Open access for operational research publications from low- and middle-income countries: who pays?

Open-access journal publications aim to ensure that new knowledge is widely disseminated and made freely accessible in a timely manner so that it can be used to improve people''s health, particularly those in low- and middle-income countries. In this paper, we briefly explain the differences between closed- and open-access journals, including the evolving idea of the ‘open-access spectrum’. We highlight the potential benefits of supporting open access for operational research, and discuss the conundrum and ways forward as regards who pays for open access.     

High time to use rapid tests to detect multidrug resistance in sputum smear-negative tuberculosis in Belarus

Setting: Belarus (Eastern Europe) is facing an epidemic of multidrug-resistant tuberculosis (MDR-TB). In 2012, rapid molecular diagnostics were prioritised for sputum smear-positive pulmonary tuberculosis (PTB) patients to diagnose MDR-TB, while pulmonary sputum smear-negative pulmonary TB (SN-PTB) patients were investigated using conventional methods, often delaying the diagnosis of MDR-TB by 2–4 months.Objective: To determine the proportion of MDR-TB among SN-PTB patients registered in 2012 and associated clinical and demographic factors.Design: Retrospective cohort study using countrywide data from the national electronic TB register.Results: Of the 5377 TB cases registered, 2960 (55%) were SN-PTB. Of the latter, 1639 (55%) were culture-positive, of whom 768 (47%) had MDR-TB: 33% (363/1084) were new and 73% (405/555) previously treated patients. Previous history of treatment, age, region, urban residence, human immunodeficiency virus (HIV) status and being a pensioner were independently associated with MDR-TB.Conclusion: About half of culture-positive SN-PTB patients have MDR-TB and this rises to over 7/10 for retreatment cases. A national policy decision to extend rapid molecular diagnostics universally to all PTB patients, including SN-PTB, seems justified. Steps need to be taken to ensure implementation of this urgent priority, given the patient and public health implications of delayed diagnosis.     

Emerging Treatment Targets for Migraine and Other Headaches

Migraine is a complex disorder that is characterized by an assortment of neurological and systemic effects. While headache is the most prominent feature of migraine, a host of symptoms affecting many physiological functions are also observed before, during, and after an attack. Furthermore, migraineurs are heterogeneous and have a wide range of responses to migraine therapies. The recent approval of calcitonin gene-related-peptide based therapies has opened up the treatment of migraine and generated a renewed interest in migraine research and discovery. Ongoing advances in migraine research have identified a number of other promising therapeutic targets for this disorder. In this review, we highlight emergent treatments within the following biological systems: pituitary adenylate cyclase activating peptdie, 2 non-mu opioid receptors that have low abuse liability – the delta and kappa opioid receptors, orexin, and nitric oxide-based therapies. Multiple mechanisms have been identified in the induction and maintenance of migraine symptoms; and this divergent set of targets have highly distinct biological effects. Increasing the mechanistic diversity of the migraine tool box will lead to more treatment options and better patient care.     

Neuropathological profile of long‐duration amyotrophic lateral sclerosis in military Veterans

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long‐duration (≥10 years). The ALS Functional Rating Scale‐Revised (ALSFRS‐R) was administered at study entry and semi‐annually thereafter until death. Microglial density was determined in a subset of participants. long‐duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long‐duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS‐R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long‐duration ALS was associated with less frequent TDP‐43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long‐duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long‐duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long‐duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long‐duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.     

Development and characterization of 16 microsatellites for Hoffmann’s two-toed sloth, Choloepus hoffmanni

Hoffmann’s two-toed sloth (Choloepus hoffmanni) is an arboreal mammal found throughout the Neotropics. Due to its limited dispersal power and reliance on forested habitats, C. hoffmanni could serve as a model species for understanding the response of mammals to land cover change. To better understand sloth life history and their response to tropical forest fragmentation and loss, we developed and characterized 16 polymorphic microsatellite markers. We tested each locus with 16–23 C. hoffmanni individuals sampled in northeastern Costa Rica. The number of alleles per locus ranged from three to seven, while mean observed heterozygosity was 0.56 and ranged from 0.33 to 0.75. All loci met Hardy–Weinberg expectations and none of the loci exhibited significant linkage disequilibrium. The microsatellite markers developed herein will be used to investigate dispersal rates and gene flow among habitat patches in Costa Rica, as well as provide insights into the life history of two-toed sloths.     

Effects of 10 mg and 15 mg oral procyclidine on critical flicker fusion threshold and cardiac functioning in healthy human subjects

The critical flicker fusion threshold (CFFT) is thought to index alertness and cortical arousal. Sedative drugs reduce CFFT while psychostimulants increase it. Procyclidine is an anticholinergic that is used to control the extrapyramidal side-effects of antipsychotics in schizophrenia. This study examined the effects of clinically relevant doses of oral procyclidine administration on CFFT and heart rate in two separate experiments (Experiment 1, drug dose: 10 mg, n = 16; Experiment 2, drug dose: 15 mg, n = 12) involving healthy subjects using a double-blind, placebo-controlled, cross-over design. 10 mg procyclidine had no significant effect on CFFT, heart rate or self-ratings of mood, but the 15 mg dose significantly lowered CFFT at 1 h and 2 h after procyclidine administration, increased drowsiness ratings and produced a drop in heart rate. The effects observed in this study may have implications for treatment compliance of schizophrenic patients, choice of antipsychotics, prescribing to patients with heart disease and monitoring of cardiac function under treatment. Further investigations are required to quantify the effects of procyclidine on CFFT and cardiac function in patients with schizophrenia.