Magnetic resonance imaging of regional gray matter volume in persons who died by suicide.

In vivo neuroimaging research in suicide attempters has shown alterations in frontal system brain regions subserving emotional regulation, motivation, and self-perception; however, data from living individuals is limited in clarifying risk for suicide death. Postmortem neuroimaging provides an approach to study the brain in persons who died by suicide. Here, whole brain voxel-based analyses of magnetic resonance imaging gray matter volume measures were performed comparing persons confirmed by forensic investigation to have died by suicide (n = 24), versus other causes (n = 24), in a univariate model covarying for age and total brain volume; all subjects were scanned within 24 hours after death. Consistent with the hypothesis that persons who died by suicide would show lower gray matter volume in frontal system brain regions, this study of suicides showed lower gray matter volume in ventral frontal and its major connection sites including insula, striatum, and amygdala.

What importance do donors and recipients attribute to the nuclear DNA-related genetic heritage of oocyte donation?

STUDY QUESTION: How do oocyte donors and recipients perceive the genetic link related to the transfer of nuclear DNA between donors and offspring? SUMMARY ANSWER: Whether they are donors or recipients, individuals attach great importance to the transmission of their genetic heritage, since 94.5% would opt for the pronuclear transfer method to preserve this genetic link in the context of oocyte donation. WHAT IS KNOWN ALREADY: Since 1983, the use of oocyte donation has increased worldwide. Performed in France since the late 1980s and initially offered to women with premature ovarian insufficiency, its indications have progressively expanded and now it is proposed in many indications to prevent the transmission of genetically inherited diseases. This has resulted in an increase in the waiting time for access to oocyte donation due to the difficulty in recruiting oocyte donors in French ART centres. Several articles have discussed how to fairly distribute donor oocytes to couples, but few have interviewed women in the general population to record their feelings about oocyte donation, as either the donor or recipient and the importance given to the genetic link between the oocyte donors and the children born. Mitochondrial replacement therapy (MRT) is a technique originally developed for women at risk of transmitting a mitochondrial DNA mutation. Recently, MRT has been considered for embryo arrest and oocyte rejuvenation as it could help females to reproduce with their own genetic material through the transfer of their oocyte nucleus into a healthy donor oocyte cytoplasm. STUDY DESIGN, SIZE, DURATION: We conducted an opinion survey from January 2021 to December 2021, during which 1956 women completed the questionnaire. Thirteen participants were excluded from the analysis due to incomplete responses to all the questions. Consequently, 1943 women were included in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: We specifically developed a questionnaire for this study, which was created and distributed using the Drag'n Survey® software. The questionnaire consisted of 21 items presented alongside a video created with whiteboard animation software. The aim was to analyse whether certain factors, such as age, education level, marital status, number of children, use of ART for pregnancy, video viewing, and knowledge about oocyte donation, were associated with feelings towards oocyte donation, by using a univariate conditional logistic regression model. This statistical method was also used to assess whether women would be more inclined to consider oocyte donation with the pronuclear transfer technique rather than the whole oocyte donation. All parameters found to be statistically significant in the univariate analysis were subsequently tested in a multivariate model using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Most women were concerned about the biological genetic contribution of the donated oocyte (94.8%). The most common reason for a women's reluctance to donate their oocytes was their unwillingness to pass on their genetic material (33.3%). Nearly 70% of women who were initially hesitant to donate their oocytes indicated that they would reconsider their decision if the oocyte donation was conducted using donated cytoplasm and the pronuclear transfer technique. Concomitantly, >75% of the respondents mentioned that it would be easier to receive a cytoplasm donation. The largest proportion of the population surveyed (94.5%) expressed their support for its legalization. LIMITATIONS, REASONS FOR CAUTION: In this study, a substantial portion of the responses came from individuals with medical or paramedical backgrounds, potentially introducing a recruitment bias among potential donors. The rate of missing responses to the question regarding the desire to become an oocyte donor was 13.6%, while the question about becoming an oocyte cytoplasm donor had a missing response rate of 23%. These missing responses may introduce a bias in the interpretation of the data. WIDER IMPLICATIONS OF THE FINDINGS: This study was the first to demonstrate that, for the French population studied, the combination of oocyte cytoplasm donation with pronuclear transfer could offer a promising approach to enhance the acceptance of oocyte donation for both the donor and the recipient. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin.

Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.

Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.

A novel methodological approach for group classification during fission of a semi-free-ranging group of Japanese macaques (Macaca fuscata).

The self-initiated split of a social group, known as fission, is a challenge faced by many group-living animals. The study of group fission and the social restructuring process in real time provides insights into the mechanism of this biologically important process. Previous studies on fission in Japanese macaques (Macaca fuscata) assigned individuals to newly reorganized groups mainly using behavioral observations and group attendance records based on periods before or after fission itself. Here, we present a novel framework for group classification during the process of fission that uses quantifiable behavioral variables and statistical analyses. The framework was tested on a group fission process at Affenberg Landskron (Austria), a park that housed around 160 semi-free-ranging Japanese macaques. The behavioral data were collected for 26 days during fission. We analyzed three behavioral developments recurrent in fissions in Japanese macaques, that is, independence of behavior, participation in group movements, and separation of nomadic ranges. These analyses were combined to assign individuals to different groups. Our study resulted in one main group (N = 33), one subgroup (N = 36) and 56 individuals whose group membership was still undefined. The demographic characteristics of these newly formed groups were comparable with those of fissioned groups in wild populations. Furthermore, we found that these newly forming groups showed early social dynamics of fission five months before group level movements, that is: grouping based on spatial proximity and spatial withdrawal of the subgroup to the periphery. These results underline the validity of our novel framework to study social dynamics in Japanese macaques during the process of fission. It represents an important addition to existing methods, and we recommend testing its scope in other primate societies.

Population Pharmacokinetic Modelling and Limited Sampling Strategies for Therapeutic Drug Monitoring of Pyrazinamide in Patients with Tuberculosis.

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve (AUC24) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC24. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (ka). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC24 with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.

Clinical Relevance of Rifampicin-Moxifloxacin Interaction in Isoniazid-Resistant/Intolerant Tuberculosis Patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

Cannabis use assessment and its impact on pain in rheumatologic diseases: a systematic review and meta-analysis.

OBJECTIVES: Despite classic analgesic or effective treatments in rheumatic diseases, such as synthetic DMARDs in RA, patients remain in pain and often turn to non-prescribed pharmacological alternatives, such as cannabis self-therapeutic use. However, this medical use of cannabis has not been thoroughly studied. METHODS: We performed a systematic literature review up to June 2020. The incidence of cannabis consumption was calculated by metaproportion. Differences between cannabis users and non-users were expressed as standardized mean differences using the inverse-variance method. We also assessed the effects of cannabis on pain. RESULTS: A total of 2900 patients reported cannabis consumption in a sample of 10 873 patients [incidence 40.4% (95% confidence interval (CI): 0.28, 0.54)], and 15.3% (95% CI: 0.07, 0.27) specified that they were currently taking cannabis. Cannabis use was higher in the four fibromyalgia studies [68.2% (95% CI: 0.41, 0.90), n = 611] compared with seven articles concerning RA or lupus [26.0% (95% CI: 0.14, 0.41), n = 8168]. Cannabis consumption was associated with a decrease in pain intensity [VAS pain at baseline 8.2 (2.9) vs 5.6 (3.5) mm over time; pooled effect size -1.75 (95% CI: -2.75, -0.76)]. Cannabis users were younger [58.4 (11.4) vs 63.6 (12.1) years; P <0.001], more often smokers [OR 2.91 (95% CI: 1.84, 4.60)] or unemployed [OR 2.40 (95% CI: 1.31, 4.40)], and had higher pain intensity [5.0 (2.4) vs 4.1(2.6) mm; P <0.001] than non-users. CONCLUSION: Nearly 20% of patients suffering from rheumatologic diseases actively consume cannabis, with an improvement in pain. The issue of cannabis use in the management of these patients should be addressed during medical consultation, essentially with cannabis-based standardized pharmaceutical products.

The value of five blood markers in differentiating mycosis fungoides and Sézary syndrome: a validation cohort.

BACKGROUND: Clinical and histological diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF) is challenging in clinical routine. OBJECTIVES: We investigated five blood markers previously described for SS (T-plastin, Twist, KIR3DL2, NKp46 and Tox) in a prospective validation cohort of patients. METHODS: We included 447 patients in this study and 107 patients were followed up for prognosis. The markers were analysed by reverse transcriptase quantitative real-time polymerase chain reaction (RT-qPCR) on peripheral blood leucocytes and CD4+ T cells in a cohort of consecutive patients with early MF, erythrodermic MF and SS and compared with patients presenting with benign inflammatory dermatoses (BID) and erythrodermic BID. The markers were assessed in parallel to gold standard values such as CD4/CD8 ratio, loss of CD7 and CD26 membrane expression and CD4 absolute values. Sensitivity and specificity were analysed by receiver operator characteristic curves. The prognostic value of selected markers was analysed on a subset of patients. This study was conducted in one centre. RESULTS: We defined cut-off values for each marker. T-plastin, Twist and KIR3DL2 had the best validity. SS may be overrepresented. The combination of T-plastin and Twist was able to differentiate between erythrodermic MF or BID and SS. The additional analysis of KIR3DL2 may be useful to predict the prognosis. CONCLUSIONS: We propose T-plastin, Twist and KIR3DL2 measured by RT-qPCR as new diagnostic markers for Sézary syndrome.

Evaluation and application of a new scintillator-based heat-resistant back-scattered electron detector during heat treatment in the scanning electron microscope.

A new high-temperature detector dedicated to the collection of backscattered electrons is used in combination with heating stages up to 1050°C, in high-vacuum and low-vacuum modes in order to evaluate its possibilities through signal-to-noise ration measurements and different applications. Four examples of material transformations occurring at high temperature are herein reported: grain growth during annealing of a rolled platinum foil, recrystallisation of a multiphased alloy, oxidation of a Ni-based alloy and complex phase transformations occurring during the annealing of an Al-Si coated boron steel. The detector could be potentially adapted to any type of SEM and it offers good opportunities to perform high-temperature experiments in various atmospheres.

Disease-modifying drug retention rate according to patient age in patients with early rheumatoid arthritis: analysis of the ESPOIR cohort.

Physicians are sometimes hesitant to use disease-modifying antirheumatic drugs (DMARDs) in elderly patients with rheumatoid arthritis (RA), as they are deemed too fragile, although there are no sufficient scientific evidence. We aimed to compare DMARD treatment retention in early RA patients from the ESPOIR cohort, according to age upon inclusion. Overall, treatment retention was evaluated as the percentage of patients whose DMARDs were not stopped, with stratification by age group: < 50, 50-64, and > 65 years. Survival curves were measured using the Kaplan-Meier method. Of the entire ESPOIR cohort (n = 813), 7% were > 65 years old. Methotrexate (MTX) was used by 521 patients, and was the sole DMARD for 198 patients. MTX treatment retention appeared better in patients > 65 years old compared to < 50 years old [HR 0.45 (0.25; 0.81); p = 0.008, n = 195/198] with adjustment on sex, smoking, positive anti-cyclic citrullinated peptide antibodies, positive rheumatoid factor, body mass index, changes in DAS28 and corticosteroid treatment. The proportion of patients using etanercept (n = 111), and this drug's retention rate, did not differ according to patient age. The proportion of patients treated with adalimumab (n = 104) was significantly higher in patients < 50 years old (p = 0.003), and treatment retention was marginally better among younger patients [HR 1.68 (0.88; 3.22), p = 0.12]. Within the ESPOIR cohort, DMARD retention did not appear to differ according to age-except for better retention of MTX treatment in patients 50-64 years old, and of adalimumab in patients < 50 years old.

Three-Dimensional Phthalocyanine Metal-Catecholates for High Electrochemical Carbon Dioxide Reduction.

The synthesis of a new anionic 3D metal-catecholate framework, termed MOF-1992, is achieved by linking tetratopic cobalt phthalocyanin-2,3,9,10,16,17,23,24-octaol linkers with Fe3(-C2O2-)6(OH2)2 trimers into an extended framework of roc topology. MOF-1992 exhibits sterically accessible Co active sites together with charge transfer properties. Cathodes based on MOF-1992 and carbon black (CB) display a high coverage of electroactive sites (270 nmol cm-2) and a high current density (-16.5 mA cm-2; overpotential, -0.52 V) for the CO2 to CO reduction reaction in water (faradaic efficiency, 80%). Over the 6 h experiment, MOF-1992/CB cathodes reach turnover numbers of 5800 with turnover frequencies of 0.20 s-1 per active site.

Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment.

Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring.

Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment.

Background: Amikacin has been used for over 40 years in multidrug resistant tuberculosis (MDR-TB), but there is still debate on the right dose. The aim of this review was to search relevant pharmacokinetic (PK) and pharmacodynamic (PD) literature for the optimal dose and dosing frequency of amikacin in MDR-TB regimens trying to optimize efficacy while minimizing toxicity. Methods: A systematic review on the value of amikacin as second-line drug in the treatment of MDR-TB was performed. Results: Five articles were identified with data on PK, hollow-fiber system model for TB and or early bactericidal activity of amikacin. Despite the long period in which amikacin has been available for the treatment of MDR-TB, very little PK data is available. This highlights the need for more research. Conclusions: Maximum concentration (Cmax) of amikacin related to MIC proved to be the most important PK/PD index for efficacy. The target Cmax/MIC ratio should be 10 at site of infection. Cumulative area under the concentration-time curve (AUC) corresponding with cumulative days of treatment was associated with an increased risk of toxicity.

Systematic Review of Salivary Versus Blood Concentrations of Antituberculosis Drugs and Their Potential for Salivary Therapeutic Drug Monitoring.

BACKGROUND: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of antituberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative. METHODS: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of antituberculosis drugs. Data on study population, study design, analytical method, salivary Cmax, salivary area under the time-concentration curve, plasma/serum Cmax, plasma/serum area under the time-concentration curve, and saliva-plasma or saliva-serum ratio were extracted. All included articles were assessed for risk of bias. RESULTS: In total, 42 studies were included in this systematic review. For the majority of antituberculosis drugs, including the first-line drugs ethambutol and pyrazinamide, no pharmacokinetic studies in saliva were found. For amikacin, pharmacokinetic studies without saliva-plasma or saliva-serum ratios were found. CONCLUSIONS: For gatifloxacin and linezolid, salivary therapeutic drug monitoring is likely possible due to a narrow range of saliva-plasma and saliva-serum ratios. For isoniazid, rifampicin, moxifloxacin, ofloxacin, and clarithromycin, salivary therapeutic drug monitoring might be possible; however, a large variability in saliva-plasma and saliva-serum ratios was observed. Unfortunately, salivary therapeutic drug monitoring is probably not possible for doripenem and amoxicillin/clavulanate, as a result of very low salivary drug concentrations.

Clinical recommendations in the management of the patient with type 1 diabetes on insulin pump therapy in the perioperative period: a primer for the anaesthetist.

Insulin pump therapy is increasingly common in patients with type 1 diabetes. Many of these patients will require surgery at some point in their lifetime. Few doctors will have experience of managing these patients, and little evidence exists to assist in the development of guidelines for patients with insulin pump therapy, undergoing surgery.It is clear that during emergency surgery insulin pump therapy is not appropriate and should be discontinued, but patients undergoing some elective surgery can and should continue insulin pump therapy, without any adverse effect on their blood sugar control, or on the outcome of their surgery. Individual hospitals need to formalize guidance on the management of patients receiving continuous subcutaneous insulin therapy, to allow patients the choice to continue their therapy during surgery. This expert opinion presents anaesthetists with a suggested clinical framework to help facilitate continued insulin pump therapy, during elective surgery and into the postoperative period.

Direct Light-Driven Water Oxidation by a Ladder-Type Conjugated Polymer Photoanode.

A conjugated polymer known for high stability (poly[benzimidazobenzophenanthroline], coded as BBL) is examined as a photoanode for direct solar water oxidation. In aqueous electrolyte with a sacrificial hole acceptor (SO3(2-)), photoelectrodes show a morphology-dependent performance. Films prepared by a dispersion-spray method with a nanostructured surface (feature size of ∼20 nm) gave photocurrents up to 0.23 ± 0.02 mA cm(-2) at 1.23 VRHE under standard simulated solar illumination. Electrochemical impedance spectroscopy reveals a constant flat-band potential over a wide pH range at +0.31 VNHE. The solar water oxidation photocurrent with bare BBL electrodes is found to increase with increasing pH, and no evidence of semiconductor oxidation was observed over a 30 min testing time. Characterization of the photo-oxidation reaction suggests H2O2 or •OH production with the bare film, while functionalization of the interface with 1 nm of TiO2 followed by a nickel-cobalt catalyst gave solar photocurrents of 20-30 µA cm(-2), corresponding with O2 evolution. Limitations to photocurrent production are discussed.