Locoregional control and toxicity following high-dose hypofractionated and accelerated palliative radiotherapy regimens in breast cancer.

AIMS: For patients with locally advanced primary/recurrent breast cancer, radiotherapy is an effective treatment for locoregional control. 36 Gy in 6 Gy once-weekly fractions is a commonly used schedule, but there are no data comparing local control and toxicity between 36 Gy delivered once-weekly versus accelerated schedules of multiple 6 Gy fractions per week. This retrospective study compared local control rates and acute and late toxicity in patients undergoing 30-36 Gy in 6 Gy fractions over 6 weeks versus more accelerated schedules over 2-3 weeks for an unresected breast cancer. MATERIALS AND METHODS: Patients who received 30-36 Gy in 6 Gy fractions to an unresected breast cancer ± involved lymph nodes between December 2011 and August 2020 were identified. Patients were grouped into once-weekly versus accelerated fractionation schedules. Response rates, local control and toxicity data were analysed. RESULTS: In total, 109 patients were identified. The median follow-up duration was 46 months. Forty-seven patients (43%) received once-weekly fractions and 62 patients (57%) received accelerated fractionation schedules. There were no significant differences in baseline tumour characteristics between the groups. Eighty-seven per cent of patients had an objective (complete or partial) response (81% in the once-weekly group; 91% in the accelerated group). The median time to local progression was 23.5 months overall (95% confidence interval 17.8-29.2); 23.5 months (95% confidence interval 18.8-28.1) in the once-weekly group and 19.0 months (95% confidence interval 7.0-31.1) in the accelerated group (P = 0.99). Acute toxicity of any grade occurred in 75% of patients (76% in the once-weekly group; 74% in the accelerated group) and grade 3 toxicity occurred in 7% of patients (7% in the once-weekly group; 8% in the accelerated group). There were no associations between the groups and acute or late toxicity grade (P = 0.78 and P = 0.26, respectively), although one grade 4 late toxicity (skin radionecrosis) occurred in a patient who received five fractions a week and therefore this regimen is not recommended. Study limitations included a lack of statistical power analysis, the necessary grouping of all accelerated patients for analysis and a high rate of censored data. CONCLUSION: There were no apparent differences in response rate, time to local progression or toxicity between patients who received 30-36 Gy in 6 Gy fractions once-weekly compared with twice-weekly as palliative treatment for locally advanced breast cancer. This regimen appears to be a safe alternative and may be preferred by patients.

Ultra-low-loss nanofiber Fabry-Perot cavities optimized for cavity quantum electrodynamics.

We demonstrate the fabrication of ultra-low-loss, all-fiber Fabry-Perot cavities that contain a nanofiber section, optimized for cavity quantum electrodynamics. By continuously monitoring the finesse and fiber radius during the fabrication of a nanofiber between two fiber Bragg gratings, we were able to precisely evaluate taper transmission as a function of radius. The resulting cavities have an internal round-trip loss of only 0.31% at a nanofiber waist radius of 207 nm, with a total finesse of 1380, and a maximum expected internal cooperativity of ∼1050 for a cesium atom on the nanofiber surface. Our ability to fabricate such high-finesse nanofiber cavities may open the door for the realization of high-fidelity scalable quantum networks.

Preserving US microbe collections sparks future discoveries.

Collections of micro-organisms are a crucial element of life science research infrastructure but are vulnerable to loss and damage caused by natural or man-made disasters, the untimely death or retirement of personnel, or the loss of research funding. Preservation of biological collections has risen in priority due to a new appreciation for discoveries linked to preserved specimens, emerging hurdles to international collecting and decreased funding for new collecting. While many historic collections have been lost, several have been preserved, some with dramatic rescue stories. Rescued microbes have been used for discoveries in areas of health, biotechnology and basic life science. Suggestions for long-term planning for microbial stocks are listed, as well as inducements for long-term preservation.

Disciplinary boundaries and integrating care: using Q-methodology to understand trainee views on being a good doctor.

BACKGROUND: Rising numbers of patients with multiple-conditions and complex care needs mean that it is increasingly important for doctors from different specialty areas to work together, alongside other members of the multi-disciplinary team, to provide patient centred care. However, intra-professional boundaries and silos within the medical profession may challenge holistic approaches to patient care. METHODS: We used Q methodology to examine how postgraduate trainees (n = 38) on a range of different specialty programmes in England and Wales could be grouped based on their rankings of 40 statements about 'being a good doctor'. Themes covered in the Q-set include: generalism (breadth) and specialism (depth), interdisciplinarity and multidisciplinary team working, patient-centredness, and managing complex care needs. RESULTS: A by-person factor analysis enabled us to map distinct perspectives within our participant group (P-set). Despite high levels of overall commonality, three groups of trainees emerged, each with a clear perspective on being a good doctor. We describe the first group as 'generalists': team-players with a collegial and patient-centred approach to their role. The second group of 'general specialists' aspired to be specialists but with a generalist and patient-centred approach to care within their specialty area. Both these two groups can be contrasted to those in the third 'specialist' group, who had a more singular focus on how their specialty can help the patient. CONCLUSIONS: Whilst distinct, the priorities and values of trainees in this study share some important aspects. The results of our Q-sort analysis suggest that it may be helpful to understand the relationship between generalism and specialism as less of a dichotomy and more of a continuum that transcends primary and secondary care settings. A nuanced understanding of trainee views on being a good doctor, across different specialties, may help us to bridge gaps and foster interdisciplinary working.

The prevalence of community programmes and policies to prevent childhood obesity in a diverse sample of US communities: the Healthy Communities Study.

INTRODUCTION: This manuscript describes the prevalence and attributes of community programmes and policies (CPPs) to address childhood obesity documented as occurring in 130 diverse US communities. METHODS: Key informant interviews (N = 1420) and document abstraction were used to identify and characterize CPPs to promote physical activity and healthy nutrition occurring during a 10-year retrospective study period. Data were collected in 2013-2015 and analysed in 2016. RESULTS: Across all 130 communities, 9681 distinct CPPs were reported as occurring by key informants. Of these, 5574 (58%) focused on increasing physical activity, 2596 (27%) on improving nutrition and 1511 (16%) on both behaviours. The mean number of CPPs per community was 74.0, with a range of 25 to 295 across all communities. Most CPPs occurred more than once (63%) and on average lasted 6.1 years. The greatest number of reported CPPs occurred in school settings (44%). CONCLUSIONS: Communities showed a wide range of investment in the amount of CPPs occurring in settings that affect opportunities for children to engage in physical activity and healthy nutrition. The pattern of implementation of CPPs showed variation over time, with an increase in more recent years. This observational study provides new and valuable information about what US communities are doing to prevent childhood obesity.

Community characteristics modify the relationship between obesity prevention efforts and dietary intake in children: the Healthy Communities Study.

BACKGROUND: The influence of community characteristics on the effectiveness of childhood obesity prevention efforts is not well understood. OBJECTIVE: Examine the interaction of community characteristics with the relationship between community programmes and policies (CPPs) and dietary intake. METHODS: An observational study of 5138 children in grades K-8 in 130 US communities was conducted in 2013-2015. Key informant interviews identified and characterized CPPs. CPP scores were generated for the number of target behaviours (CPP-Behav) and the number of behaviour change strategies (CPP-Strat) addressed by all CPPs and CPPs with nutrition goals over the prior 6 years in each community. Dietary intake was assessed by dietary screener and included intake of sugar from sugar-sweetened beverages; energy-dense foods; fruits and vegetables; whole grains; and fibre. Multivariate statistical models assessed the interactions between US region, urbanicity, community-level income, and community-level race/ethnicity and CPP scores in relation to dietary intake. RESULTS: CPP-Strat was positively associated with healthier dietary intakes in the Northeast and West, and in high Hispanic communities; the reverse was true in the South, and in high African-American and low-income communities. The CPP-Behav was positively associated with healthier dietary intakes in the South and rural areas, and the reverse was true in the West. CONCLUSION: The relationships between CPP index scores and dietary intake were most strongly influenced by region and urbanicity and to a lesser extent by community-level race/ethnicity and income. Findings suggest that different considerations may be needed for childhood obesity prevention efforts in communities with different characteristics.

Associations of community programs and policies with children's dietary intakes: the Healthy Communities Study.

BACKGROUND: The impact of community-based obesity prevention efforts on child nutrition has not been adequately studied. OBJECTIVE: Examine relationships between number, type and intensity of community programs and policies (CPPs) and child nutrition. METHODS: An observational study of 5138 children (grades K-8) in 130 U.S. communities was conducted in 2013-2015. CPPs were identified by 10-14 key informant interviews per community. CPPs were characterized based on: count, intensity, number of different strategies used and number of different behaviours targeted. Scores for the prior 6 years were calculated separately for CPPs that addressed primarily nutrition, primarily physical activity (PA) or total combined. Child intakes were calculated from a dietary screener and dietary behaviours were based on survey responses. Multi-level statistical models assessed associations between CPP indices and nutrition measures, adjusting for child and community-level covariates. RESULTS: Implementing more types of strategies across all CPPs was related to lower intakes of total added sugar (when CPPs addressed primarily PA), sugar-sweetened beverages (for nutrition and PA CPPs) and energy-dense foods of minimal nutritional value (for total CPPs). Addressing more behaviours was related to higher intakes of fruit and vegetables (for nutrition and total CPPs) and fibre (total CPPs). Higher count and intensity (PA and total CPPs) were related to more consumption of lower fat compared with higher fat milk. A higher count (PA CPPs) was related to fewer energy-dense foods and whole grains. No other relationships were significant at P < 0.05. CONCLUSION: Multiple characteristics of CPPs to prevent obesity appear important to improve children's diets.

Objectives of community policies and programs associated with more healthful dietary intakes among children: findings from the Healthy Communities Study.

BACKGROUND: Rational planning of community policies and programs (CPPs) to prevent obesity requires an understanding of CPP objectives associated with dietary behaviours. OBJECTIVE: The objective of the study is to identify objectives of CPPs associated with healthful dietary behaviours. METHODS: An observational study identified 4026 nutrition CPPs occurring in 130 communities in the prior 6 years. Dietary intakes of fruits and vegetables, added sugar and sugar-sweetened beverages, among others, were reported among 5138 children 4-15 years of age from the communities, using a Dietary Screener Questionnaire with children age 9 years and older (parent assisted) or parent proxies for younger children. CPPs were documented through key informant interviews and characterized by their intensity, count, and objectives including target dietary behaviour and food environment change strategy. Associations between dietary intakes and CPP objectives were assessed using hierarchical statistical models. RESULTS: CPPs with the highest intensity scores that targeted fast food or fat intake or provided smaller portions were associated with greater fruit and vegetable intake (0.21, 0.19, 0.23 cup equivalents/day respectively with p values <0.01, 0.04, 0.03). CPPs with the highest intensity scores that restricted the availability of less healthful foods were associated with lower child intakes of total added sugar (-1.08 tsp/day, p < 0.01) and sugar from sugar-sweetened beverages (-1.63 tsp/day, p = 0.04). Similar associations were observed between CPP count and dietary outcomes. No other significant associations were found between CPP target behaviours or environmental strategies and dietary intakes/behaviours. CONCLUSION: CPPs that targeted decreases in intakes of less healthful foods and/or aimed to modify the availability of less healthful foods and portions were associated with healthier child dietary behaviours.

The longitudinal relationship between community programmes and policies to prevent childhood obesity and BMI in children: the Healthy Communities Study.

BACKGROUND: Although a national epidemic of childhood obesity is apparent, how community-based programmes and policies (CPPs) affect this outcome is not well understood. OBJECTIVES: This study examined the longitudinal relationship between the intensity of CPPs in 130 communities over 10 years and body mass index (BMI) of resident children. We also examined whether these relationships differ by key family or community characteristics. METHODS: Five thousand one hundred thirty-eight children in grades K-8 were recruited through 436 schools located within 130 diverse US communities. Measures of height, weight, nutrition, physical activity and behavioural and demographic family characteristics were obtained during in-home visits. A subsample of families consented to medical record review; these weight and height measures were used to calculate BMI over time for 3227 children. A total of 9681 CPPs were reported during structured interviews of 1421 community key informants, and used to calculate a time series of CPP intensity scores within each community over the previous decade. Linear mixed effect models were used to assess longitudinal relationships between childhood BMI and CPP intensity. RESULTS: An average BMI difference of 1.4 kg/m2 (p-value < 0.01) was observed between communities with the highest and lowest observed CPP intensity scores, after adjusting for community and child level covariates. BMI/CPP relationships differed significantly by child grade, race/ethnicity, family income and parental education; as well as community-level race/ethnicity. CONCLUSIONS: These results indicate that, over time, more intense CPP interventions are related to lower childhood BMI, and that there are disparities in this association by sociodemographic characteristics of families and communities.

One-year outcomes of early-crossover patients in a cohort receiving nonoperative care for lumbar disc herniation.

OBJECTIVE The authors comprehensively studied the recovery course and 1-year outcomes of early-crossover patients who were randomized to the nonoperative care arm of the Leiden-The Hague Spine Intervention Prognostic Study. The primary goal was to gain insight into the differences in the recovery patterns of early-crossover patients and those treated nonoperatively; secondary goals were to identify predictors of good 1-year outcomes, and to understand when and why patients were likely to cross over. METHODS Individual EuroQol-5D scores were obtained at baseline and at 2, 4, 8, 12, 26, 38, and 52 weeks for 142 patients. Early-crossover patients were defined as those electing to undergo surgery during the first 12 weeks of treatment. Crossover and noncrossover groups were compared using Kruskal-Wallis, Wilcoxon-Mann-Whitney, and chi-square tests. Linear mixed-effects models were used to examine the growth trajectories of crossover and noncrossover groups. Recursive partitioning trees were used to model crossover events and the timing of crossover decisions. Multivariable logistic regression models were used to identify predictors of good 1-year outcomes. RESULTS Of the 142 patients randomized to receive prolonged nonoperative care, 136 were selected for the study. In this cohort, 43/136 (32%) opted for surgery, and 31/43 (72%) of crossover events occurred before the 12-week time point. Early-crossover patients had significantly greater functional impairment at Week 2 than noncrossover patients (p = 0.031), but experienced greater recovery by 26 weeks and better 1-year outcomes (p = 0.045). Patients who did not experience an improvement in their symptoms between 2 and 8 weeks were more likely to cross over (OR 3.5, 95% CI 1.2-10.1; p = 0.01). Recursive partitioning trees were able to identify crossover patients with 76% accuracy. Regression models suggested that better recovery at 26 weeks (p < 0.01) was predictive of good 1-year outcome; declining health status between Weeks 4 and 8 was negatively predictive of good outcome (p < 0.01). CONCLUSIONS This study is the first to comprehensively analyze the recovery and outcomes of crossover patients, and compare them to nonoperatively treated patients. The results suggest that patients who have a low EuroQol-5D score during the early weeks of treatment and who do not respond to nonoperative care during the first few weeks of treatment are most likely to cross over. Early-crossover patients experience a greater rate of recovery and more frequently have a good 1-year outcome when compared with nonoperatively treated patients. The current results motivate a broader investigation into the timing of surgery and the identification of patient populations that will be most benefited by early surgical treatment for lumbar disc herniation.

Detection of Potential Chloroplastic Substrates for Polyphenol Oxidase Suggests a Role in Undamaged Leaves.

Polyphenol oxidases (PPOs) have a recognized role during pathogen and arthropod attack. As an immediate consequence of such wounding, cellular compartmentation is destroyed allowing the chloroplastic PPO enzyme to interact with vacuolar substrates catalyzing the oxidation of monophenols and/or o-diphenols to o-diquinones. This ultimately results in a reduction in the nutritional value of wounded tissue through the formation of non-digestible secondary melanin pigments. However, the chloroplastic location of PPO enzyme could indicate a role for PPO in undamaged tissues. In this study, a wild-type red clover population exhibiting high leaf PPO activity had significantly higher yield than a low leaf PPO mutant population while leaf isoflavonoids and hydroxycinnammates (PPO substrates) accumulated at similar levels in these plants. These data suggest that the presence of leaf PPO activity affects plant vigor. Understanding how this advantage is conferred requires knowledge of the cellular mechanism, including intra-organellar substrates. Here we present evidence of candidate PPO substrates within chloroplasts of wild-type red clover, including the monophenolic acid, coumaroyl malate, and low levels of the diphenolic acid, phaselic acid (caffeoyl malate). Interestingly, chloroplastic phaselic acid concentration increased significantly under certain growth conditions. We discuss the implications of this in regard to a potential role for chloroplastic PPO in undamaged leaves.

'It's surprising how differently they treat you': a qualitative analysis of trainee reflections on a new programme for generalist doctors.

OBJECTIVES: An increase in patients with long-term conditions and complex care needs presents new challenges to healthcare providers around the developed world. In response, more broad-based training programmes have developed to better prepare trainees for the changing landscape of healthcare delivery. This paper focuses on qualitative elements of a longitudinal, mixed-methods evaluation of the postgraduate, post-Foundation Broad-Based Training (BBT) programme in England. It aims to provide a qualitative analysis of trainees' evaluations of whether the programme meets its intentions to develop practitioners adept at managing complex cases, patient focused care, specialty integration and conviction in career choice. We also identify unintended consequences. SETTING: 9 focus groups of BBT trainees were held over a 12-month period. Discussions were audio-recorded and subjected to directed content analysis. Data were collected from trainees across all 7 participating regions: East Midlands; West Midlands; Severn; Northern; North Western; Yorkshire and Humber; Kent, Surry and Sussex. PARTICIPANTS: Focus group participants (61 in total) from the first and second cohorts of BBT. RESULTS: Evidence from trainees indicated that the programme was meeting its aims: trainees valued the extra time to decide on their onward career specialty, having a wider experience and developing a more integrated perspective. They thought of themselves as different and perceived that others they worked alongside also saw them as different. Being different meant benefitting from novel training experiences and opportunities for self-development. However, unintended consequences were feelings of isolation, and uncertainty about professional identity. CONCLUSIONS: By spanning boundaries between specialties, trainee generalists have the potential to improve experiences and outcomes for patients with complex health needs. However, the sense of isolation will inhibit this potential. We employ the concept of 'belongingness' to identify challenges related to the implementation of generalist training programmes within existing structures of healthcare provision.

Establishing a database of Canadian feline mitotypes for forensic use.

Hair shed by pet animals is often found and collected as evidence from crime scenes. Due to limitations such as small amount and low quality, mitochondrial DNA (mtDNA) is often the only type of DNA that can be used for linking the hair to a potential contributor. mtDNA has lower discriminatory power than nuclear DNA because multiple, unrelated individuals within a population can have the same mtDNA sequence, or mitotype. Therefore, to determine the evidentiary value of a match between crime scene evidence and a suspected contributor, the frequency of the mitotype must be known within the regional population. While mitotype frequencies have been determined for the United States' cat population, the frequencies are unknown for the Canadian cat population. Given the countries' close proximity and similar human settlement patterns, these populations may be homogenous, meaning a single, regional database may be used for estimating cat population mitotype frequencies. Here we determined the mitotype frequencies of the Canadian cat population and compared them to the United States' cat population. The two cat populations are statistically homogenous, however mitotype B6 was found in high frequency in Canada and extremely low frequency in the United States, meaning a single database would not be appropriate for North America. Furthermore, this work calls attention to these local spikes in frequency of otherwise rare mitotypes, instances of which exist around the world and have the potential to misrepresent the evidentiary value of matches compared to a regional database.

Measurement of microresonator frequency comb coherence by spectral interferometry.

We experimentally investigate the spectral coherence of microresonator optical frequency combs. Specifically, we use a spectral interference method, typically used in the context of supercontinuum generation, to explore the variation of the magnitude of the complex degree of first-order coherence across the full comb bandwidth. We measure the coherence of two different frequency combs and observe wholly different coherence characteristics. In particular, we find that the observed dynamical regimes are similar to the stable and unstable modulation instability regimes reported in previous theoretical studies. Results from numerical simulations are found to be in good agreement with experimental observations. In addition to demonstrating a new technique to assess comb stability, our results provide strong experimental support for previous theoretical analyses.

Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo.

Tumour necrosis factor (TNF)-α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-α antagonist therapeutics in reports available in the literature. We found that TNF-α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-α inhibition has proven useful for patients with progressive vitiligo, where TNF-α inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.

Polyphenol oxidase-mediated protection against oxidative stress is not associated with enhanced photosynthetic efficiency.

BACKGROUND AND AIMS: Polyphenol oxidases (PPOs) catalyse the oxidation of monophenols and/or o-diphenols to highly reactive o-quinones, which in turn interact with oxygen and proteins to form reactive oxygen species (ROS) and typical brown-pigmented complexes. Hence PPOs can affect local levels of oxygen and ROS. Although the currently known substrates are located in the vacuole, the enzyme is targeted to the thylakoid lumen, suggesting a role for PPOs in photosynthesis. The current study was designed to investigate the potential involvement of PPOs in the photosynthetic response to oxidative stress. METHODS: Photosynthesis (A, Fv/Fm, ΦPSII, qN, qP, NPQ) was measured in leaves of a wild-type and a low-PPO mutant of red clover (Trifolium pratense 'Milvus') under control conditions and under a stress treatment designed to induce photooxidative stress: cold/high light (2 °C/580 µmol m(2 )s(-1)) or 0-10 µm methyl viologen. Foliar protein content and oxidation state were also determined. KEY RESULTS: Photosynthetic performance, and chlorophyll and protein content during 4 d of cold/high light stress and 3 d of subsequent recovery under control growth conditions showed similar susceptibility to stress in both lines. However, more extensive oxidative damage to protein in mutants than wild-types was observed after treatment of attached leaves with methyl viologen. In addition, PPO activity could be associated with an increased capacity to dissipate excess energy, but only at relatively low methyl viologen doses. CONCLUSIONS: The presence of PPO activity in leaves did not correspond to a direct role for the enzyme in the regulation or protection of photosynthesis under cold stress. However, an indication that PPO could be involved in cellular protection against low-level oxidative stress requires further investigation.

Polyphenol oxidase in leaves: is there any significance to the chloroplastic localization?

Polyphenol oxidase (PPO) catalyses the oxidation of monophenols and/or o-diphenols to o-quinones with the concomitant reduction of oxygen to water which results in protein complexing and the formation of brown melanin pigments. The most frequently suggested role for PPO in plants has been in defence against herbivores and pathogens, based on the physical separation of the chloroplast-localized enzyme from the vacuole-localized substrates. The o-quinone-protein complexes, formed as a consequence of cell damage, may reduce the nutritional value of the tissue and thereby reduce predation but can also participate in the formation of structural barriers against invading pathogens. However, since a sufficient level of compartmentation-based regulation could be accomplished if PPO was targeted to the cytosol, the benefit derived by some plant species in having PPO present in the chloroplast lumen remains an intriguing question. So is there more to the chloroplastic location of PPO? An interaction between PPO activity and photosynthesis has been proposed on more than one occasion but, to date, evidence either for or against direct involvement has been equivocal, and the lack of identified chloroplastic substrates remains an issue. Similarly, PPO has been suggested to have both pro- and anti-oxidant functions. Nevertheless, several independent lines of evidence suggest that PPO responds to environmental conditions and could be involved in the response of plants to abiotic stress. This review highlights our current understanding of the in vivo functions of PPO and considers the potential opportunities it presents for exploitation to increase stress tolerance in food crops.

Condenser-free contrast methods for transmitted-light microscopy.

Phase contrast microscopy allows the study of highly transparent yet detail-rich specimens by producing intensity contrast from phase objects within the sample. Presented here is a generalized phase contrast illumination schema in which condenser optics are entirely abrogated, yielding a condenser-free yet highly effective method of obtaining phase contrast in transmitted-light microscopy. A ring of light emitting diodes (LEDs) is positioned within the light-path such that observation of the objective back focal plane places the illuminating ring in appropriate conjunction with the phase ring. It is demonstrated that true Zernike phase contrast is obtained, whose geometry can be flexibly manipulated to provide an arbitrary working distance between illuminator and sample. Condenser-free phase contrast is demonstrated across a range of magnifications (4-100×), numerical apertures (0.13-1.65NA) and conventional phase positions. Also demonstrated is condenser-free darkfield microscopy as well as combinatorial contrast including Rheinberg illumination and simultaneous, colour-contrasted, brightfield, darkfield and Zernike phase contrast. By providing enhanced and arbitrary working space above the preparation, a range of concurrent imaging and electrophysiological techniques will be technically facilitated. Condenser-free phase contrast is demonstrated in conjunction with scanning ion conductance microscopy (SICM), using a notched ring to admit the scanned probe. The compact, versatile LED illumination schema will further lend itself to novel next-generation transmitted-light microscopy designs. The condenser-free illumination method, using rings of independent or radially-scanned emitters, may be exploited in future in other electromagnetic wavebands, including X-rays or the infrared.