Extensive scintigraphic gastric motor function testing with concurrent symptom recording predicts prospectively measured daily dyspeptic symptoms.

BACKGROUND: Absent "organic" disease, dyspeptic symptoms may arise from abnormal gastric sensation, accommodation, motility or emptying (GE). Extensive gastric sensorimotor evaluation is rarely undertaken because testing is prolonged, invasive, poorly tolerated or unavailable. AIMS: To investigate whether gastric antral motor function, evaluated with scintigraphy, predicts GE. To explore whether motor testing with symptom recording predicts day-to-day symptoms in patients with dyspepsia. METHODS: GE was determined using a scintigraphic solid-meal protocol (296 kcal, 35% fat). Antral motility was estimated from 10 min of scintigraphic time-activity curves acquired 40 min after meal consumption. An antral motility index (MI) was derived from contraction amplitude and frequency. Intra-gastric distribution of the meal on scintograms at 1 h (IGD1) was determined. Meal-induced symptoms were evaluated by questionnaire. Patients completed the Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD) for 14 days. RESULTS: Twelve healthy participants and 23 prospectively recruited patients completed the study. Nine patients had delayed, and 2 had rapid, GE. In univariate analysis MI explained 42% of GE half-time. In multivariate analysis MI and GE half-time explained 25% of the variance in meal-induced symptoms. While scintigraphic evaluation of gastric motor function with symptom recording explained 80% of the variance in the GCSI-DD, meal-induced symptoms were the only significant predictor. However, among patients with delayed GE, MI, GE half-time, IGD1, and meal-induced symptoms all significantly predicted GCSI-DD. CONCLUSIONS: Antral motility predicts GE. In exploratory analyses, only meal-induced symptoms predicted daily symptoms among patients with dyspepsia. However, motor function also predicted symptoms in patients with delayed GE.

Coronal translation of the forearm, proximal capitate, and ulnar styloid predict radial inclination in distal radius fractures in older female patients.

Aims: The aims of this study were to identify means to quantify coronal plane displacement associated with distal radius fractures (DRFs), and to understand their relationship to radial inclination (RI). Methods: From posteroanterior digital radiographs of healed DRFs in 398 female patients aged 70 years or older, and 32 unfractured control wrists, the relationships of RI, quantifiably, to four linear measurements made perpendicular to reference distal radial shaft (DRS) and ulnar shaft (DUS) axes were analyzed: 1) DRS to radial aspect of ulnar head (DRS-U); 2) DUS to volar-ulnar corner of distal radius (DUS-R); 3) DRS to proximal capitate (DRS-PC); and 4) DRS to DUS (interaxis distance, IAD); and, qualitatively, to the distal ulnar fracture, and its intersection with the DUS axis. Results: In the study (fracture) and control groups, respectively, the mean values were: RI, 17.2° (SD 7.2°; -7° to 35°) and 25.6° (SD 2.6°; 21° to 30°); DRS-U, 13.5 mm (SD 1.7; 4.9 to 20.8) and 15.3 mm (SD 0.72; 13.8 to 16.3); DUS-R, 13.4 mm (SD 2.1; 4.8 to 18.5) and 12.0 mm (SD 0.99; 9.7 to 13.9); DRS-PC (positive value radial to DRS, negative value ulnar), 0.14 mm (SD 5.4; -10.9 to 22.7) and -6.1 mm (SD 1.6; -10.6 to -2.3); and IAD, 25.3 mm (SD 2.5; 17.6 to 31.1) and 27.1 mm (SD 1.5; 24.5 to 31.0). All means were significantly different between the study and control groups. RI correlated strongly with DRS-PC. Ulnar styloid fracture intersection with the DUS axis, reflective of ulnar translation of both radial and ulnar shafts, was associated with significantly lower RI. Conclusion: After DRF, the relationship of the proximal capitate to the DRS axis in the coronal plane correlates with the final radial inclination. Additionally, ulnar styloid intersection with the DUS axis is associated with even lower radial inclination. DRF reduction should seek to restore the normal coronal relationship of both radial and ulnar shafts to their distal counterparts.

Target occupancy biomarker assay development using a conformation-selective antibody against small-molecule-bound TNF.

Background: An antibody specific to small-molecule inhibitor-bound TNF has enabled the development of target occupancy biomarker assays to support the development of novel treatments for autoimmune disorders. Materials & methods: ELISAs were developed for inhibitor-bound and total TNF to determine the percentage of TNF occupancy in samples from stimulated blood. Inhibitor-saturated samples allowed measurement of total and inhibitor-bound TNF in a single electrochemiluminescence immunoassay. Results: TNF occupancy was proportional to inhibitor concentration in plasma samples. An electrochemiluminescence method for inhibitor-bound TNF was validated for use as a potential clinical occupancy biomarker assay. Conclusion: Development of these assays has allowed measurement of a target occupancy biomarker, which has supported progression of the first small-molecule inhibitors of TNF.

Magnitude, Direction, Temporal Patterns, and Frequency of Loss of Distal Radius Fracture Reduction in Women 50 Years and Older.

PURPOSE: To determine the magnitude, direction, temporal patterns, and frequency of reduction loss following nonsurgical, closed treatment of distal radius fractures in women 50 years and older and correlate these observations with bone mineral density and age. METHODS: We reviewed registry data on 1,148 patients 50 years and older with distal radius fractures managed by closed reduction and cast immobilization. Radial inclination (RI), ulnar variance (UV), and radial tilt (RT) were measured immediately and at 1, 2, 3, 6, 9, and 12 weeks after reduction. Magnitude, direction, frequency, and patterns of change were compared at each time point and correlated with bone mineral density T-scores and age using paired t tests in a mixed effects model. RESULTS: Over 12 weeks, RI decreased by 3° ± 5°, the majority occurring in the first 2 weeks and significantly correlated with bone mineral density T-score and age. Unexpectedly, RI increased over time in 5% of patients. Ulnar variance increased by 2.3 ± 1.7 mm, the majority occurring in the first 3 weeks and correlated with age. Radial tilt changed by 7° ± 11° in those displacing dorsally and 8° ± 12° in those displacing volarly at 12 weeks, with the majority occurring in the first 3 weeks and significantly correlating with age. Ulnar variance and RT continued to change by small increments between weeks 3 and 6. Nearly 90% of our cohort experienced measurable loss of reduction and 50% changed at least 5° RI, 11° RT, and 2 mm UV. CONCLUSIONS: Most distal radius fracture managed with closed reduction and casting have some loss of reduction, the majority occurring in the first 3 weeks and correlated with increased age and osteoporosis. This guides clinicians in informing patients about expected reduction loss, frequency of clinical and radiographic follow-up, and timing of discussions regarding the need for surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren's syndrome.

OBJECTIVES: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS). METHODS: Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. RESULTS: Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. CONCLUSION: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT02610543.

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies.

Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for ≤96 wk.

Improved precision of radiographic measurements for distal radius fractures after a technique-teaching tutorial.

Background: For the management of distal radius fractures, surgical decision-making depends on radiographic measurements of indicators including radial inclination (RI), ulnar variance (UV) and radial tilt (RT). Evaluation of the inter- and intrarater reliability of surgeons' measurements of these criteria has been limited. Methods: Twelve physicians were invited to participate in this study. Anonymously, they measured RI, UV and RT on 30 digitally stored radiographs of distal radius fractures on 3 occasions, each at least 1 week apart, using online measuring tools. After taking the third set of measurements, the participants were given a tutorial by the senior author (G.J.) on a single technique to measure all 3 indicators. The participants then took 3 more sets of measurements using only the technique they had been taught. Intraclass correlation coefficients (ICCs) were used to evaluate interrater reliability each week. Multiple logistic regression was used to calculate the effect of the tutorial, controlling for week of study along with reader (participant) and patient variance. Results: The ICCs indicated that the participants' measurement precision improved promptly after the tutorial, and this improvement was sustained through subsequent readings. The odds of an "accurate" measurement (within 2° of the senior author's measurements for RI, 1 mm for UV and 4° for RT) was 1.7 times higher for RI, 2.7 times higher for UV and 2.3 times higher for RT after the tutorial; all of these results were statistically significant. Conclusion: Surgeons ought to be familiar with a method to reproducibly measure the indicators used in the published guidelines for surgical intervention. The tutorial on a single standardized technique for online measurement of RI, UV and RT in distal radius fractures improved measurement precision.

Contexte: Pour la prise en charge des fractures du radius distal, la prise de décisions chirurgicales dépend de la mesure de plusieurs indicateurs sur les images radiographiques : l'inclinaison radiale (IR), la variance ulnaire (VU) et l'inclinaison sagittale du radius (ISR). La fiabilité interévaluateurs et intra-évaluateur des mesures de ces critères par les chirurgiens a été peu étudiée. Méthodes: Nous avons invité 12 médecins à participer à l'étude. En tout anonymat, ils ont déterminé l'IR, la VU et l'ISR au moyen d'outils de mesure en ligne sur 30 radiographies numérisées de fractures du radius distal. Ils ont répété l'exercice à 3 reprises, à au moins 1 semaine d'intervalle. Après la troisième série, les participants ont suivi un tutoriel de l'auteur principal (G. J.) sur une technique qui peut à elle seule mesurer les 3 indicateurs. Les participants ont ensuite fait 3 autres séries de mesures en utilisant seulement cette technique. Nous avons évalué la fiabilité interévaluateurs pour chaque semaine à partir des coefficients de corrélation intraclasse (CCI). De plus, nous avons calculé l'effet du tutoriel par régression logistique multiple, en tenant compte de la semaine de l'étude et de la variation selon les lecteurs (participants) et les patients. Résultats: Les CCI indiquent que la précision des mesures s'est améliorée rapidement après le tutoriel; cette amélioration a d'ailleurs persisté tout au long des séries subséquentes. La probabilité d'une mesure « exacte ¼ (dont l'écart par rapport aux mesures de l'auteur principal est inférieur à 2° pour l'IR, à 1 mm pour la VU et à 4° pour l'ISR) était 1,7 fois plus grande pour l'IR, 2,7 fois plus grande pour la VU et 2,3 fois plus grande pour l'ISR après le tutoriel. Tous ces résultats sont statistiquement significatifs. Conclusion: Les chirurgiens doivent connaître une méthode de mesure reproductible des indicateurs utilisés dans les directives cliniques publiées pour guider l'intervention chirurgicale. Le tutoriel sur la technique normalisée de mesure en ligne de l'IR, de la VU et de l'ISR dans les cas de fracture du radius distal a amélioré la précision des mesures.

Changes in fall risk and functional status in women aged 50 years and older after distal radius fracture: A prospective 1-year follow-up study.

STUDY DESIGN: Prospective cohort study. INTRODUCTION: Few studies have evaluated the course of recovery after distal radius fracture (DRF) when functional decline and fracture risk may be affected. PURPOSE OF THE STUDY: The purpose of this study was to determine changes in overall functional status over the first year after a DRF in women aged 50 years and older. METHODS: Seventy-eight women were assessed for balance, balance confidence, lower extremity strength, gait speed, fall history, physical activity levels, and self-reported wrist pain and function (Patient-Rated Wrist Evaluation) at weeks 1, 3, 9, 12, 26, and 52 after DRF. Descriptive data were generated for all variables; a 3-way mixed analysis of variance with repeated measures was used to compare differences between participants aged 50-65 years and 65 years and older. RESULTS: There was a significant improvement in functional status measures for both age categories except single-leg balance and fast gait speed, from 1 week after fracture extending up to 1 year after fracture (ranging from 6.1% improvement to 25% improvement, P < .05). There was no significant time × age interaction, as both age groups had the same pattern of recovery; however, there was significantly lower functional status in the older group across all time points. CONCLUSION: Regardless of age, monitoring and addressing functional status including upper limb function, overall strength, balance, confidence, usual gait speed, and physical activity right up to 1 year after fracture is an important consideration for clinicians treating women recovering from DRF. Given the high future fracture risk for these women, identifying functional recovery patterns can help to direct future research and determine preventative strategies.

Mitochondrial dysfunction and increased glycolysis in prodromal and early Parkinson's blood cells.

BACKGROUND: Although primarily a neurodegenerative process, there is increasing awareness of peripheral disease mechanisms in Parkinson's disease. To investigate disease processes in accessible patient cells, we studied peripheral blood mononuclear cells in recently diagnosed PD patients and rapid eye movement-sleep behavior disorder patients who have a greatly increased risk of developing PD. We hypothesized that peripheral blood mononuclear cells may recapitulate cellular pathology found in the PD brain and investigated these cells for mitochondrial dysfunction and oxidative stress. METHODS: Peripheral blood mononuclear cells were isolated and studied from PD patients, rapid eye movement-sleep behavior disorder patients and age- and sex-matched control individuals from the well-characterized Oxford Discovery cohort. All participants underwent thorough clinical assessment. RESULTS: Initial characterization showed that PD patients had elevated levels of CD14 + monocytes and monocytes expressing C-C motif chemokine receptor 2. Mitochondrial dysfunction and oxidative stress were increased in PD patient peripheral blood mononuclear cells, with elevated levels of mitochondrial reactive oxygen species specifically in patient monocytes. This was combined with reduced levels of the antioxidant superoxide dismutase in blood cells from PD patients and, importantly, also in rapid eye movement-sleep behavior disorder patients. This mitochondrial dysfunction was associated with a concomitant increase in glycolysis in both PD and rapid eye movement-sleep behavior disorder patient blood cells independent of glucose uptake or monocyte activation. CONCLUSIONS: This work demonstrates functional bioenergetic deficits in PD and rapid eye movement-sleep behavior disorder patient blood cells during the early stages of human disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Intrarater Reliability of Range of Motion Measurements of the Uninjured Wrist in Women After Distal Radius Fracture.

PURPOSE: To determine the intrarater reliability of serial wrist and forearm range of motion (ROM) measurements of the uninjured limb, by 1 evaluator using a standardized technique of measurement, in women who have sustained a distal radius fracture. METHODS: From December 2007 to December 2014, skeletally mature women who had sustained an isolated distal radius fracture routinely had sequential measurements of wrist extension and flexion as well as forearm supination and pronation in both their injured and their uninjured limbs, at a minimum of 3-week intervals. The senior author (G.H.F.J.) used a standardized technique of measurement of ROM throughout this period, and these data related to the uninjured wrist and forearm were retrospectively reviewed. RESULTS: Of 508 women who had a distal radius fracture, 506 had the measurements made of the uninjured wrist and forearm on 2, 300 on 3, and 128 on 4 separate occasions. The average age of the women was 61 years, with a range from 16 to 94 years. The intraclass correlation coefficients between measurements over time for extension, flexion, and supination measurements were 0.71, 0.63, 0.68, respectively, and 0.47 for pronation. The intraclass correlation coefficient varied according to patient age, but without specific progression in any age group for any ROM. Extension, flexion, and supination decreased significantly as age increased, whereas forearm pronation did not. CONCLUSIONS: Measurement of wrist and forearm motion of the uninjured limb can be reliably reproduced by a single rater, most so for extension, flexion, and supination, and less so for pronation. Interrater reliability assessment remains to be evaluated. CLINICAL RELEVANCE: Given the intrarater reliability of wrist and forearm motion measurement, the opposite (uninjured) wrist probably represents a useful reference metric for motion restoration for recovery from injury to the opposite limb.

A technique for the removal of a wedged implant abutment fragment or debonded titanium base.

A technique for the retrieval of wedged implant fragments is described. The technique is suitable for fractured zirconia and metal abutments and titanium bases left behind after fracture or debonding of the custom zirconia abutment from the titanium base of an implant-supported prosthesis. This straightforward, noninvasive, technique facilitates the removal of the fragments or titanium bases without risking damage to the implant, surrounding bone, or soft tissues.

Saskatchewan's Successful Strategy for Surgical Waitlist Reduction.

By 2015, Saskatchewan's surgical wait times, once among Canada's longest, were arguably the nation's shortest. This paper highlights the principal strategies that were implemented to address the exceptionally lengthy surgical wait times in Saskatchewan's SHR. These included the province's funding the establishment of a fair operating room allocation system, a centralized provincial surgery registry, integration of priority scoring tools and creation of the Saskatchewan Surgical Care network. This coordinated backdrop facilitated the integration of Lean principles, hospital service consolidation, private third-party surgical care delivery services and policy direction setting by the provincial government.

Repeated administration of dapirolizumab pegol in a randomised phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with diffuse immune cell dysfunction. CD40-CD40 ligand (CD40L) interaction activates B cells, antigen-presenting cells and platelets. CD40L blockade might provide an innovative treatment for systemic autoimmune disorders. We investigated the safety and clinical activity of dapirolizumab pegol, a polyethylene glycol conjugated anti-CD40L Fab' fragment, in patients with SLE. METHODS: This 32-week randomised, double-blind, multicentre study (NCT01764594) evaluated repeated intravenous administration of dapirolizumab pegol in patients with SLE who were positive for/had history of antidouble stranded DNA/antinuclear antibodies and were on stable doses of immunomodulatory therapies (if applicable). Sixteen patients were randomised to 30 mg/kg dapirolizumab pegol followed by 15 mg/kg every 2 weeks for 10 weeks; eight patients received a matched placebo regimen. Randomisation was stratified by evidence of antiphospholipid antibodies. Patients were followed for 18 weeks after the final dose. RESULTS: No serious treatment-emergent adverse events, thromboembolic events or deaths occurred. Adverse events were mild or moderate, transient and resolved without intervention. One patient withdrew due to infection.Efficacy assessments were conducted only in patients with high disease activity at baseline. Five of 11 (46%) dapirolizumab pegol-treated patients achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment response (vs 1/7; 14% placebo) and 5/12 (42%) evaluable for SLE Responder Index-4 responded by week 12 (vs 1/7; 14% placebo). Mechanism-related gene expression changes were observed in blood RNA samples. CONCLUSIONS: Dapirolizumab pegol could be an effective biological treatment for SLE. Further studies are required to address efficacy and safety. TRIAL REGISTRATION NUMBER: NCT01764594.

Quantitative, model-based estimates of variability in the generation and serial intervals of Plasmodium falciparum malaria.

BACKGROUND: The serial interval is a fundamentally important quantity in infectious disease epidemiology that has numerous applications to inferring patterns of transmission from case data. Many of these applications are apropos of efforts to eliminate falciparum malaria from locations throughout the world, yet the serial interval for this disease is poorly understood quantitatively. METHODS: To obtain a quantitative estimate of the serial interval for falciparum malaria, the sum of the components of the falciparum malaria transmission cycle was taken based on a combination of mathematical models and empirical data. During this process, a number of factors were identified that account for substantial variability in the serial interval across different contexts. RESULTS: Treatment with anti-malarial drugs roughly halves the serial interval due to an abbreviated period of human infectiousness, seasonality results in different serial intervals at different points in the transmission season, and variability in within-host dynamics results in many individuals whose serial intervals do not follow average behaviour. Furthermore, 24.5 % of secondary cases presenting clinically did so prior to the primary cases being identified through active detection of infection. CONCLUSIONS: These results have important implications for epidemiological applications that rely on quantitative estimates of the serial interval of falciparum malaria and other diseases characterized by prolonged infections and complex ecological drivers.

Falls and Wrist Fracture: Relationship to Women's Functional Status after Age 50.

Women experience a rapid rise in the incidence of wrist fracture after age 50. Accordingly, this study aimed to (1) determine the internal and environmental fall-related circumstances resulting in a wrist fracture, and (2) examine the relationship of functional status to these circumstances. Women aged 50 to 94 years reported on the nature of the injury (n = 99) and underwent testing for physical activity status, balance, strength, and mobility (n = 72). The majority of falls causing wrist fracture occurred outdoors, during winter months, as a result of a slip or trip while walking. Half of these falls resulted in other injuries including head, neck, and spine injuries. Faster walking speed, lower grip strength, and higher balance confidence were significantly associated with outdoor versus indoor falls and slips and trips versus other causes. This study provides insights into potential screening and preventive measures for fall-related wrist fractures in women.

Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

The path of least resistance: aggressive or moderate treatment?

The evolution of resistance to antimicrobial chemotherapy is a major and growing cause of human mortality and morbidity. Comparatively little attention has been paid to how different patient treatment strategies shape the evolution of resistance. In particular, it is not clear whether treating individual patients aggressively with high drug dosages and long treatment durations, or moderately with low dosages and short durations can better prevent the evolution and spread of drug resistance. Here, we summarize the very limited available empirical evidence across different pathogens and provide a conceptual framework describing the information required to effectively manage drug pressure to minimize resistance evolution.

Recasting the theory of mosquito-borne pathogen transmission dynamics and control.

Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. That framework, especially Macdonald's formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases. A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross-Macdonald assumption of homogeneous transmission in a well-mixed population. Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory. Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement. Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.

Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination.

Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vectors. Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R 0<10 based on 2010 data. Our modeling predicts that treating 93-98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ∼91% of the at-risk population of Southeast Asia and ∼74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81-85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ∼180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment.