Mapping the global distribution of C4 vegetation using observations and optimality theory.

Plants with the C4 photosynthesis pathway typically respond to climate change differently from more common C3-type plants, due to their distinct anatomical and biochemical characteristics. These different responses are expected to drive changes in global C4 and C3 vegetation distributions. However, current C4 vegetation distribution models may not predict this response as they do not capture multiple interacting factors and often lack observational constraints. Here, we used global observations of plant photosynthetic pathways, satellite remote sensing, and photosynthetic optimality theory to produce an observation-constrained global map of C4 vegetation. We find that global C4 vegetation coverage decreased from 17.7% to 17.1% of the land surface during 2001 to 2019. This was the net result of a reduction in C4 natural grass cover due to elevated CO2 favoring C3-type photosynthesis, and an increase in C4 crop cover, mainly from corn (maize) expansion. Using an emergent constraint approach, we estimated that C4 vegetation contributed 19.5% of global photosynthetic carbon assimilation, a value within the range of previous estimates (18-23%) but higher than the ensemble mean of dynamic global vegetation models (14 ± 13%; mean ± one standard deviation). Our study sheds insight on the critical and underappreciated role of C4 plants in the contemporary global carbon cycle.

Nanocarriers and their Actions to Improve Skin Permeability and Transdermal Drug Delivery.

Transdermal drug delivery is impeded by the natural barrier of epidermis namely stratum corneum. This limits the route to transport of drugs with a log octanol-water partition coefficient of 1 to 3, molecular weight of less than 500 Da and melting point of less than 200°C. Nanotechnology has received widespread investigation as nanocarriers are deemed to be able to fluidize the stratum corneum as a function of size, shape, surface charges, and hydrophilicity-hydrophobicity balance, while delivering drugs across the skin barrier. This review provides an overview and update on the latest designs of liposomes, ethosomes, transfersomes, niosomes, magnetosomes, oilin- water nanoemulsions, water-in-oil nanoemulsions, bicontinuous nanoemulsions, covalently crosslinked polysaccharide nanoparticles, ionically crosslinked polysaccharide nanoparticles, polyelectrolyte coacervated nanoparticles and hydrophobically modified polysaccharide nanoparticles with respect to their ability to fuse or fluidize lipid/protein/tight junction regimes of skin, and effect changes in skin permeability and drug flux. Universal relationships of nanocarrier size, zeta potential and chemical composition on transdermal permeation characteristics of drugs will be developed and discussed.

Current pharmaceutical design on adhesive based transdermal drug delivery systems.

Drug-in-adhesive transdermal drug delivery matrix exploits intimate contact of the carrier with stratum corneum, the principal skin barrier to drug transport, to deliver the actives across the skin and into the systemic circulation. The main application challenges of drug-in-adhesive matrix lie in the physicochemical properties of skin varying with age, gender, ethnicity, health and environmental condition of patients. This in turn poses difficulty to design a universal formulation to meet the intended adhesiveness, drug release and drug permeation performances. This review focuses on pressure-sensitive adhesives, and their adhesiveness and drug release/permeation modulation mechanisms as a function of adhesive molecular structure and formulation attributes. It discusses approaches to modulate adhesive tackiness, strength, elasticity, hydrophilicity, molecular suspension capability and swelling capacity, which contribute to the net effect of adhesive on skin bonding, drug release and drug permeation.

Oral calcium pectinate-insulin nanoparticles: influences of alginate, sodium chloride and Tween 80 on their blood glucose lowering performance.

OBJECTIVE: Examine the formation of pectin-insulin nanoparticles and their blood glucose lowering properties. METHODS: The calcium pectinate nanoparticles were prepared by ionotropic gelation method, with alginate, sodium chloride or Tween 80 as additive. Their in vitro physicochemical, drug release and in vivo blood glucose lowering characteristics were evaluated. KEY FINDINGS: Spherical calcium pectinate-insulin nanoparticles were characterized by size, zeta potential, insulin content and insulin association efficiency of 348.4 ± 12.9 nm, -17.9 ± 0.8 mV, 8.4 ± 1.0% and 63.8 ± 7.4%, respectively. They released less than 25% insulin following 24 h in simulated intestinal medium and exhibited delayed blood glucose lowering effect in rats. Incorporation of solubilizer sodium chloride or Tween 80 into nanoparticles did not enhance blood glucose lowering capacity owing to sodium chloride reduced matrix insulin content and Tween 80 interacted with water and had its blood glucose dilution effect negated. Combination of nanoparticles with alginate gel to allow prolonged intestinal residence and more insulin release did not enhance their blood glucose lowering capacity because of calcium alginate-cross-linked gel formation that could retard insulin release and migration into systemic circulation. CONCLUSION: Physicochemical responses of additives in vivo affected blood glucose regulation property of pectin-insulin nanoparticles.

Oral fast-release solid dispersion-paradigm shift to nanoparticles.

Design of oral fast-release solid dispersion of poorly water-soluble drugs has been a great challenge over past decades on issues of drug recrystallization, drug polymorphism, formulation limited to low drug-to-carrier ratio and drug particle aggregation in matrix. The complexity in solid dispersion design is envisaged to be resolvable by the use of nanoparticulate system as solid dosage form. This manuscript reviews several patented processing approaches of nanoparticulate solid dispersion that have been reported recently. Through drug nanoencapsulation, a higher content of drug may be delivered with less aggregation via placing the same drug mass in a greater number of tinier carriers. Nanoencapsulation, by its own process of formation, brings about submicron particles. Keeping drug in these nanoparticles, a remarkable rise in specific surface area of drug is realized for dissolution. The augmentation of drug dissolution can be sufficiently high to the extent that the influences of polymorphism and crystallization phenomenon on drug dissolution in a solid dispersion may be negligible.

Towards BioDBcore: a community-defined information specification for biological databases.

The present article proposes the adoption of a community-defined, uniform, generic description of the core attributes of biological databases, BioDBCore. The goals of these attributes are to provide a general overview of the database landscape, to encourage consistency and interoperability between resources; and to promote the use of semantic and syntactic standards. BioDBCore will make it easier for users to evaluate the scope and relevance of available resources. This new resource will increase the collective impact of the information present in biological databases.

Chitosan and its use in design of insulin delivery system.

The global burden of diabetes is estimated to escalate from about 171 million in 2000 to 366 million people in 2030. The routine of diabetes treatment by injection of insulin incurs pain and has been one major factor negating the quality of life of diabetic patients. The possibility of administering insulin via alternative routes such as oral and nasal pathways has been investigated over the years, but with insulin experiencing risks of enzymatic degradation and poor transmucosal absorption. This leads to the rising needs to develop new formulation strategies emphasizing on the assembly of insulin and excipients into a physical structure to maintain the stability and increase the bioavailability of insulin. Chitosan and its derivatives or salts have been widely investigated as functional excipients of delivering insulin via oral, nasal and transdermal routes. The overview of various recent patented strategies on non-injection insulin delivery denotes the significance of chitosan for its mucoadhesive and able to protect the insulin from enzymatic degradation, prolong the retention time of insulin, as well as, open the inter-epithelial tight junction to facilitate systemic insulin transport. The chitosan can be employed to strengthen the physicochemical stability of insulin and multi-particulate matrix. The introduction of chitosan coat or co-formulation of chitosan with cationic gelatin or electrolytes which provide solidified or partially crosslinked structures retain and/or enhance the positive charges of dosage form necessary to induce mucoadhesiveness. The chitosan is modifiable chemically to produce water-soluble low molecular weight polymer which renders insulin able to be processed under mild conditions, and sulphated chitosan which markedly opens the paracellular channels for insulin transport. Combination of chitosan and fatty acid as hydrophobic nanoparticles promotes the insulin absorption via lymphoid tissue. Attainment of optimized formulations with higher levels of pharmacological bioavailability is deemed possible in future through targeted delivery of insulin using chitosan with specific adhesiveness to the intended absorption mucosa.

Optimum oxygen therapy in preterm babies.

Oxygen is the most commonly used therapy in neonatal nurseries as an integral part of respiratory support. The goal of oxygen therapy is to achieve adequate delivery of oxygen to the tissue without creating oxygen toxicity. Oxygen must have been given to newborn preterm babies more than any other medicinal product in the past 60 years. Despite this, we still know very little about how much oxygen these babies actually need, or how much oxygen is safe to give, especially in the first few weeks of life. Recent observational studies have raised concerns that giving oxygen to target the saturation at "physiological" levels in newborn preterm babies may do more harm than good, but to date, clinicians have not been able to resolve the uncertainties surrounding optimum oxygen therapy.

Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation.

AIM: To determine whether differing policies with regard to the control of oxygen saturation have any impact on the number of babies who develop retinopathy of prematurity and the number surviving with or without signs of cerebral palsy at one year. METHODS: An examination of the case notes of all the 295 babies who survived infancy after delivery before 28 weeks gestation in the north of England in 1990-1994. RESULTS: Babies given enough supplemental oxygen to maintain an oxygen saturation of 88-98%, as measured by pulse oximetry, for at least the first 8 weeks of life developed retinopathy of prematurity severe enough to be treated with cryotherapy four times as often as babies only given enough oxygen to maintain an oxygen saturation of 70-90% (27.2% v 6.2%). Surviving babies were also ventilated longer (31.4 v 13.9 days), more likely to be in oxygen at a postmenstrual age of 36 weeks (46% v 18 %), and more likely to have a weight below the third centile at discharge (45% v 17%). There was no difference in the proportion who survived infancy (53% v 52%) or who later developed cerebral palsy (17% v 15%). The lowest incidence of retinopathy in the study was associated with a policy that made little use of arterial lines. CONCLUSIONS: Attempts to keep oxygen saturation at a normal "physiological" level may do more harm than good in babies of less than 28 weeks gestation.

Six years' experience of prophylactic oral vitamin K.

AIMS: The ability of oral vitamin K to eliminate all risk of vitamin K deficiency bleeding during the first three months of life was studied. METHODS: Babies (n=182,000) in the north of England judged well enough to be offered milk within 12 hours of birth were given 1 mg of phytomenadione (vitamin K(1)) suspended in a medium chain triglyceride oil by mouth at delivery between 1993 and 1998. The parents of those who were breastfed were given a further three doses to give to the baby once every two weeks after discharge. RESULTS: Four breastfed babies developed late vitamin K deficiency bleeding. In two, staff failed to follow policy guidelines, and in two there was undiagnosed alpha(1) antitrypsin deficiency. Audit suggested that 93% of breastfed babies had all four doses, as advised. CONCLUSIONS: An oral product that parents can administer themselves would be popular if licensed, but the total dose offered may need to be more than in this study if babies with undiagnosed liver disease are to be protected.

Ocular abnormalities associated with cerebral palsy after preterm birth.

PURPOSE: To document the ocular abnormalities in children with cerebral palsy (CP) after premature birth. METHODS: All the children born before 32 weeks gestation between 1 January 1990 and 31 December 1991 in a geographically defined population of approximately 3 million, were examined by an ophthalmologist and a paediatrician at 2 years old. RESULTS: Five hundred and fifty-eight children (98.8% of the study group) were examined, of whom 41 had disabling CP and 13 had non-disabling CP. Children with CP had a higher incidence of abnormalities compared with children without CP: cicatricial retinopathy of prematurity occurred in 8 children with CP (14.8%) compared with 8 without CP (1.6%, p < 0.0001), cortical visual impairment occurred in 6 with CP (11.1%) compared with 1 child without CP (0.2%, p < 0.0001) and concomitant strabismus in 28 with CP (51.9%) compared with 42 without CP (8.4%, p < 0.0001). The prevalence of refractive error without other ocular abnormalities was similar for children with CP (4/54, 7.4%) and those without CP (54/504, 10.7%, p = 0.90). Significant ocular abnormalities had been previously unrecognised in 8 children with CP (14.8%). CONCLUSION: There are some differences between these results and previous series. These differences probably reflect the fact that previous work has studied severe CP of more diverse aetiology. The high frequency of abnormalities highlights the importance of ocular assessment of these children.

Bias due to incomplete follow up in a cohort study.

AIM: To investigate the bias introduced by incomplete follow up in a cohort study of ocular outcome after premature birth. METHODS: A geographically defined cohort of children born before 32 weeks' gestation was prospectively recruited at birth to study the ocular outcome at 2 years. On the basis of attendance at 2 years, the children's families were allocated to one of three groups: group 1 attended for follow up, group 2 were difficult to trace, and group 3 were very reluctant for assessment. All children were examined by a single ophthalmologist, masked to these groupings. RESULTS: 558 children (98.8% of study group) were examined, of whom 505 were in group 1, 20 in group 2, and 33 in group 3. The groups which were more difficult to study (groups 2 and 3) showed a significantly higher prevalence of ocular abnormalities, including strabismus (p=0. 02) and cicatricial retinopathy of prematurity (p=0.002) compared with those attending for follow up. Further, not all of these cases could have been identified by review of the children's previous records. Ocular abnormalities would be underestimated by 16% (11.3% in group 1 compared with 13.4% in the total cohort, p=0.77). CONCLUSIONS: This study suggests that the prevalence of abnormalities would be underestimated by incomplete follow up, as those subjects who were most difficult to obtain for study had a significantly higher prevalence of abnormalities.

Risk factors for strabismus in children born before 32 weeks' gestation.

AIM: To investigate risk factors associated with strabismus in children born prematurely. METHODS: Prospective study of all children born before 32 weeks' gestation between 1 January 1990 and 31 December 1991 in a geographically defined population of approximately 3 million in the Northern Region of the United Kingdom. All children were examined aged 2 years by the same ophthalmologist and paediatrician. RESULTS: 558 children (98.6% of study group) were examined. Logistic regression showed an increased risk of strabismus in children with cicatricial retinopathy of prematurity (p=0.02), refractive error (p=0.003), family history of strabismus (p<0.0001), and poor neurodevelopmental outcome (p<0.0001), in particular impaired locomotor skills (p=0.008) and hand-eye coordination (p=0. 001). Gestational age and regressed acute ROP were not independent risk factors for strabismus (p=0.92 and 0.85 respectively). CONCLUSIONS: This study has identified factors which are independently related to strabismus (although not necessarily causative) and others which are related only indirectly. This may contribute both to the management of children born prematurely and to future studies of the aetiology of strabismus.

Outcome of very preterm birth: children reviewed with ease at 2 years differ from those followed up with difficulty.

AIM: To determine whether those most easily reviewed in a population prevalence study differ from those followed up only with difficulty. METHODS: All babies born before 32 weeks of gestation in the North of England in 1983, 1990, and 1991 were traced, and all the survivors assessed at two years by one of two independent clinicians. RESULTS: 818 of the 1138 live born babies survived to discharge. There was some non-significant, excess disability in the 5% of long term survivors who were difficult to trace because of social mobility, but eight times as much severe disability in the 1% (9/796) in care and in the 5% (38/796) whose parents initially failed to keep a series of home or hospital appointments for interview, and five times as much emergent disability in the 2.7% (22/818) who died after discharge but before their second birthday. Had the babies who were seen without difficulty been considered representative of all the babies surviving to discharge, the reported disability rate would have been two thirds what it really was (6.9% instead of 11.0%). CONCLUSIONS: Population prevalence studies that ignore those who seem reluctant to cooperate risk serious ascertainment bias.

A comparison of two methods of follow-up in a trial of prophylactic volume expansion in preterm babies.

The outcome at age 2 years of preterm babies recruited into a three-arm randomised controlled trial of prophylactic volume expansion was ascertained in two ways: from a neurodevelopmental assessment performed by a paediatrician and from responses on a brief questionnaire completed by the child's personal health visitor. Of 776 babies recruited into the trial, 604 survived to the age of 2 years and the findings of a paediatric assessment were available for all survivors. Questionnaires were sent to the health visitors of 601 of the survivors; 513 (85.4%) were returned. There was sufficient information on the returned questionnaires to categorise 449 of the children as normal, impaired, moderately disabled or severely disabled. We were unable to detect a response bias by severity of disability. Agreement on individual questions ranged between 86.3% and 98.4%. There was some mismatch in the reporting of vision (weighted kappa = 0.71) and hearing (weighted kappa = 0.73), with differences in perception of level of severity of sensory loss. Health visitors tended to underestimate the child's functional level compared with the paediatrician. However, of 56 children classified as severely disabled by the paediatrician, 48 were classified similarly and eight as moderately disabled on the basis of the questionnaire. The end point of the trial was death or severe disability at 2 years of age. There was close similarity in the trial results whether based on the paediatric assessment or on the questionnaire. Further refinement of the questionnaire is needed, but this methodology may be useful in ascertaining the frequency of severe disability in large cohorts of babies.

Selection biases invalidate current low birthweight weight-for-gestation standards. The Northern Neonatal Network.

OBJECTIVE: To obtain unbiased estimates of the variation of birthweight with gestation in infants born before 32 weeks of gestation. SETTING: The former Northern Regional Health Authority. DESIGN: Information on birthweight was collected during a collaborative study of every registered and unregistered birth at 22 to 31 weeks of gestation in the region in 1983 and 1990 to 1991. These birthweights were then related to computer-generated Tyneside norms for all registered births at 28 to 42 weeks of gestation between 1984 and 1991. Some local information was also collected on fetal weight after termination of pregnancy on social grounds at 16 to 21 weeks of gestation. RESULTS: Weight centiles constructed after excluding infants with a gross, externally visible, malformation and those dying before the onset of labour suggest that previously published European standards have overestimated birthweight in infants < 28 weeks of gestation, some low centiles being 30% in error. Female and first-born infants weighed 4% less than their male and later-born counterparts at all gestations studied. A single correction factor can therefore be used to correct for sex and parity, eliminating the need for separate centile graphs. Twin pregnancy was associated with a 10% reduction in mean birthweight in pregnancies lasting < 37 weeks, and this difference increased progressively in pregnancies lasting longer than this. CONCLUSION: The small number of low birthweight infants in previous datasets and the selective exclusion of all nonregistered births have made previous second trimester weight-for-gestation norms unreliable.

Changing prognosis for babies of less than 28 weeks' gestation in the north of England between 1983 and 1994. Northern Neonatal Network.

OBJECTIVE: To investigate the changing prognosis for babies of less than 28 weeks' gestation. DESIGN: A prospective, collaborative, population based survey. SETTING: The former Northern Regional Health Authority. SUBJECTS: All the births between 1983 and 1994 at 22 to 27 completed weeks' gestation to women normally resident in the region. MAIN OUTCOME MEASURES: Miscarriage, stillbirth, death in the first year of life, and disability in survivors. RESULTS: There were 479070 registered births in the study period. No baby of 22 weeks' gestation survived; only eight (4%) of the 197 babies of 23 weeks who were alive at the onset of labour survived for a year-a proportion that did not change during the study period. Survival among other babies of less than 28 weeks improved progressively between 1983-6 and 1991-4, but administration of artificial surfactant to babies requiring ventilation from mid-1990 was associated with further improvement in survival only in those over 25 weeks' gestation. Babies of 24 weeks required three times as much high dependency care per survivor as babies of 27 weeks (76 v 26 days). The rate of severe disability in the one year survivors of less than 26 weeks' gestation (30/123; 24%) was similar to that seen in the sampled survivors of 26 and 27 weeks (29/108; 27%); the proportion disabled did not change significantly during the study period. All the children born in 1983, 1987, and 1991 were later reassessed in greater detail: 10% (13/136) seemed destined for a continuing life of total dependency. CONCLUSIONS: Gestation, if accurately assessed, can give a woman facing very preterm delivery a clear indication of the prognosis for her baby and help her judge the appropriateness of accepting obstetric intervention and sustained perinatal support.