihypertensives during the last two weeks varied among municipalities in Scania (i.e., cross-level interaction). CONCLUSION: Low social participation seems to be associated with low adherence with antihypertensives during the last two weeks, and this association may be modified by the municipality of residence. Future studies aimed at investigating health-related behaviours in general and low adherence with medication in particular might benefit if they consider area of residence

Community-based provision of direct-acting antiviral therapy for hepatitis C: Study protocol and challenges of a randomized controlled trial

Background: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to treatment. Direct-acting antiviral (DAA) treatment can be provided in primary healthcare services (PHCS), improving accessibility, and, potentially, retention in care. Here, we describe our protocol for assessing the effectiveness of providing DAAs in PHCS, and the impact on the HCV care cascade. In addition, we reflect on the challenges of conducting a model of care study during a period of unprecedented change in HCV care and treatment. Methods: Consenting patients with HCV infection attending 13 PHCS in Australia or New Zealand are randomized to receive DAA treatment at the local tertiary institution (standard care arm), or their PHCS (intervention arm). The primary endpoint is the proportion commenced on DAAs and cured. Treatment providers at the PHCS include: hepatology nurses, primary care practitioners, or, in two sites, a specialist physician. All PHCS offer opioid substitution therapy. Discussion: The Prime Study is the first real-world, randomized, model of care study exploring the impact of community provision of DAA therapy on HCV-treatment uptake and cure. Although the study has faced challenges unique to this period of time characterized by changing treatment and service delivery, the data gained will be of critical importance in shaping health service policy that enables the elimination of HCV

Working with pain : sustainable work participation of workers with chronic nonspecific musculoskeletal pain

Dit proefschrift is een van de eerste studies specifiek gericht op mensen die blijven werken met chronische pijn aan het bewegingsapparaat. Unieke kennis over duurzame arbeidsparticipatie van werknemers met chronische pijn werd vergaard. Doel van dit promotieonderzoek was meer inzicht te krijgen in de groep mensen die werkt met pijn en te achterhalen hoe zij in staat zijn ondanks hun klachten te blijven werken. In het proefschrift staan kenmerken en determinanten beschreven van werknemers die doorwerken met chronische pijn, waardoor een completer beeld is ontstaan van arbeidsparticipatie bij mensen met chronische pijn aan het bewegingsapparaat. Uit de vergelijking van mensen die doorwerken ondanks chronische pijn en mensen met arbeidsverzuim die in revalidatiebehandeling komen met chronische pijn blijkt dat deze groepen op diverse factoren significant verschillen. In het onderzoek werd onder andere aangetoond dat de motivatie voor werk, zelfmanagementvaardigheden en het belang dat wordt toegekend aan pijn, belangrijke factoren zijn die werken met chronische pijn faciliteren. Chronische pijn op zichzelf is vaak niet de reden voor arbeidsverzuim, maar meestal spelen persoonlijke- en omgevingsfactoren daarin een beslissende rol. Deze factoren kunnen dienen als aangrijpingspunt voor het verhogen van duurzame inzetbaarheid en preventie van arbeidsverzuim van mensen met chronische pijn aan het bewegingsapparaat. De effectieve manier waarop deelnemende werknemers in het onderzoek met hun pijn omgingen en productief bleven, kan anderen inspireren aan het werk te blijven. Daarnaast biedt het onderzoek een nieuw referentiekader voor de bedrijfs-, verzekerings-, en revalidatiegeneeskunde. This thesis was one of the first studies that focused specifically on people who continued work with chronic nonspecific musculoskeletal pain (CMP), and collected (identified) unique data concerning sustainable work participation of workers with CMP. It provides a large range of characteristics of workers with CMP who continued work despite pain, which has added to our understanding of sustainable work participation in people suffering from CMP. Comparison of workers who continued work with CMP with sick listed workers with CMP admitted for rehabilitation revealed that these groups differ significantly on several factors. In this thesis, evidence was found that the workers’ motivation to work, self-management skills, and the attributed importance of pain on their (working) lives are important factors to manage staying at work with CMP. It is recommended to be aware of the fact that CMP standing on itself is often not the reason for sick leave and disability, but regularly personal and environmental factors play an additional decisive role. Because these factors can be influenced, they offer opportunity to promote staying at work. In the process of guiding workers back to work, the results of the project ‘Working with pain’ may be used. The findings of this thesis potentially contribute to promotion of sustained work participation and prevention of sick-leave in workers with CMP. The effective way workers in this project coped with CMP and remained productive, may inspire others in their efforts to stay work. Finally, this thesis offers a new reference for rehabilitation-, occupational-,and insurance medicine.

‘Making the invisible visible’ through alcohol screening and brief intervention in community pharmacies: an Australian feasibility study

Background: Screening and brief interventions (SBI) for alcohol related problems have been shown to be effective in health settings such as general practice or emergency departments. Recent data from the United Kingdom and New Zealand suggest that SBI can be delivered through community pharmacies, but this approach has not been tested in Australia. This study assesses the feasibility of delivering alcohol SBI via community pharmacists. Method: We recruited five pharmacies and developed an SBI training package to be delivered by pharmacy staff, who screened consumers and delivered the brief intervention where appropriate. Consumers also completed a questionnaire on the process. At three months consumers were telephoned to enable ‘retention’ to be quantified. After completing recruitment, a semi-structured interview was conducted with pharmacists on the process of delivering the intervention, potential improvements and sustainability. Results: Fifty consumer participants were screened, ten from each pharmacy. There were 28 (57 %) men and 21 (43 %) women with one not responding. Most (67 %) were aged 25-55 years. Their AUDIT scores had a range of 0 to 39 (mean 10.9, SD 9.8) with 11 categorised as ‘hazardous (8-15)’, four as ‘harmful (16-19)’ and eight as ‘probably dependent (20+)’ consumers of alcohol. Reactions to the process of SBI were generally favourable: for example 75 % agreed that it was either appropriate or very appropriate being asked about their alcohol consumption. With respect to follow-up interviews, 23 (46 %) agreed that they could be contacted, including five from the highest AUDIT category. Subsequently 11 (48 %) were contactable at three months. Three of the five non-low risk drinkers had reduced their level of risk over the three months. Ten pharmacists participated in semi-structured telephone interviews. Overall these pharmacists were positive about the intervention and five main themes emerged from the interviews: 1) flexibility applied in recruitment of participants, 2) easiness in use of AUDIT score to facilitate discussions, 3) perceived positive intervention impact, 4) enhanced role of community pharmacists and 5) facilitators and challenges experienced. Conclusions: Pharmacy-based SBI appears to be acceptable to consumers and feasible for pharmacy staff to deliver. Challenges remain in translating this potential into actual services