A Multireference View of Photosynthesis: Uncovering Significant Site Energy Variations among Isolated Photosystem II Reaction Center Chlorophylls.

Oxygenic photosynthesis begins in the reaction center (RC) of the protein complex photosystem II (PSII). PSII has an intriguing, nearly symmetrical arrangement of cofactors within its RC. Despite this symmetry, evolution has favored only one of the two branches of PSII for efficient electron transfer. Current spectroscopic experiments explore the electronic dynamics during the picoseconds after energy has entered the RC and until the electron transfers to the pheophytin of the first branch. We present state-of-the-art multiconfigurational multireference calculations of the excitation energies or site energies of the four chlorophyll pigments of the RC without protein environment considerations. We see a significant variation that breaks the apparent symmetry of the RC. The inner chlorophyll of the productive RC branch possessed the lowest excitation energy of the four central chlorophylls. Our computational method used here is expensive; thus, geometry optimization of the crystal structure is currently not possible. In future work, charge and energy dynamics within the RC will be included as well as a dynamic description of the protein environment and its coupling to the RC. Other state-of-the-art studies of the RC, at lower levels of electronic structure, include a static treatment of the protein environment. These almost unanimously report that the outer chlorophyll of the active branch had the lowest excitation energy. Future work is needed to reconcile this discrepancy.

Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (article I): a systematic review and description of methods.

ABSTRACT: Blinding is challenging in randomised controlled trials of physical, psychological, and self-management therapies for pain, mainly because of their complex and participatory nature. To develop standards for the design, implementation, and reporting of control interventions in efficacy and mechanistic trials, a systematic overview of currently used sham interventions and other blinding methods was required. Twelve databases were searched for placebo or sham-controlled randomised clinical trials of physical, psychological, and self-management treatments in a clinical pain population. Screening and data extraction were performed in duplicate, and trial features, description of control methods, and their similarity to the active intervention under investigation were extracted (protocol registration ID: CRD42020206590). The review included 198 unique control interventions, published between 2008 and December 2021. Most trials studied people with chronic pain, and more than half were manual therapy trials. The described control interventions ranged from clearly modelled based on the active treatment to largely dissimilar control interventions. Similarity between control and active interventions was more frequent for certain aspects (eg, duration and frequency of treatments) than others (eg, physical treatment procedures and patient sensory experiences). We also provide an overview of additional, potentially useful methods to enhance blinding, as well as the reporting of processes involved in developing control interventions. A comprehensive picture of prevalent blinding methods is provided, including a detailed assessment of the resemblance between active and control interventions. These findings can inform future developments of control interventions in efficacy and mechanistic trials and best-practice recommendations.

Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (article II): a meta-analysis relating methods to trial results.

ABSTRACT: Sham interventions in randomized clinical trials (RCTs) of physical, psychological, and self-management (PPS) therapies for pain are highly variable in design and believed to contribute to poor internal validity. However, it has not been formally tested whether the extent to which sham controls resemble the treatment under investigation consistently affects trial outcomes, such as effect sizes, differential attrition, participant expectancy, and blinding effectiveness. Placebo- or sham-controlled RCTs of PPS interventions of clinical pain populations were searched in 12 databases. The similarity of control interventions to the experimental treatment was rated across 25 features. Meta-regression analyses assessed putative links between employed control interventions, observed effect sizes in pain-related outcomes, attrition, and blinding success. The sample included 198 unique control interventions, dominated by manual therapy and chronic musculoskeletal pain research. Meta-analyses indicated small-to-moderate benefits of active treatments over control interventions, across subgroups of manual therapies, exercise, and rehabilitation, and psychological intervention trials. Multiple meta-regression modelling demonstrated that similarity between sham control and tested interventions predicted variability in pain-related outcomes, attrition, and blinding effectiveness. Influential variables were differences relating to the extent of intervention exposure, participant experience, and treatment environments. The results support the supposed link between blinding methods and effect sizes, based on a large and systematically sourced overview of methods. However, challenges to effective blinding are complex and often difficult to discern from trial reports. Nonetheless, these insights have the potential to change trial design, conduct, and reporting and will inform guideline development.

The Chronic Liver Disease Nurse Role in Australia: Describing 10 Years of a New Role in Cirrhosis Management.

Cirrhosis of the liver is increasing, with growing patient numbers in hospital outpatient departments, as well as increasing admissions due to decompensated liver disease. Decompensated cirrhosis of the liver is a common and debilitating illness causing disability, readmissions to hospital, and decreased quality of life, and can lead to liver cancer. The advent of the chronic liver disease nurse (CLDN) position in our hospital in 2009 was the first role in Australia dedicated to providing care to patients with cirrhosis. The role incorporates the care of patients with stable compensated disease, case management of patients with complications of decompensated disease, and hepatocellular carcinoma coordination. After a pilot randomized controlled trial and almost 10 years of service, this article describes the role of the CLDN and presents key performance indicators that will assist other centers considering introducing the role or elements of it into their service.

Differences in metabolites in pain-processing brain regions in patients with diabetes and painful neuropathy.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) (specifically, (1)H-MRS) has been used to show changes in the brain following peripheral nerve injury in subjects without diabetes. This study used (1)H-MRS to examine the brain in subjects with or without painful diabetic neuropathy. RESEARCH DESIGN AND METHODS: Twenty-six diabetic subjects (12 with and 14 without chronic neuropathic pain) were compared, with 18 subjects without diabetes and pain. The left thalamus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) were assessed using (1)H-MRS. RESULTS: In the DLPFC, diabetic subjects had a decrease in N-acetyl aspartate (NAA) and creatine relative to the control group. In the thalamus, there was a reduction of NAA in the diabetic group with pain compared with that in patients with diabetes and no pain. CONCLUSION: Subjects with diabetes have metabolite differences in the brain compared with control subjects. Subjects with painful neuropathy showed reduced NAA in the thalamus, which may explain the genesis of pain in some cases.

The outer membrane protein OmpA of Mannheimia haemolytica A1 is involved in the binding of fibronectin.

An enzyme-linked immunosorbent assay using bovine fibronectin as the substrate was used to demonstrate that Mannheimia haemolytica A1 binds to fibronectin. This binding to fibronectin was specific as no binding was observed with bovine fibrinogen. The binding to fibronectin was not observed if the M. haemolytica A1 cells were pretreated with trypsin or proteinase K, suggesting that it involved a protein molecule on the cell surface. Interestingly, the fibronectin-binding activity was found to be higher in an acapsular mutant compared with its parent strain. The fibronectin-binding protein was shown to be present in the outer membrane fraction of M. haemolytica A1. A 45 kDa outer membrane protein that binds to fibronectin was identified by Far-Western immunoblot analysis. This protein was purified and subjected to MS matrix-assisted laser desorption ionization time-of-flight analysis. The results identified it to be outer membrane OmpA based on comparison with the M. haemolytica A1 genomic sequence.

The level of small nerve fiber dysfunction does not predict pain in diabetic Neuropathy: a study using quantitative sensory testing.

OBJECTIVES: To determine whether small nerve fiber dysfunction predicts pain in diabetic neuropathy using quantitative sensory testing of thermal thresholds. METHODS: Diabetic patients with or without painful neuropathy (n=191) were studied. Small nerve fiber function was assessed by quantitative sensory testing of cold detection and heat pain thresholds. Subjects were also categorized as being hyperalgesic (<10th percentile) or hyposensitive (>90th percentile) by comparing with normative data. Vibration perception threshold, a large nerve fiber function, was measured using a biothesiometer (Bio-medical Instrument, Newbury, OH). RESULTS: In the patients with pain, cold stimulus was detected after a greater reduction in temperature from baseline (-3.7 degrees C vs. -0.6 in the no-pain group, P<0.0001). There were no differences between the pain and painless groups in the heat pain tests, with hyperalgesia noted in about 60% of subjects. Vibration perception threshold and loss of ankle reflexes were significant determinants of pain, but together they accounted for only 6.8% of the variance. If these were removed from the model, cold detection threshold became a significant determinant of pain but accounted for only 3.0% of the variance. CONCLUSIONS: Quantitative sensory testing of small nerve fiber function is a useful test to detect the presence of neuropathy, and overall diabetic patients with neuropathic pain have more sensory loss. However, small nerve fiber abnormalities detected by quantitative sensory testing do not predict the presence of pain in diabetic neuropathy.

The relationship among pain, sensory loss, and small nerve fibers in diabetes.

OBJECTIVE: Many individuals with diabetes experience neuropathic pain, often without objective signs of large-fiber neuropathy. We examined intraepidermal nerve fibers (IENFs) to evaluate the role of small nerve fibers in the genesis of neuropathic pain. RESEARCH DESIGN AND METHODS: Twenty-five diabetic subjects with neuropathic pain and 13 without were studied. The pain was present for at least 6 months for which no other cause could be found. Punch skin biopsies were obtained from the distal leg. IENFs were stained using antibody to protein gene product 9.5 and counted with confocal microscopy. Neuropathy was graded by vibration perception and cold detection thresholds and the Michigan Neuropathy Screening Instrument. RESULTS: In the total cohort, IENF density was significantly lower in those with pain compared with those without (3 [1-6] vs. 10 [3-19], respectively, P = 0.02). There were significant inverse correlations between IENF and severity of neuropathy, with the pain group having a flatter gradient than their pain-free counterparts (P < 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P < or = 0.01). CONCLUSIONS: More severe loss of IENF is associated with the presence of neuropathic pain only in those with little or no objective sign of neuropathy. Thus, loss of IENF cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.

Considerations on blood glucose management in Type 2 diabetes mellitus.

In recent years the benefits of more intensive management in preventing or delaying the development and progression of diabetic complications have been well documented. What is not as well documented is how to motivate the person with diabetes to manage the condition, how to set, assess and quantify glucose goals, and the glucose variables that should be routinely measured. This review discusses the importance of setting targets and communicating them in a way that the patient understands. When aiming for a glycaemia target, balance is required (1) between achieving reduction of complications and causing an increased degree of hypoglycaemia, and (2) between what is achievable and what degree of benefit is gained. Target values given in guidelines should be adapted by the clinician to take into account the patient's susceptibility to hypoglycaemia, stage and type of complications, age and life expectancy, co-morbidity, social environment, understanding of the steps required and level of commitment to the treatment. Several suggestions are given regarding possible improvements and amendments to existing guidelines for diabetes management in treating to glucose goal. For example, attention should be drawn to the need to individualize goals and to consider education, long-term support, patient needs and treatment outcome when formulating diabetes management plans. The relative properties of the different glucose variables-fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated haemoglobin A(1c) (HbA(1c)), and glycated protein-in terms of their convenience of measurement, usefulness and relevance to the physician and patient are also evaluated. When prioritising the variables to be measured it is suggested that where feasible, HbA(1c) should be the standard measurement by which to gauge risk and treatment efficacy. Serial measurements should be made and, where possible, the use of blood glucose meters encouraged, in order to obtain a blood glucose profile for the patient.

Insensate versus painful diabetic neuropathy: the effects of height, gender, ethnicity and glycaemic control.

AIMS/HYPOTHESIS: To study similarities and differences between people with insensate or painful diabetic peripheral neuropathy, particularly in relation to height, gender, ethnicity and glycaemic control. METHODS: We studied prospectively 2610 patients with Type 2 diabetes attending our Diabetes Centre. Subjects were compared according to degree of sensory loss, and presence or absence of neuropathic pain. The effects of gender and ethnicity were evaluated by studying patients in different height bands. RESULTS: Insensate neuropathy and painful neuropathy was present in 11.4 and 3.3% of subjects, respectively. Age, duration of diabetes, height, vibration perception and HbA(1c) (P<0.0001) were independent determinants of insensate neuropathy, whereas only duration of diabetes and vibration perception (P<0.0001) were predictive of pain. There was more insensate neuropathy in males (OR 1.9) and anglo-celtics (OR 1.4) but stratification by height showed that these effects were due to height. Height has no influence on the development of pain. CONCLUSIONS: There is significant overlap but also considerable dichotomy in the two major forms of diabetic sensory peripheral neuropathy. The insensate type is more explainable by duration, degree of hyperglycaemia and length of peripheral nerves, factors that are likely to reflect severity of underlying structural nerve damage. Glycaemic control was not a predictor of painful neuropathy.