Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. RESULTS: 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. CONCLUSION: aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.

Editing the 19 kDa alpha-zein gene family generates non-opaque2-based quality protein maize.

Maize grain is deficient in lysine. While the opaque2 mutation increases grain lysine, o2 is a transcription factor that regulates a wide network of genes beyond zeins, which leads to pleiotropic and often negative effects. Additionally, the drastic reduction in 19 kDa and 22 kDa alpha-zeins causes a floury kernel, unsuitable for agricultural use. Quality protein maize (QPM) overcame the undesirable kernel texture through the introgression of modifying alleles. However, QPM still lacks a functional o2 transcription factor, which has a penalty on non-lysine amino acids due to the o2 mutation. CRISPR/cas9 gives researchers the ability to directly target genes of interest. In this paper, gene editing was used to specifically target the 19 kDa alpha zein gene family. This allows for proteome rebalancing to occur without an o2 mutation and without a total alpha-zein knockout. The results showed that editing some, but not all, of the 19 kDa zeins resulted in up to 30% more lysine. An edited line displayed an increase of 30% over the wild type. While not quite the 55% lysine increase displayed by QPM, the line had little collateral impact on other amino acid levels compared to QPM. Additionally, the edited line containing a partially reduced 19 kDa showed an advantage in kernel texture that had a complete 19 kDa knockout. These results serve as proof of concept that editing the 19 kDa alpha-zein family alone can enhance lysine while retaining vitreous endosperm and a functional O2 transcription factor.

Large and stable genome edits at the sorghum alpha kafirin locus result in changes in chromatin accessibility and globally increased expression of genes encoding lysine enrichment.

Introduction: Sorghum is a resilient and widely cultivated grain crop used for feed and food. However, it's grain is deficient in lysine, an essential amino acid. This is due to the primary seed storage proteins, the alpha-kafirins, lacking lysine. It has been observed that reductions in alpha-kafirin protein results in rebalancing of the seed proteome and a corresponding increase in non-kafirin proteins which leads to an increased lysine content. However, the mechanisms underlying proteome rebalancing are unclear. This study characterizes a previously developed gene edited sorghum line, with deletions at the alpha kafirin locus. Methods: A single consensus guide RNA leads to tandem deletion of multiple members of the gene family in addition to the small target site mutations in remaining genes. RNA-seq and ATAC-seq were utilized to identify changes in gene expression and chromatin accessibility in developing kernels in the absence of most alpha-kafirin expression. Results: Several differentially accessible chromatin regions and differentially expressed genes were identified. Additionally, several genes upregulated in the edited sorghum line were common with their syntenic orthologues differentially expressed in maize prolamin mutants. ATAC-seq showed enrichment of the binding motif for ZmOPAQUE 11, perhaps indicating the transcription factor's involvement in the kernel response to reduced prolamins. Discussion: Overall, this study provides a resource of genes and chromosomal regions which may be involved in sorghum's response to reduced seed storage proteins and the process of proteome rebalancing.

Improving access to affordable quality-assured inhaled medicines in low- and middle-income countries.

BACKGROUND: Access to affordable inhaled medicines for chronic respiratory diseases (CRDs) is severely limited in low- and middle-income countries (LMICs), causing avoidable morbidity and mortality. The International Union Against Tuberculosis and Lung Disease convened a stakeholder meeting on this topic in February 2022.METHODS: Focused group discussions were informed by literature and presentations summarising experiences of obtaining inhaled medicines in LMICs. The virtual meeting was moderated using a topic guide around barriers and solutions to improve access. The thematic framework approach was used for analysis.RESULTS: A total of 58 key stakeholders, including patients, healthcare practitioners, members of national and international organisations, industry and WHO representatives attended the meeting. There were 20 pre-meeting material submissions. The main barriers identified were 1) low awareness of CRDs; 2) limited data on CRD burden and treatments in LMICs; 3) ineffective procurement and distribution networks; and 4) poor communication of the needs of people with CRDs. Solutions discussed were 1) generation of data to inform policy and practice; 2) capacity building; 3) improved procurement mechanisms; 4) strengthened advocacy practices; and 5) a World Health Assembly Resolution.CONCLUSION: There are opportunities to achieve improved access to affordable, quality-assured inhaled medicines in LMICs through coordinated, multi-stakeholder, collaborative efforts.

Staphylococcus hominis cellulitis and bacteremia associated with surgical clips.

Streptococcus spp. and Staphylococcus aureus are the most common pathogens causing skin and soft tissue infections (SSTI). Guideline-recommended empiric antibiotics targeting these organisms would also treat coagulase negative Staphylococci, which are not typically considered skin and soft tissue pathogens. Coagulase negative Staphylococci are, however, well known for their propensity to cause indolent infections in the setting of prosthetic material. Here, we present a case of a patient with surgical clips from a femoral artery surgical repair one year prior, presenting with cellulitis at the prior surgical site, complicated by high-grade Staphylococcus hominis bacteremia. Signs of infection persisted after 4 days of appropriate antibiotic therapy and resolved rapidly upon non-steroidal anti-inflammatory administration. This case highlights the importance of recognizing coagulase negative Staphylococci as a possible etiology of cellulitis in patients with prosthetic material, and of considering anti-inflammatory medications as a supplement to antibiotic therapy to hasten resolution of cellulitis in appropriate patients.

"We can't carry the weight of the whole world": illness experiences among Peruvian older adults with symptoms of depression and anxiety.

BACKGROUND: Despite the high levels of depression and anxiety symptoms in old age, the use of mental health services in this population is low. Help-seeking behaviors are shaped by how an individual perceives and experiences their illness. The objective of this study was to characterize the illness experiences of Peruvian older adults with depression and anxiety symptoms in order to lay the foundation for tailored community-based mental health interventions. METHODS: In this qualitative study, we conducted in-depth interviews with a purposively selected sample of older adults (≥ 60 years) from peri-urban areas of Lima, Peru. We included individuals with only depressive symptoms (Patient Health Questionnaire-9 ≥ 10), only anxiety symptoms (Beck Anxiety Inventory ≥ 16), with depressive and anxiety symptoms, and older adults who mentioned they had received mental health treatment/care. The interview guide included the following topics: perceptions and experiences about depression and anxiety; perceptions about the relationship between physical chronic diseases and mental health; experiences with mental health professionals and treatments, and coping mechanisms. Data collection was conducted between October 2018 and February 2019. RESULTS: We interviewed 38 participants (23 women, 15 men) with a mean age of 67.9 years. Participants' ideas and perceptions of depression and anxiety showed considerable overlap. Participants attributed depression and anxiety mainly to familial and financial problems, loneliness, loss of independence and past traumatic experiences. Coping strategies used by older adults included 'self-reflection and adaptation' to circumstances, 'do your part', and seeking 'emotional support' mainly from non-professionals (relatives, friends, acquaintances, and religion). CONCLUSIONS: Illness experiences of depression and anxiety set the pathway for tailored community-based mental health interventions for older adults. Overlapping narratives and perceptions of depression and anxiety suggest that these conditions should be addressed together. Mental health interventions should incorporate addressing areas related to depression and anxiety such as prevention of loss of independence, trauma, and loneliness. Good acceptability of receiving emotional support for non-professionals might offer an opportunity to incorporate them when delivering mental health care to older adults.

Magnetic force fields of isolated small nanoparticle clusters.

The usage of magnetic nanoparticles (NPs) in applications necessitates a precise mastering of their properties at the single nanoparticle level. There has been a lot of progress in the understanding of the magnetic properties of NPs, but incomparably less when interparticle interactions govern the overall magnetic response. Here, we present a quantitative investigation of magnetic fields generated by small clusters of NPs assembled on a dielectric non-magnetic surface. Structures ranging from individual NPs to fifth-fold particulate clusters are investigated in their magnetization saturation state by magnetic force microscopy and numerical calculations. It is found that the magnetic stray field does not increase proportionally with the number of NPs in the cluster. Both measured and calculated magnetic force fields underline the great importance of the exact spatial arrangement of NPs, shedding light on the magnetic force field distribution of particulate clusters, which is relevant for the quantitative evaluation of their magnetization and perceptibly for many applications.

Pollution and respiratory disease: can diet or supplements help? A review.

Pollution is known to cause and exacerbate a number of chronic respiratory diseases. The World Health Organisation has placed air pollution as the world's largest environmental health risk factor. There has been recent publicity about the role for diet and anti-oxidants in mitigating the effects of pollution, and this review assesses the evidence for alterations in diet, including vitamin supplementation in abrogating the effects of pollution on asthma and other chronic respiratory diseases. We found evidence to suggest that carotenoids, vitamin D and vitamin E help protect against pollution damage which can trigger asthma, COPD and lung cancer initiation. Vitamin C, curcumin, choline and omega-3 fatty acids may also play a role. The Mediterranean diet appears to be of benefit in patients with airways disease and there appears to be a beneficial effect in smokers however there is no direct evidence regarding protecting against air pollution. More studies investigating the effects of nutrition on rapidly rising air pollution are urgently required. However it is very difficult to design such studies due to the confounding factors of diet, obesity, co-morbid illness, medication and environmental exposure.

[Nanoparticles as drug delivery systems in ophthalmology]. / Nanopartikel als Drug-Delivery-Systeme für die Ophthalmologie.

Nanoparticles are perfectly suited as drug delivery systems due to their size and the diversity of materials used. They are able to penetrate biological barriers, can directly deliver drugs to the target site and provide a sustained release profile. Having long been established in oncology, in the last decade research has started to take a closer look at the potential of nanoparticles for ocular drug delivery. Obstacles, such as poor delivery of drugs via eye drops and the side effects of invasive methods, such as placing implants as drug depots could be overcome. Among the most relevant investigated structures are polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles, dendrimers and cyclodextrins. Besides the composition of the nanoparticle itself, its efficacy and stability can be optimized through coatings; however, long-term stability, standardization of production and toxicity remain the major challenges. The preclinical and partly clinical results obtained so far will hopefully give impulse to the idea of applying nanoparticles for optimized ocular drug delivery in the near future.

Prevalence and risk factors of restrictive spirometry in a cohort of Peruvian adults.

INTRODUCTION: Few studies have described the prevalence of and lung function decline among those with a restrictive spirometric pattern (RSP) in low- and middle-income countries. METHODS: We analyzed prospective data from 3055 adults recruited across four diverse settings in Peru over a 3-year period. Multivariable logistic regression was used to study the association between the presence of restriction and associated risk factors. Multivariable linear mixed models were used to determine lung function decline. RESULTS: Among 3055 participants, the average age was 55.4 years (SD 12.4); 49% were male. Overall prevalence of RSP was 4.7%, ranging from 2.8% (Lima) to 6.9% (Tumbes). The odds of having RSP were higher among those who lived in a rural environment (OR 2.19, 95%CI 1.43-3.37), had a diagnosis of diabetes (OR 1.94, 95%CI 1.10-3.40) and among women (OR 2.09, 95%CI 1.41-3.09). When adjusting for baseline lung function, adults with RSP had accelerated decline in forced expiratory volume in 1 s (FEV1) compared with non-obstructed, non-restricted individuals. DISCUSSION: RSP is prevalent particularly among women and in individuals living in rural settings of Peru. When adjusted for baseline lung function, participants with RSP had accelerated rates of FEV1 decline. Our findings are consistent with the notion that RSP is an insidious inflammatory condition with deleterious effects of lung function decline.

Establishment of a retinal hypoxia organ culture model.

Hypoxia plays an important role in several retinal diseases, especially in central retinal artery occlusion (CRAO). Although CRAO has been known for over a hundred years, no cure or sufficient treatment is available. Potential therapies are being evaluated in several in vivo models or primary cultures. However, in vivo models or primary cultures are very time-consuming, expensive, and furthermore several therapies or agents cannot be tested. Therefore, we aimed to develop a standardized organotypic ex vivo retinal hypoxia model. A chamber was developed in which rat retinal explants were incubated for different hypoxia durations. Afterwards, the retinas were adjusted to normal air and incubated for 24, 48 or 72 h under standard conditions. To analyze the retinal explants, and in particular the retinal ganglion cells (RGC) immunohistology, western blot and optical coherence tomography (OCT) measurements were performed. To compare our model to a standardized degeneration model, additional retinal explants were treated with 0.5 and 1 mM glutamate. Depending on hypoxia duration and incubation time, the amount of RGCs decreased and accordingly, the amount of TUNEL-positive RGCs increased. Furthermore, ß-III-tubulin expression and retinal thickness significantly decreased with longer-lasting hypoxia. The reduction of RGCs induced by 75 min of hypoxia was comparable to the one of 1 mM glutamate treatment after 24 h (20.27% versus 19.69%) and 48 h (13.41% versus 14.41%) of incubation. We successfully established a cheap, standardized, easy-to-use organotypic culture model for retinal hypoxia. We selected 75 min of hypoxia for further studies, as approximately 50% of the RGC died compared to the control group after 48 h.

Degenerative effects of cobalt-chloride treatment on neurons and microglia in a porcine retina organ culture model.

In order to understand the pathological processes of retinal diseases, experimental models are necessary. Cobalt, as part of the vitamin B12 complex, is important for neuronal integrity. However, it is known that high quantities of cobalt induce cytotoxic mechanisms via hypoxia mimicry. Therefore, we tested the degenerative effect of cobalt chloride (CoCl2) on neurons and microglia in a porcine retina organ culture model. Organotypic cultures of porcine retinas were cultured and treated with different concentrations of CoCl2 (0, 100, 300 and 500 µM) for 48 h. After four and eight days, CoCl2 induced a strong degeneration of the porcine retina, starting at 300 µM. A loss of retinal ganglion cells (RGCs, Brn-3a), amacrine cells (calretinin) and bipolar cells (PKCα) was observed. Additionally, a high expression of hypoxia induced factor-1a (HIF-1a) and heat shock protein 70 (HSP70) was noted at both points in time. Also, the Caspase 3 protein was activated and P21 expression was induced. However, only at day four, the Bax/Bcl-2 ratio was increased. The effect of CoCl2 was not restricted to neurons. CoCl2 concentrations reduced the microglia amount (Iba1) and activity (Iba1 + Fcγ-Receptor) at both points in time. These damaging effects on microglia were surprising, since CoCl2 causes hypoxia and a pro-inflammatory environment. However, high concentrations of CoCl2 also seem to be toxic to these cells. Similar degenerative mechanisms as in comparison to retinal ischemia animal models were observed. In summary, an effective and reproducible hypoxia-mimicking organotypic model for retinal degeneration was established, which is easy to handle and ready for drug studies.

Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. REPORT: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. DISCUSSION: Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI. CONCLUSIONS: Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

Early outcomes of twin-peg mobile-bearing unicompartmental knee arthroplasty compared with primary total knee arthroplasty.

AIMS: Since redesign of the Oxford phase III mobile-bearing unicompartmental knee arthroplasty (UKA) femoral component to a twin-peg design, there has not been a direct comparison to total knee arthroplasty (TKA). Thus, we explored differences between the two cohorts. PATIENTS AND METHODS: A total of 168 patients (201 knees) underwent medial UKA with the Oxford Partial Knee Twin-Peg. These patients were compared with a randomly selected group of 177 patients (189 knees) with primary Vanguard TKA. Patient demographics, Knee Society (KS) scores and range of movement (ROM) were compared between the two cohorts. Additionally, revision, re-operation and manipulation under anaesthesia rates were analysed. RESULTS: The mean follow-up for UKA and TKA groups was 5.4 and 5.5 years, respectively. Six TKA (3.2%) versus three UKAs (1.5%) were revised which was not significant (p = 0.269). Manipulation was more frequent after TKA (16; 8.5%) versus none in the UKA group (p < 0.001). UKA patients had higher post-operative KS function scores versus TKA patients (78 versus 66, p < 0.001) with a trend toward greater improvement, but there was no difference in ROM and KS clinical improvement (p = 0.382 and 0.420, respectively). CONCLUSION: We found fewer manipulations, and higher functional outcomes for patients treated with medial mobile-bearing UKA compared with TKA. TKA had twice the revision rate as UKA although this did not reach statistical significance with the numbers available. Cite this article: Bone Joint J 2016;98-B(10 Suppl B):28-33.

Viruses and exacerbations of chronic obstructive pulmonary disease: unmet clinical need.

Chronic obstructive pulmonary disease (COPD) is a non-communicable long-term condition characterised by accelerated lung-function decline and intermittent episodes of respiratory illness called exacerbations. We discuss the current understanding of the role of viruses in these elements of COPD. The burden of acute viral illness in COPD is great and largely unrecognised. Because naturally occurring exacerbations are inherently difficult to study, only recently have we understood underlying pathophysiological mechanisms and the true prevalence of viral exacerbations. Data are also emerging to support a potential role for chronic viral infection in the progression of stable COPD. As knowledge in these two areas develops, it is clear that the role of viruses in COPD represents a significant unmet clinical need.

Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort.

OBJECTIVES: Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers. METHODS: Data were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1-107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics. RESULTS: Although there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P<0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio=2.25, CI=1.12-3.94, P=0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio=2.07, CI=1.07-3.55, P=0.02). CONCLUSIONS: Our findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.

Bio-inspired swing leg control for spring-mass robots running on ground with unexpected height disturbance.

We proposed three swing leg control policies for spring-mass running robots, inspired by experimental data from our recent collaborative work on ground running birds. Previous investigations suggest that animals may prioritize injury avoidance and/or efficiency as their objective function during running rather than maintaining limit-cycle stability. Therefore, in this study we targeted structural capacity (maximum leg force to avoid damage) and efficiency as the main goals for our control policies, since these objective functions are crucial to reduce motor size and structure weight. Each proposed policy controls the leg angle as a function of time during flight phase such that its objective function during the subsequent stance phase is regulated. The three objective functions that are regulated in the control policies are (i) the leg peak force, (ii) the axial impulse, and (iii) the leg actuator work. It should be noted that each control policy regulates one single objective function. Surprisingly, all three swing leg control policies result in nearly identical subsequent stance phase dynamics. This implies that the implementation of any of the proposed control policies would satisfy both goals (damage avoidance and efficiency) at once. Furthermore, all three control policies require a surprisingly simple leg angle adjustment: leg retraction with constant angular acceleration.

Randomized trial of a diabetes self-management education and family teamwork intervention in adolescents with Type 1 diabetes.

AIMS: To evaluate the effectiveness of a family-centred group education programme, in adolescents with Type 1 diabetes. METHODS: Three hundred and five adolescents with Type 1 diabetes; age 13.1 ± 1.9 years, diabetes duration 5.6 ± 3.3 years, BMI 20.9 ± 3.7 kg/m(2) , HbA(1c) 78 ± 6 mmol/mol (9.3 ± 1.9%) were randomly allocated to the Families and Adolescents Communication and Teamwork Study (FACTS) diabetes education programme; (six 90-min monthly sessions attended by parents and adolescents incorporating skills training and family teamwork) or conventional clinical care. Primary outcome was HbA(1c) at 18 months (12 months post-intervention). Secondary outcomes were HbA(1c) at 9 months, psychosocial outcomes, adolescent quality of life, well-being, family responsibility and insulin dose adjustment behaviours at 12 months (6 months post-intervention) and episodes of severe hypoglycaemia and diabetic ketoacidois during the 12 months post-intervention. All analyses are intention to treat. RESULTS: Session attendance was poor with 48/158 families (30.4%) not attending any sessions and only 75/158 (47.5%) families attending ≥ 4 group education sessions. All biomedical and psychosocial outcomes were comparable between groups. At 18 months there was no significant difference in HbA(1c) in either group and no between-group differences over time: intervention group 75 mmol/mol (9.0%) to 78 mmol/mol (9.3%), control group 77 mmol/mol (9.2%) to 80 mmol/mol (9.5%). Adolescents perceived no changes in parental input at 12 months. CONCLUSION: Poor attendance of group education sessions delivered in routine clinics was a major challenge. More personalized educational approaches may be required to support and motivate families who are struggling to integrate the demands of intensive insulin regimens into their daily lives.

Sperm competition roles and ejaculate investment in a promiscuous mammal.

Theoretical models of sperm competition predict how males should allocate sperm and seminal fluid components to ejaculates according to their mating role (dominant vs. subordinate). Here, we present a detailed analysis of ejaculate expenditure according to male roles in the bank vole (Myodes glareolus). Sperm competition occurs regularly in this species, and dominant males typically achieve higher fertilization success than subordinates. Contrary to theoretical predictions, we found that dominant male bank voles invest more sperm per ejaculate than subordinates, both absolutely and relative to body and testes mass. The testes of dominant males were also absolutely (although not relatively) larger than those of subordinates. However, we found no evidence that subordinate males compensate for lower sperm numbers per ejaculate by increasing ejaculation frequency or sperm velocity. Similarly, we found no evidence for differential investment in copulatory plug size according to male roles in sperm competition, although dominant males had significantly larger seminal vesicles (both absolutely and relative to body mass) compared with subordinates. We conclude that sperm competition roles can have significant but unexpected influences on ejaculate investment in mammals with clearly defined differences in male social status.