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Global declines in bird and arthropod abundance highlights the importance of understanding the role of food limitation and arthropod community composition for the performance of insectivorous birds. In this study, we link data on nestling diet, arthropod availability and nesting performance for the Coastal Cactus Wren (Campylorhynchus brunneicapillus sandiegensis), an at-risk insectivorous bird native to coastal southern California and Baja Mexico. We used DNA metabarcoding to characterize nestling diets and monitored 8 bird territories over two years to assess the relationship between arthropod and vegetation community composition and bird reproductive success. We document a discordance between consumed prey and arthropod biomass within nesting territories, in which Diptera and Lepidoptera were the most frequently consumed prey taxa but were relatively rare in the environment. In contrast other Orders (e.g., Hemiptera, Hymenoptera)were abundant in the environment but were absent from nestling diets. Accordingly, variation in bird reproductive success among territories was positively related to the relative abundance of Lepidoptera (but not Diptera), which were most abundant on 2 shrub species (Eriogonum fasciculatum, Sambucus nigra) of the 9 habitat elements characterized (8 dominant plant species and bare ground). Bird reproductive success was in turn negatively related to two invasive arthropods whose abundance was not associated with preferred bird prey, but instead possibly acted through harassment (Linepithema humile; Argentine ants) and parasite transmission or low nutritional quality (Armadillidium vulgare; "pill-bug"). These results demonstrate how multiple aspects of arthropod community structure can influence bird performance through complementary mechanisms, and the importance of managing for arthropods in bird conservation efforts.

ObjectivesTo estimate the cost-effectiveness to the US Veterans Health Administration (VA) of the use of complementary and integrative health (CIH) approaches by younger Veterans with chronic musculoskeletal disorder (MSD) pain.PerspectiveVA healthcare system.MethodsWe used a propensity score-adjusted hierarchical linear modeling (HLM), and 2010-2013 VA administrative data to estimate differences in VA healthcare costs, pain intensity (0-10 numerical rating scale), and opioid use between CIH users and nonusers. We identified CIH use in Veterans' medical records through Current Procedural Terminology, VA workload tracking, and provider-type codes.ResultsWe identified 30,634 younger Veterans with chronic MSD pain as using CIH and 195,424 with no CIH use. CIH users differed from nonusers across all baseline covariates except the Charlson comorbidity index. They also differed on annual pre-CIH-start healthcare costs ($10,729 versus $5,818), pain (4.33 versus 3.76), and opioid use (66.6% versus 54.0%). The HLM results indicated lower annual healthcare costs (-$637; 95% CI: -$1,023, -$247), lower pain (-0.34; -0.40, -0.27), and slightly higher (less than a percentage point) opioid use (0.8; 0.6, 0.9) for CIH users in the year after CIH start. Sensitivity analyses indicated similar results for three most-used CIH approaches (acupuncture, chiropractic care, and massage), but higher costs for those with eight or more CIH visits.ConclusionsOn average CIH use appears associated with lower healthcare costs and pain and slightly higher opioid use in this population of younger Veterans with chronic musculoskeletal pain. Given the VA's growing interest in the use of CIH, further, more detailed analyses of its impacts are warranted.

Global declines in bird and arthropod abundance highlights the importance of understanding the role of food limitation and arthropod community composition for the performance of insectivorous birds. In this study, we link data on nestling diet, arthropod availability and nesting performance for the Coastal Cactus Wren (Campylorhynchus brunneicapillus sandiegensis), an at-risk insectivorous bird native to coastal southern California and Baja Mexico. We used DNA metabarcoding to characterize nestling diets and monitored 8 bird territories over two years to assess the relationship between arthropod and vegetation community composition and bird reproductive success. We document a discordance between consumed prey and arthropod biomass within nesting territories, in which Diptera and Lepidoptera were the most frequently consumed prey taxa but were relatively rare in the environment. In contrast other Orders (e.g., Hemiptera, Hymenoptera)were abundant in the environment but were absent from nestling diets. Accordingly, variation in bird reproductive success among territories was positively related to the relative abundance of Lepidoptera (but not Diptera), which were most abundant on 2 shrub species (Eriogonum fasciculatum, Sambucus nigra) of the 9 habitat elements characterized (8 dominant plant species and bare ground). Bird reproductive success was in turn negatively related to two invasive arthropods whose abundance was not associated with preferred bird prey, but instead possibly acted through harassment (Linepithema humile; Argentine ants) and parasite transmission or low nutritional quality (Armadillidium vulgare; "pill-bug"). These results demonstrate how multiple aspects of arthropod community structure can influence bird performance through complementary mechanisms, and the importance of managing for arthropods in bird conservation efforts.

During the Covid-19 pandemic, older people have been in the spotlight of the public debate. Given their higher risk of severe outcomes of the disease, they have been described as especially vulnerable and as a burden to others and society. We thus wanted to investigate how older people’s perception of their own age, that is their subjective age, as well as their Covid-19 related risks and worries were related during the pandemic and whether these relationships varied according to participants’ subjective health. We used data from the longitudinal CRISIS study which was conducted in the Grand-Duchy of Luxembourg in June and October 2020. Participants were aged 60–98 and responded on questionnaires regarding their subjective age, worry of falling ill with Covid-19, perceived risk of contracting the virus, perceived risk of falling seriously ill if they contracted Covid-19, as well as their subjective health and covariates. Three cross-lagged panel models were constructed to explore the longitudinal, bidirectional relationships between the variables. Cross-sectionally, a higher subjective age was related to more perceived risk of a serious course of disease. Longitudinally, subjective age and worry did not show any significant association over time, and neither did subjective age and perceived risk of contracting the virus. However, subjective health significantly moderated the relationship of worry and subjective age, showing different trajectories in the relationship depending on whether subjective health was good or bad. Higher perceived risk of falling seriously ill increased subjective age over time. Again, subjective health moderated this relationship: the perceived risk of falling seriously ill affected subjective age only for those with better subjective health. Our findings show the interactive relationship between subjective age and Covid-19 related cognitions and emotions and provide guidance for identifying older people that are most susceptible for negative age-related communication during the pandemic.

The purpose of this study was to describe the ocular findings, structural ocular complications, and vision impairment in a cohort of Lassa fever survivors in Kenema, Sierra Leone. A retrospective, uncontrolled, cross-sectional study of 31 Lassa fever survivors (62 eyes) who underwent an ophthalmic evaluation in January 2018 at the Kenema Government Hospital in Kenema, Sierra Leone was performed. Data collection included demographic information, ocular/systemic symptoms, visual acuity (VA), and ophthalmic examination findings. Main outcome measures included anterior and posterior segment ophthalmic manifestations and level of VA impairment in Lassa fever survivors. Anterior segment findings included cataract (18%) and pterygium (2%), while posterior segment manifestations consisted of glaucoma (6%), preretinal hemorrhage (2%), and lattice degeneration (2%). Findings suggestive of prior sequelae of uveitis included chorioretinal scarring (5%), retinal fibrosis (3%), and vitreous opacity (2%). Visual acuity was normal/mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind by the World Health Organization (WHO) criteria. Median VA was worse in Lassa fever survivors with ophthalmic disease findings (p

IntroductionStandard multidrug-resistant tuberculosis (MDR-TB) treatment is lengthy, toxic, and insufficiently effective. New drugs and a shorter treatment regimen (SCR) are now recommended. However, patient and health-care worker (HCW) perspectives regarding the SCR are unknown. We aimed to determine the views and experiences of patients with MDR-TB and HCW regarding the SCR in Karakalpakstan, Uzbekistan.MethodsIn a qualitative study, we conducted 48 in-depth interviews with 24 people with MDR-TB and 20 HCW, purposively recruited to include those with a range of treatment-taking experiences and employment positions. Data were analysed thematically using Nvivo 12, to identify emergent patterns, concepts, and categories. Principles of grounded theory were drawn upon to generate findings inductively from participants' accounts.ResultsAll patients viewed the SCR favourably. The SCR was seen as enabling an expedited return to work, studies, and "normality". This reduced the burden of treatment and difficulties with treatment fatigue. The SCR appeared to improve mental health, ease difficulties with TB-related stigma, and foster improved adherence. While patients wanted shorter treatment, it was also important that treatment be tolerable and effective. However, HCW doubted the appropriateness and effectiveness of the SCR, which influenced their confidence in prescribing the regimen.ConclusionThe SCR was said to benefit treatment completion and patients' lives. HCW concerns about SCR appropriateness and effectiveness may influence who receives the regimen. These are important considerations for SCR implementation and MDR-TB treatment developments, and dissonance between patient and HCW perspectives must be addressed for successful implementation of shorter regimens in the future.

The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. CpG methylation in the TERT promoter (TERTp) was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to facilitate binding of transcription factor ETS/TCF and subsequent TERT expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and chromatin accessibility) and genetic (promoter mutations) mechanisms in regulating TERT gene expression in healthy skin samples and in melanoma cell lines (n = 61). We unexpectedly observed that the methylation of TERTp was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with either high methylation or intermediate methylation in combination with TERT mutations. TERTp methylation was positively correlated with chromatin accessibility and TERT mRNA expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to high methylation throughout the promoter or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T or C250T mutations.

OBJECTIVE:Chronic suppurative otitis media (CSOM) is a chronic infectious disease with worldwide prevalence that causes hearing loss and decreased quality of life. As current (antibiotic) treatments often unsuccessful and antibiotic resistance is emerging, alternative agents and/or strategies are urgently needed. We considered the synthetic antimicrobial and anti-biofilm peptide P60.4Ac to be an interesting candidate because it also displays anti-inflammatory activities including lipopolysaccharide-neutralizing activity. The aim of the present study was to investigate the safety and efficacy of ototopical drops containing P60.4Ac in adults with CSOM without cholesteatoma. METHODS:We conducted a range-finding study in 16 subjects followed by a randomized, double blinded, placebo-controlled, multicentre phase IIa study in 34 subjects. P60.4Ac-containing ototopical drops or placebo drops were applied twice a day for 2 weeks and adverse events (AEs) and medication use were recorded. Laboratory tests, swabs from the middle ear and throat for bacterial cultures, and audiometry were performed at intervals up to 10 weeks after therapy. Response to treatment was assessed by blinded symptom scoring on otoscopy. RESULTS:Application of P60.4Ac-containing ototopical drops (0.25-2.0 mg of peptide/ml) in the ear canal of patients suffering from CSOM was found to be safe and well-tolerated. The optimal dose (0.5 mg of peptide/ml) was selected for the subsequent phase IIa study. Safety evaluation revealed only a few AEs that were unlikely related to study treatment and all, except one, were of mild to moderate intensity. In addition to this excellent safety profile, P60.4Ac ototopical drops resulted in a treatment success in 47% of cases versus 6% in the placebo group. CONCLUSION:The efficacy/safety balance assessed in the present study provides a compelling justification for continued clinical development of P60.4Ac in therapy-resistant CSOM.

ObjectivesTo estimate the cost-effectiveness to the US Veterans Health Administration (VA) of the use of complementary and integrative health (CIH) approaches by younger Veterans with chronic musculoskeletal disorder (MSD) pain.PerspectiveVA healthcare system.MethodsWe used a propensity score-adjusted hierarchical linear modeling (HLM), and 2010-2013 VA administrative data to estimate differences in VA healthcare costs, pain intensity (0-10 numerical rating scale), and opioid use between CIH users and nonusers. We identified CIH use in Veterans' medical records through Current Procedural Terminology, VA workload tracking, and provider-type codes.ResultsWe identified 30,634 younger Veterans with chronic MSD pain as using CIH and 195,424 with no CIH use. CIH users differed from nonusers across all baseline covariates except the Charlson comorbidity index. They also differed on annual pre-CIH-start healthcare costs ($10,729 versus $5,818), pain (4.33 versus 3.76), and opioid use (66.6% versus 54.0%). The HLM results indicated lower annual healthcare costs (-$637; 95% CI: -$1,023, -$247), lower pain (-0.34; -0.40, -0.27), and slightly higher (less than a percentage point) opioid use (0.8; 0.6, 0.9) for CIH users in the year after CIH start. Sensitivity analyses indicated similar results for three most-used CIH approaches (acupuncture, chiropractic care, and massage), but higher costs for those with eight or more CIH visits.ConclusionsOn average CIH use appears associated with lower healthcare costs and pain and slightly higher opioid use in this population of younger Veterans with chronic musculoskeletal pain. Given the VA's growing interest in the use of CIH, further, more detailed analyses of its impacts are warranted.

PURPOSE:To provide population-based reference values for cervical spinal canal parameters and vertebral body (VB) width and to study their associations with sex, age, body height, body weight and body mass index (BMI) using MRI. METHODS:Cross-sectional analyses included data from 2,453 participants, aged 21-89 years, of the population-based Study of Health in Pomerania (SHIP) who underwent whole-body MRI at 1.5 Tesla between July 2008 and March 2011. A standardised reading was performed for the C2-C7 cervical spine levels at sagittal T2 TSE weighted sequences. RESULTS:Reference intervals for spinal canal parameters were similar in males and females, while VB width was on average 2.1-2.2 mm larger in males. Age effects were only substantial regarding VB width with a 0.5 mm per ten-year age increase. Body height effects were only substantial regarding the osseous spinal canal and VB width. Body weight and BMI effects are mostly not substantial. CONCLUSIONS:Our study provides MRI-based reference values for the cervical spinal canal parameters in an adult Caucasian population. Except for VB width, associations with sex, age and somatometric measures are mostly small and thus have only limited clinical implications. Some available cut-off values may need a revision because they likely overestimate risks.

BackgroundPerinatal and newborn complications are major risk factors for unfavorable fetal and neonatal outcomes. Gestational dating and growth monitoring can be instrumental in the identification and management of high-risk pregnancies and births. The INTERGROWTH-21st Project developed the first global standards for gestational dating and fetal and newborn growth monitoring, supplying a toolkit for clinicians. This study aimed to assess the feasibility and acceptability of the first known implementation study of these standards in a low resource setting.MethodsThe study was performed in two 12-month phases from March 2016 to March 2018 at Jacaranda Health, a private maternity hospital in peri-urban Nairobi, Kenya. In-depth interviews, focus group discussions and a provider survey were utilized to evaluate providers' experiences during implementation. Client chart data, for pregnant women attending antenatal care and/or delivering at Jacaranda Health along with their newborns, were captured to assess uptake and effect of the standards on clinical decision-making.ResultsFacility-level support and provider buy-in proved to be critical factors driving the success of implementing the standards. However, additional support was needed to strengthen capacity to conduct and interpret ultrasounds and maintain motivation among providers. We observed a significant increase in the uptake of obstetric ultrasounds, particularly gestational dating, during the implementation of the standards. Although no significant changes were detected in the identification of high-risk pregnancies, referrals and deliveries by Cesarean section during implementation, we did observe a significant reduction in inductions for post-date. No significant barriers were reported regarding the use of the newborn standards. Over 80% of providers advocated for the standards to remain in place with some enhancements related mainly to training, advocacy and procurement.ConclusionsThe findings are timely with increasing global adoption of the standards and the challenging and multi-faceted nature of translating new, evidence-based guidelines into routine clinical practice.

A large proportion of COPD patients do not achieve the recommended level of physical activity. It is suggested that feedback on the level of activity by using an activity monitoring device (PAM) increases awareness and may stimulate patients to increase their physical activity in daily life. Our objective was to assess the validity and usability of a simple and low-cost physical activity monitor (Polar A300™) when compared with the validated and established Bodymedia-SenseWear™ (SWA) device.To assess the diagnostic equivalent, two different PAM devices were used in parallel in 20 COPD patients GOLD I to IV during 3 consecutive days of daily life. Both systems were compared in terms of steps, calories burned, daily activity time and metabolic equivalents using linear regression analysis and Bland-Altman plots. Practical usability was examined by a 16-item-questionnaire.High correlations of both devices were observed with regard to the sensed step count (r = 0.96; p < 0.01) and calories burned (r = 0.74; p < 0.01), and a lower correlation of daily activity (r = 0.25; p < 0.01) was found. Data analysis over 3 days showed that 90% of the steps (95% CI -4223 to 1887), 100% of the calories (95% CI -2798 to 1887), 90% of the daily activity data (95% CI -12.32, 4065) and 95% of the MET (95% CI -3.11 to 2.75) were within the limits of agreement. A favorable usability (system-, information- and interface quality) of the A300™ device was shown (p < 0.01).The A300™ device with easy practical usability was shown not to be inferior for assessment of physical activity time, step count and calorie consumption in COPD patients when compared with the SWA. It is suggested to consider widespread available devices as commonly used for monitoring recreational sporting activities also in patients for assessment of physical activity in daily life.

Ecological associations where one species enhances habitat for another nearby species (facilitations) shape fundamental community dynamics and can promote niche expansion, thereby influencing how and where species persist and coexist. For the many breeding birds facing high nest-predation pressure, enemy-free space can be gained by nesting near more formidable animals for physical protection. While the benefits to protected species seem well documented, very few studies have explored whether and how protector species are affected by nest protection associations. Long-legged wading birds (Pelecaniformes and Ciconiiformes) actively choose nesting sites above resident American alligators (Alligator mississippiensis), apparently to take advantage of the protection from mammalian nest predators that alligator presence offers. Previous research has shown that wading bird nesting colonies could provide substantial food for alligators in the form of dropped chicks. We compared alligator body condition in similar habitat with and without wading bird nesting colonies present. Alligator morphometric body condition indices were significantly higher in colony than in non-colony locations, an effect that was statistically independent of a range of environmental variables. Since colonially nesting birds and crocodilians co-occur in many tropical and subtropical wetlands, our results highlight a potentially widespread keystone process between two ecologically important species-groups. These findings suggest the interaction is highly beneficial for both groups of actors, and illustrate how selective pressures may have acted to form and reinforce a strongly positive ecological interaction.

Alzheimer's disease (AD) is diagnosed based upon medical history, neuropsychiatric examination, cerebrospinal fluid analysis, extensive laboratory analyses and cerebral imaging. Diagnosis is time consuming and labour intensive. Parkinson's disease (PD) is mainly diagnosed on clinical grounds.The primary aim of this study was to differentiate patients suffering from AD, PD and healthy controls by investigating exhaled air with the electronic nose technique. After demonstrating a difference between the three groups the secondary aim was the identification of specific substances responsible for the difference(s) using ion mobility spectroscopy. Thirdly we analysed whether amyloid beta (Aβ) in exhaled breath was causative for the observed differences between patients suffering from AD and healthy controls.We employed novel pulmonary diagnostic tools (electronic nose device/ion-mobility spectrometry) for the identification of patients with neurodegenerative diseases. Specifically, we analysed breath pattern differences in exhaled air of patients with AD, those with PD and healthy controls using the electronic nose device (eNose). Using ion mobility spectrometry (IMS), we identified the compounds responsible for the observed differences in breath patterns. We applied ELISA technique to measure Aβ in exhaled breath condensates.The eNose was able to differentiate between AD, PD and HC correctly. Using IMS, we identified markers that could be used to differentiate healthy controls from patients with AD and PD with an accuracy of 94%. In addition, patients suffering from PD were identified with sensitivity and specificity of 100%. Altogether, 3 AD patients out of 53 participants were misclassified. Although we found Aβ in exhaled breath condensate from both AD and healthy controls, no significant differences between groups were detected.These data may open a new field in the diagnosis of neurodegenerative disease such as Alzheimer's disease and Parkinson's disease. Further research is required to evaluate the significance of these pulmonary findings with respect to the pathophysiology of neurodegenerative disorders.

ObjectivesTo evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection.Methods and findingsDouble-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation.ConclusionThis Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical phase.Trial registrationClinicalTrials.gov NCT01136161.

BACKGROUND: To date the influence of herpesviruses on the development of equine ocular diseases has not been clearly determined. OBJECTIVE: The purpose of this study was to illustrate the course of equine ocular findings over a period of 18 months at 6 month intervals, in correlation with the results of herpesvirus detection. METHODS: 266 Lipizzaners in 3 federal states of Austria underwent complete ophthalmologic examination 4 times. Blood samples, nasal- and conjunctival swabs were obtained at the same time and used for the detection of the equid gammaherpesviruses EHV-2 and EHV-5 using consensus herpesvirus PCR and type-specific qPCRs. Ophthalmic findings and results of herpesvirus PCRs were recorded and statistically analysed using one-way ANOVA, and multiple logistic regression analysis to determine the influence of herpesvirus infections and other contributing factors on the presence of ophthalmic findings. RESULTS: In the first, second, third and fourth examination period 266, 261, 249 and 230 horses were included, respectively. Ophthalmic findings consistent with herpesvirus infections included conjunctival- and corneal pathologies. Statistical analysis revealed that the probability of positive herpesvirus PCR results decreased with progressing age; however the presence of corneal findings increased over time. At the time of each examination 45.1%, 41.8%, 43.0%, and 57.0% of horses with conjunctival or corneal findings, respectively, were positive for EHV-2 and/or EHV-5. However, 31.6%, 17.6%, 20.1%, and 13.0% of clinically sound horses were positive for these herpesviruses at each examination period, too. CONCLUSION: Based on the results of our study there is a significant influence of young age on EHV-2 and/or EHV-5 infection. Corneal pathologies increased over time and with progressing age. Whether the identified findings were caused by herpesviruses could not be unequivocally determined.

Individuals with HIV infection exhibit high cytomegalovirus (CMV) IgG levels, but there are few data regarding the association of hepatitis C virus (HCV) with the immune response against CMV.Associations of HCV with CMV seropositivity and CMV IgG levels were studied in 635 HIV-infected women, 187 of whom were HCV-seropositive, with adjustment in multivariable models for age, race/ethnicity, and HIV disease characteristics. Eighty one percent of the women reported receipt of highly active antiretroviral therapy (HAART) prior to or at CMV testing.In adjusted models women with chronic HCV had higher CMV IgG levels than those without HCV RNA (β = 2.86, 95% CI:0.89 - 4.83; P = 0.004). The association of HCV RNA with CMV IgG differed by age (P(interaction) = 0.0007), with a strong association observed among women in the low and middle age tertiles (≤ 45.3 years of age; β = 6.21, 95% CI:3.30 - 9.11, P

BACKGROUND: In resource-limited settings where viral load (VL) monitoring is scarce or unavailable, clinicians must use immunological and clinical criteria to define HIV virological treatment failure. This study examined the performance of World Health Organization (WHO) clinical and immunological failure criteria in predicting virological failure in HIV patients receiving antiretroviral therapy (ART). METHODS: In a HIV/AIDS program in Busia District Hospital, Kenya, a retrospective, cross-sectional cohort analysis was performed in April 2008 for all adult patients (>18 years old) on ART for ≥12 months, treatment-naive at ART start, attending the clinic at least once in last 6 months, and who had given informed consent. Treatment failure was assessed per WHO clinical (disease stage 3 or 4) and immunological (CD4 cell count) criteria, and compared with virological failure (VL >5,000 copies/mL). RESULTS: Of 926 patients, 123 (13.3%) had clinically defined treatment failure, 53 (5.7%) immunologically defined failure, and 55 (6.0%) virological failure. Sensitivity, specificity, positive predictive value, and negative predictive value of both clinical and immunological criteria (combined) in predicting virological failure were 36.4%, 83.5%, 12.3%, and 95.4%, respectively. CONCLUSIONS: In this analysis, clinical and immunological criteria were found to perform relatively poorly in predicting virological failure of ART. VL monitoring and new algorithms for assessing clinical or immunological treatment failure, as well as improved adherence strategies, are required in ART programs in resource-limited settings.

INTRODUCTION: Consequences of lack of viral monitoring in predicting the effects of development of HIV drug resistance mutations during HAART in resource-limited settings (RLS) is still a matter of debate. DESIGN: To assess, among HIV+ patients receiving their first-line HAART, prevalence of virological failure and genotypic resistance mutations pattern in a Médécins Sans Frontières/Ministry of Health programme in Busia District (Kenya). METHODS: Patients with HAART treatment for ≥12 months were eligible for the study and those with HIV-RNA ≥5000 copies/ml underwent genotypic study. Total HIV-1 RNA from Dried Blood Spots was extracted using Nuclisens method. RESULTS: 926 patients were included. Among 274 (29.6%) patients with detectable viral load, 55 (5.9%) experienced treatment failure (viral load >5.000 copies/ml); 61.8% were female and 10 (18.2%) had clinical failure. Median CD4 cell count was 116 cell/mm3 (IQR: 54-189). Median HIV-RNA was 32,000 copies/ml (IQR: 11000-68000). Eighteen out of 55 (33%) samples could be sequenced on PR and RT genes, with resistance associated mutations (RAMs) in 15 out of 18 samples (83%). Among patients carrying RAMs, 12/15 (81%) harboured RAMs associated to thymidine analogues (TAMs). All of them (100%) showed M184V resistance associated mutation to lamivudine as well as NNRTI's RAMS. CONCLUSIONS: Virological failure rate in resource-limited settings are similar to those observed in developed countries. Resistance mutation patterns were concordant with HAART received by failing patients. Long term detectable viral load confers greater probability of developing resistance and as a consequence, making difficult to find out a cost-effective subsequent treatment regimen.

In the Addona et al. paper (Nature Biotechnology 2009), a large-scale multi-site study was performed to quantify Multiple Reaction Monitoring (MRM) measurements of proteins spiked in human plasma. The unlabeled signature peptides derived from the seven target proteins were measured at nine different concentration levels, and their isotopic counterparts were served as the internal standards.In this paper, the sources of variation are analyzed by decomposing the variance into parts attributable to specific experimental factors: technical replicates, sites, peptides, transitions within each peptide, and higher-order interaction terms based on carefully built mixed effects models. The factors of peptides and transitions are shown to be major contributors to the variance of the measurements considering heavy (isotopic) peptides alone. For the light ((12)C) peptides alone, in addition to these factors, the factor of study*peptide also contributes significantly to the variance of the measurements. Heterogeneous peptide component models as well as influence analysis identify the outlier peptides in the study, which are then excluded from the analysis. Using a log-log scale transformation and subtracting the heavy/isotopic peptide [internal standard] measurement from the peptide measurements (i.e., taking the logarithm of the peak area ratio in the original scale establishes that), the MRM measurements are overall consistent across laboratories following the same standard operating procedures, and the variance components related to sites, transitions and higher-order interaction terms involving sites have greatly reduced impact. Thus the heavy peptides have been effective in reducing apparent inter-site variability. In addition, the estimates of intercepts and slopes of the calibration curves are calculated for the sub-studies.The MRM measurements are overall consistent across laboratories following the same standard operating procedures, and heavy peptides can be used as an effective internal standard for reducing apparent inter-site variability. Mixed effects modeling is a valuable tool in mass spectrometry-based proteomics research.

Background: Perinatal and newborn complications are major risk factors for unfavorable fetal and neonatal outcomes. Gestational dating and growth monitoring can be instrumental in the identification and management of high-risk pregnancies and births. The INTERGROWTH-21st Project developed the first global standards for gestational dating and fetal and newborn growth monitoring, supplying a toolkit for clinicians. This study aimed to assess the feasibility and acceptability of the first known implementation study of these standards in a low resource setting. Methods: The study was performed in two 12-month phases from March 2016 to March 2018 at Jacaranda Health, a private maternity hospital in peri-urban Nairobi, Kenya. In-depth interviews, focus group discussions and a provider survey were utilized to evaluate providers’ experiences during implementation. Client chart data, for pregnant women attending antenatal care and/or delivering at Jacaranda Health along with their newborns, were captured to assess uptake and effect of the standards on clinical decision-making. Results: Facility-level support and provider buy-in proved to be critical factors driving the success of implementing the standards. However, additional support was needed to strengthen capacity to conduct and interpret ultrasounds and maintain motivation among providers. We observed a significant increase in the uptake of obstetric ultrasounds, particularly gestational dating, during the implementation of the standards. Although no significant changes were detected in the identification of high-risk pregnancies, referrals and deliveries by Cesarean section during implementation, we did observe a significant reduction in inductions for post-date. No significant barriers were reported regarding the use of the newborn standards. Over 80% of providers advocated for the standards to remain in place with some enhancements related mainly to training, advocacy and procurement. Conclusions: The findings are timely with increasing global adoption of the standards and the challenging and multi-faceted nature of translating new, evidence-based guidelines into routine clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Consequences of lack of viral monitoring in predicting the effects of development of HIV drug resistance mutations during HAART in resource-limited settings (RLS) is still a matter of debate. Design: To assess, among HIV+ patients receiving their first-line HAART, prevalence of virological failure and genotypic resistance mutations pattern in a Médécins Sans Frontières/Ministry of Health programme in Busia District (Kenya). Methods: Patients with HAART treatment for ⩾12 months were eligible for the study and those with HIV-RNA ⩾5000 copies/ml underwent genotypic study. Total HIV-1 RNA from Dried Blood Spots was extracted using Nuclisens method. Results: 926 patients were included. Among 274 (29.6%) patients with detectable viral load, 55 (5.9%) experienced treatment failure (viral load >5.000 copies/ml); 61.8% were female and 10 (18.2%) had clinical failure. Median CD4 cell count was 116 cell/mm3 (IQR: 54-189). Median HIV-RNA was 32,000 copies/ml (IQR: 11000-68000). Eighteen out of 55 (33%) samples could be sequenced on PR and RT genes, with resistance associated mutations (RAMs) in 15 out of 18 samples (83%). Among patients carrying RAMs, 12/15 (81%) harboured RAMs associated to thymidine analogues (TAMs). All of them (100%) showed M184V resistance associated mutation to lamivudine as well as NNRTI's RAMS. Conclusions: Virological failure rate in resource-limited settings are similar to those observed in developed countries. Resistance mutation patterns were concordant with HAART received by failing patients. Long term detectable viral load confers greater probability of developing resistance and as a consequence, making difficult to find out a cost-effective subsequent treatment regimen. [ABSTRACT FROM AUTHOR]