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Objectives/Goals: Many left hemisphere stroke survivors have a reading disorder (alexia), which is experienced as decreasing well-being. Therapies produce inconsistent results, demonstrating a need for treatment response predictors. We identify neural correlates of a computational model of reading, which may provide biomarkers to improve therapeutic outcomes. Methods/Study Population: Left hemisphere stroke survivors (LHSS) (n = 52) performed an oral reading task and tests of semantic and phonological processing. Artificial neural network (ANN) models, mapping between orthography (visual word form), phonology (auditory word form), and semantics (word meaning), were trained to read single words at an adult reading level. Stroke was simulated by removing percentages (in 10% intervals) of the connections into and out of semantics, phonology, and the combination thereof. The lesioned model producing the smallest average Euclidean distance over word and pseudoword reading accuracy to each LHSS was selected as the matched model. Two voxelwise lesion-symptom mapping (VLSM) analyses identified the neural correlates of the percent of phonological and semantic links removed in the matched models. Results/Anticipated Results: Model reading was correlated with LHSS reading (high-frequency regular words, r(48) = 0.96; high-frequency irregular words, r(48) = 0.94; low-frequency regular words, r(48) = 0.97); low-frequency irregular words, r(48) = 0.85; all p’s Discussion/Significance of Impact: Our results show that ANN models of reading, when closely matched to LHSS reading performance, directly connect cognitive processes to the brain. Using matched models as a precision medicine framework to predict therapy response or to identify targets for neurostimulation provides a valuable route toward improving poststroke language outcomes.
Foliar-applied postemergence applications of glufosinate are often applied to glufosinate-resistant crops to provide nonselective weed control without significant crop injury. Rainfall, air temperature, solar radiation, and relative humidity near the time of application have been reported to affect glufosinate efficacy. However, previous research may have not captured the full range of weather variability to which glufosinate may be exposed before or following application. Additionally, climate models suggest more extreme weather will become the norm, further expanding the weather range to which glufosinate can be exposed. The objective of this research was to quantify the probability of successful weed control (efficacy ≥85%) with glufosinate applied to some key weed species across a broad range of weather conditions. A database of >10,000 North American herbicide evaluation trials was used in this study. The database was filtered to include treatments with a single postemergence application of glufosinate applied to waterhemp [Amaranthus tuberculatus (Moq.) Sauer], morningglory species (Ipomoea spp.), and/or giant foxtail (Setaria faberi Herrm.) <15 cm in height. These species were chosen because they are well represented in the database and listed as common and troublesome weed species in both corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] (Van Wychen 2020, 2022). Individual random forest models were created. Low rainfall (≤20 mm) over the 5 d before glufosinate application was detrimental to the probability of successful control of A. tuberculatus and S. faberi. Lower relative humidity (≤70%) and solar radiation (≤23 MJ m−1 d−1) on the day of application reduced the probability of successful weed control in most cases. Additionally, the probability of successful control decreased for all species when average air temperature over the first 5 d after application was ≤25 C. As climate continues to change and become more variable, the risk of unacceptable control of several common species with glufosinate is likely to increase.
Globally, the grey-headed albatross Thalassarche chrysostoma is listed as Endangered due to decreasing populations at its major breeding colonies. We analysed the population trend at Marion Island using annual counts of incubating pairs and fledglings from 1984 to 2021 and three methods: TRends and Indices for Monitoring data (TRIM), a generalized additive model and a state-space model. In contrast to rapid decreases at most other colonies, all three methods indicated a local population increase at an average annual rate of 1.3%. The latter two models indicated a decreasing trend from 1997 to 2002, presumably related to mortality on longlines set for Patagonian toothfish Dissostichus eleginoides around the island, which peaked from 1996 to 1998. Grey-headed albatrosses exhibit greater variation in annual counts than other seabird species at Marion Island, possibly linked to interannual variation in breeding success because they are biennial breeders. However, breeding success alone was not significant in any of the models, presumably because it cannot capture the complexities of both population processes and environmental variation. Although all three models predicted the overall trends well, integrated population models, which can account for demographic processes, might be more appropriate to model long-term population trends.
Wilkins’s Finch Nesospiza wilkinsi is endemic to Nightingale Island (2.5 km2), Tristan da Cunha. It feeds on the woody fruits of the Island Tree Phylica arborea and in 2017 had a population of 120 breeding pairs. In 2021 it was uplisted from “Endangered” to “Critically Endangered” following damage to P. arborea woodland during severe storms in 2019. During a brief visit to Nightingale in February 2024, we confirmed that the finch population in the area of storm-damaged woodland has decreased by up to 75%, but the density in other areas was similar to that prior to 2019. Extrapolating from the 2017 survey, we estimated the current population to be 60–90 breeding pairs. Surveys of P. arborea structure in the storm-affected area indicated that some large trees had survived, despite being flattened, that recruitment of new trees is occurring, and that fruit loads on surviving trees are similar to those in 2017. Satellite imagery from 2005 showed similar woodland loss during another severe storm in 2001 to that experienced in 2019, indicating that the finch has survived similar events in the past. Coupled with the successful release of a biological control agent to limit the impact of the introduced brown soft scale Coccus hesperidum on Phylica fruit production, the future prospect for Wilkins’s Finch is less bleak than previously thought. However, the risk that global warming is increasing the frequency of severe storms remains a concern. Planting more woodland patches in sheltered areas would help to offset future storm damage.
Heat stress from high temperatures has been recognised as a threat to several bird species and one that is likely to increase in severity and frequency as a result of global environmental change. Many seabirds are particularly vulnerable as their adaptations to forage in cold water can make it hard for them to resist heat gain while on land. The African Penguin Spheniscus demersus forages in cool water (10–20°C) but breeds and moults on land where temperatures can exceed 30°C. Little is known about its thermal physiology and when heat stress will occur. Here, we provide the first account of changes in body temperature and behaviour in African Penguins in response to an experimental increase in ambient temperature from 20°C to 35°C. Surprisingly, the highest body temperature observed (39.2°C) was recorded at the start of the study. Presumably, this response in body temperature was due to the stress of transport and handling. Penguins returned to normal body temperature (37.3°C) after 3.5 hours and maintained normothermia for roughly an hour. We then observed the onset of heat storage at an ambient temperature of 29°C, whereafter body temperature increased steadily at a rate of ca.0.2°C per 1°C increase in ambient temperature. Panting commenced at an ambient temperature of 31.4°C, when body temperature was 37.8°C. In addition to panting, penguins changed their posture to facilitate heat dissipation by standing, raising their heads, and extending their flippers. Our results corroborate field observations and support the argument that African Penguins are highly vulnerable to heat stress in the near future as extreme heat events become more severe and frequent due to climate change. Our results also confirm that penguins are sensitive to handling, which elicits a hyperthermic response. Given the general sensitivity of penguins to disturbance, from a conservation perspective, we advise that cautionary measures be implemented at colonies during critical life-history stages.
The increased global prevalence of type II diabetes mellitus (T2DM) is associated with consumption of low fibre ‘Western diets’. Characteristic metabolic parameters of these individuals include insulin resistance, high fasting and postprandial glucose, as well as low-grade systemic inflammation. Gut microbiota composition is altered significantly in these cohorts suggesting a causative link between diet, microbiota and disease. Dietary fibre consumption has been shown to alleviate these changes and improve glucose parameters in individuals with metabolic disease. We previously reported that yeast β-glucan (yeast beta-1,3/1,6-D-glucan; Wellmune) supplementation ameliorated hyperinsulinaemia and insulin resistance in a murine model. Here, we conducted a randomised, placebo-controlled, two-armed dietary fibre phase I exploratory intervention study in patients with T2DM. The primary outcome measure was alteration to microbiota composition, while the secondary outcome measures included markers of glycaemic control, inflammation as well as metabolomics. Patients were supplemented with 2·5g/day of maltodextrin (placebo) or yeast β-1,3/1,6-D-glucan (treatment). Yeast β-glucan (Wellmune) lowered insulin resistance compared with the placebo maltodextrin after 8 weeks of consumption. TNFα was significantly lower after 4 weeks of β-glucan supplementation. Significantly higher fecal concentrations of several bile acids were detected in the treatment group when compared with the placebo after 8 weeks. These included tauroursodeoxycholic acid, which was previously shown to improve glucose control and lower insulin resistance. Interestingly, the hypoglycaemic and anti-inflammatory effect of yeast β-glucan was independent of any changes in fecal microbiota composition or short-chain fatty acid levels. Our findings highlight the potential of yeast β-glucan to lower insulin resistance in patients with T2DM.
Information regarding the prevalence and distribution of herbicide-resistant waterhemp [Amaranthus tuberculatus (Moq.) Sauer] in Minnesota is limited. Whole-plant bioassays were conducted in the greenhouse on 90 A. tuberculatus populations collected from 47 counties in Minnesota. Eight postemergence herbicides, 2,4-D, atrazine, dicamba, fomesafen, glufosinate, glyphosate, imazamox, and mesotrione, were applied at 1× and 3× the labeled doses. Based on their responses, populations were classified into highly resistant (≥40 % survival at 3× the labeled dose), moderately resistant (<40% survival at 3× the labeled dose but ≥40% survival at 1× the labeled dose), less sensitive (10% to 39% survival at 1× the labeled dose), and susceptible (<10% survival at 1× the labeled dose) categories. All 90 populations were resistant to imazamox, while 89% were resistant to glyphosate. Atrazine, fomesafen, and mesotrione resistance was observed in 47%, 31%, and 22% of all populations, respectively. Ten percent of the populations were resistant to 2,4-D, and 2 of 90 populations exhibited >40% survival following dicamba application at the labeled dose. No population was confirmed to be resistant to glufosinate. However, 22% of all populations were classified as less sensitive to glufosinate. Eighty-two populations were found to be multiple-herbicide resistant. Among these, 15 populations exhibited resistance to four different herbicide sites of action (SOAs); 7 and 4 populations were resistant to five and six SOAs, respectively. All six-way-resistant populations were from southwest Minnesota. Two populations, one from Lincoln County and the other from Lyon County, were resistant to 2,4-D, atrazine, dicamba, fomesafen, glyphosate, imazamox, and mesotrione, leaving only glufosinate as a postemergence control option for these populations in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.]. Diversified management tactics, including nonchemical control measures along with herbicide applications from effective SOAs, should be implemented to slow down the evolution and spread of herbicide-resistant A. tuberculatus populations.
OBJECTIVES/GOALS: Many left hemisphere stroke survivors have a reading disorder (alexia), which is experienced as decreasing well-being. Therapies produce inconsistent results, demonstrating a need for treatment response predictors. We are investigating neural correlates of reading computational models to identify biomarkers to improve therapeutic outcomes. METHODS/STUDY POPULATION: Artificial neural network models of reading, mapping between orthography (visual word form), phonology (auditory word form), and semantics (word meaning), are trained to read single words at a healthy, adult capacity. The models are independently damaged to reflect the individual orthography-to-semantics, semantics-to-phonology, and orthography-to-phonology deficits of a sample of left hemisphere stroke survivors (n = 85). These deficits are measured with cognitive tests assessing the intactness of mappings between representations. Model damage is enacted by removing percentages of the connections between representations. For each type of deficit, the percentages of links removed are entered into a voxel-based lesion symptom mapping analysis to identify areas of cortex associated with that mapping. RESULTS/ANTICIPATED RESULTS: We anticipate that the neural correlates of model layers will be localized to a mostly left-lateralized network. Increased damage to the links between semantics and phonology in the model will likely be related to lesions involving the left posterior superior temporal sulcus and inferior frontal gyrus (IFG). Damaged orthography-to-semantic links will be related to the left fusiform gyrus (FG) and IFG. Finally, damage to the orthography-to-phonology links will be related to the left FG and superior temporal gyrus. DISCUSSION/SIGNIFICANCE: Mapping components of language models onto the brain will improve our understanding of the neural networks supporting language processing. Identifying these neural correlates may also produce biomarkers that can be used in predicting reading impairment at the acute stage or optimizing therapy in the chronic stage of stroke.
Soils developed on Pleistocene andesitic lava flows and fluvial detritus in the Atlantic coastal plain of Costa Rica display a clay mineral assemblage that includes 10 Å and 7 Å halloysite and lesser amounts of kaolinite and dioctahedral vermiculite. Other secondary minerals include gibbsite, goethite, hematite, maghemite, allophane and amorphous Al hydroxides. Active floodplain soils are dominated by 10 Å halloysite and contain less allophane, while soil clays from Pleistocene terraces consist of a mixture of 10 Å and 7 Å halloysite as well as less dioctahedral vermiculite, kaolinite, and amorphous Al hydroxides. Residual soils formed on Pleistocene lava flows are dominated by 7 Å halloysite with less abundant kaolinite, dioctahedral vermiculite, 10 Å halloysite and amorphous Al hydroxides. This sequence suggests transformations of 10 Å halloysite to 7 Å halloysite and allophane to amorphous Al hydroxides with time. The presence of 10 Å halloysite in Pleistocene terrace soils implies slow reaction rates or metastability.
Quantitative X-ray diffraction (QXRD) analysis indicates a decrease in the amount of plagioclase feldspar from 34 wt.% in the 1–2 year floodplain to 0–1.6% in terrace and residual soils. Plagioclase weathering is paralleled by the formation of dioctahedral clay, allophane and Al hydroxides. Analysis by QXRD also indicates that crystalline minerals comprise 70–95% of the soil fraction, implying 5–30% X-ray-amorphous material. These data are verified by selective extraction using ammonium oxalate, which indicates 8–30% amorphous material. Chemical analysis of the extractant by inductively coupled plasmaatomic emission spectrometry indicates that allophane (Al:Si ratios of 0.92–3.82) occurs in floodplain and some terrace soils while amorphous Al hydroxides appear to coexist with allophane in Pleistocene terrace and residual soils with Al:Si ratios of 6.53–8.53. Retention of Mg to a greater extent than Na, Ca and K suggests Mg incorporation into hydroxide sheets in dioctahedral vermiculite as well as substitution into hydroxides.
Pedogenic smectite from a young (Holocene) tropical soil was reacted in Al-rich solution at 150ºC for a range of reaction times (3 to 120 days) in orderto study mechanisms and rates associated with the transformation of smectite to kaolinite via interstratified kaolinite-smectite (K-S). As has been observed in tropical soils, the overall reaction rate is logarithmic, with rapid initial transformation of smectite to K-S with ~50% smectite layers, followed by progressively slower transformation of intermediate K-S to kaolinite-rich K-S and eventually Fe-kaolinite. Sub-micron hexagonal non-Fe-bearing kaolinite forms in the final stage (after 120 days) as a minor mineral in an assemblage dominated by Fe-kaolinite. The pedogenic smectite used as starting material consisted of two end-members, Fe-beidellite and Al-smectite, enabling comparison of reaction pathways. Fe-beidellite transforms to K-S or Fe-kaolinite within 3 days, whereas Al-smectite transforms much more slowly, appearing to reach a maximum rate in intermediate stages. This difference is probably due to hydrolysis of relatively weak Mg-O and Fe-O bonds (relative to Al-O bonds) in Fe-beidellite octahedral sheets, which drives rapid reaction, whereas the driving force behind transformation of Al-smectite is more likely to be related to stripping of tetrahedral sheets which reaches its maximum rate at intermediate stages. Multiple analytical approaches have indicated that Al is rapidly fixed from solution into smectite interlayers within K-S, and that K-S and Fe-kaolinite inherit octahedral Fe and Mg from precursor smectite; as the reaction progresses, octahedral sheets become progressively more Al-rich and Fe and Mg are lost to solution. These results demonstrate that: (1) early-formed pedogenic smectite in tropical soils is expected to transform to kaolinite via interstratified K-S; (2) K-S has a strong potential to sequester plant-toxic Al in tropical soil; and (3) the presence in tropical soils of Fe-kaolinites with relatively large cation exchange capacities may be related to inheritance of octahedral sheets from precursor smectite and K-S.
Soils developed on Quaternary fluvial fill terraces in the humid tropics of Costa Rica display progressive changes in mineral assemblage, chemical composition and particle size with age. Clay minerals from B horizons of active floodplains are predominantly smectite with lesser amounts of disordered kaolinite. B horizons in 5 to 10 ka soils consist of sub-equal amounts of smectite and disordered kaolinite, and soils on 37–125 ka terraces consist of disordered kaolinite with only traces of smectite. The composition of the smectite, as determined by EDX scans of smectite-rich pore space, is [(Mg0.2,Ca0.1)(Fe0.6Al1.4)(Si3.6Al0.4)O10(OH)2], consistent with ferruginous beidellite.
Bulk mineral assemblage varies from a smectite-plagioclase-augite-quartz-magnetite assemblage in ⩽ 10 ka terrace soils to a disordered kaolinite-goethite-hematite-quartz-magnetite assemblage in ⩾37 ka terrace soils. Leaching results in rapid loss of soluble base cations and residual concentration of Ti and Zr indicates mass losses of ∼50% by chemical denudation by 125 ka. Plots of terrace age vs. various measures of clay mineralogy, chemical composition, and particle size produce parabolic curves consistent with rapid chemical weathering pre-37 ka and slower to imperceptible rates of change from 37 to 125 ka. For some pedogenic properties, particularly particle size and concentrations of base cations and Zr, soils appear to reach steady-state conditions within 37 ka.
These results were applied to interpretation of landscape evolution in this tectonically active region by: (1) facilitating identification of two Holocene (5 ka and 10 ka) terraces on the Esterillos Block 5–30 m above sea level (masl), and two Pleistocene terraces ⩾ 125 ka on the Parrita Block 30 masl, and, in turn, (2) documenting uplift rates as high as 4.4 m/ka between 37 and 10 ka on the Esterillos Block, and as low as 0.1 m/ka over the past 125 ka on the adjacent Parrita Block. These findings are consistent with previous work indicating that the subduction of anomalous bathymetric features at the Middle America Trench is having a significant impact on fore-arc dynamics and topography over relatively short geological time periods and spatial scales.
This study investigated the effects of Lacticaseibacillus rhamnosus HN001 supplementation on the architecture and gene expression in small intestinal tissues of piglets used as an animal model for infant humans. Twenty-four 10-d-old entire male piglets (4·3 (sd 0·59) kg body weight) were fed an infant formula (IF) (control) or IF supplemented with 1·3 × 105 (low dose) or 7·9 × 106 (high dose) colony-forming units HN001 per ml of reconstituted formula (n 8 piglets/treatment). After 24 d, piglets were euthanised. Samples were collected to analyse the histology and gene expression (RNAseq and qPCR) in the jejunal and ileal tissues, blood cytokine concentrations, and blood and faecal calprotectin concentrations. HN001 consumption altered (false discovery rate < 0·05) gene expression (RNAseq) in jejunal tissues but not in ileal tissues. The number of ileal goblet cells and crypt surface area increased quadratically (P < 0·05) as dietary HN001 levels increased, but no increase was observed in the jejunal tissues. Similarly, blood plasma concentrations of IL-10 and calprotectin increased linearly (P < 0·05) as dietary HN001 levels increased. In conclusion, supplementation of IF with HN001 affected the architecture and gene expression of small intestine tissue, blood cytokine concentration and frequencies, and blood calprotectin concentrations, indicating that HN001 modulated small intestinal tissue maturation and immunity in the piglet model.
This chapter models the idea of economic growth in the period of the Enlightenment in Britain. Using methods developed in the Cambridge Concept Lab, it demonstrates that the ideas of improvement and progress supported the slow evolution of the notion of economic growth as a necessary good. It tracks the thinking of the philosopher and political economist Adam Smith as he formulated his ideas with respect to size and operation of modern capitalist economies.
Radiation dermatitis (RD) occurs in 95% of patients receiving radiation therapy (RT) for cancer treatment, affecting 800 million patients annually. We aimed to demonstrate the feasibility of developing a historical RD cohort, Radiation Induced Skin Reactions (RISREAC) cohort.
Methods:
This retrospective study evaluated RD-related clinical documentation for 245 breast cancer patients who received RT at the University of Rochester Medical Center, to understand the RD progression, scoring, and management. All statistical analyses were performed at 0.05 level of significance.
Results:
Clinician-documented RD severity was observed for 169 (69%) patients with a mean severity of 1.57 [1.46, 1.68]. The mean descriptor-based severity score of 2.31 [2.18, 2.45] moderately correlated (r = 0.532, P < 0.0001) with documented RD grade. Most patients (91.8%) received skin care treatment during RT, with 66.7% receiving more than 2 modalities.
Conclusions:
The RISREAC cohort is the first retrospective cohort established from clinical documentation of radiation-induced skin changes for the study of RD and cutaneous radiation injury (CRI). RD symptom descriptors were more reliably documented and suitable for all skin types compared to Radiation Therapy Oncology Group (RTOG) or Common Toxicity Criteria for Adverse Events (CTCAE) grades. A new descriptor-based scoring tool would be useful for RD and CRI.
Postpartum depression (PPD) affects up to one in five mothers and birthing parents, yet as few as 10% access evidence-based treatment. One-day cognitive behavioral therapy (CBT)-based workshops for PPD have the potential to reach large numbers of sufferers and be integrated into stepped models of care.
Methods
This randomized controlled trial of 461 mothers and birthing parents in Ontario, Canada with Edinburgh Postnatal Depression Scale (EPDS) scores ⩾10, age ⩾18 years, and an infant <12 months of age compared the effects of a 1-day CBT-based workshop plus treatment as usual (TAU; i.e. care from any provider(s) they wished) to TAU alone at 12-weeks post-intervention on PPD, anxiety, the mother–infant relationship, offspring behavior, health-related quality of life, and cost-effectiveness. Data were collected via REDCap.
Results
Workshops led to meaningful reductions in EPDS scores (m = 15.77 to 11.22; b = −4.6, p < 0.01) and were associated with three times higher odds of a clinically significant decrease in PPD [odds ratio (OR) 3.00, 95% confidence interval (CI) 1.93–4.67]. Anxiety also decreased and participants had three times the odds of clinically significant improvement (OR 3.20, 95% CI 2.03–5.04). Participants reported improvements in mother–infant bonding, infant-focused rejection and anger, and effortful control in their toddlers. The workshop plus TAU achieved similar quality-adjusted life-years at lower costs than TAU alone.
Conclusions
One-day CBT-based workshops for PPD can lead to improvements in depression, anxiety, and the mother–infant relationship and are cost-saving. This intervention could represent a perinatal-specific option that can treat larger numbers of individuals and be integrated into stepped care approaches at reasonable cost.
Long-chain omega-3 polyunsaturated fatty acid (LC n-3 PUFA) supplements, rich in eicosapentaenoic acid and/or docosahexaenoic acid, are increasingly being recommended within athletic institutions. However, the wide range of doses, durations and study designs implemented across trials makes it difficult to provide clear recommendations. The importance of study design characteristics in LC n-3 PUFA trials has been detailed in cardiovascular disease research, and these considerations may guide LC n-3 PUFA study design in healthy cohorts. This systematic review examined the quality of studies and study design considerations used in evaluating the evidence for LC n-3 PUFA improving performance in physically trained adults. SCOPUS, PubMed and Web of Science electronic databases were searched to identify studies that supplemented LC n-3 PUFA in physically trained participants. Forty-six (n = 46) studies met inclusion. Most studies used a randomised control design. Risk of bias, assessed using the design-appropriate Cochrane Collaboration tool, revealed that studies had a predominant judgment of ‘some concerns’, ‘high risk’ or ‘moderate risk’ in randomised controlled, randomised crossover or non-randomised studies, respectively. A custom five-point quality assessment scale demonstrated that no study satisfied all recommendations for LC n-3 PUFA study design. This review has highlighted that the disparate range of study designs is likely contributing to the inconclusive state of outcomes pertaining to LC n-3 PUFA as a potential ergogenic aid. Further research must adequately account for the specific LC n-3 PUFA study design considerations, underpinned by a clear hypothesis, to achieve evidence-based dose, duration and composition recommendations for physically trained individuals.
This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.