The evolving landscape of pulmonary arterial hypertension clinical trials.

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.

aVR: The forgotten lead in acute coronary syndrome: A case series.

Lead aVR is often considered as a neglected lead or forgotten lead owing to its reciprocal location to the lateral leads. However, it has diagnostic and prognostic importance in cases of acute coronary syndromes. We present a series of four cases of acute coronary syndrome with ST elevation (STE) in aVR and critical stenosis in coronary vessels. Patients with STE in aVR have a poor prognosis with increased morbidity not limited to increased chances of heart failure at presentation, greater hemodynamic instability, and in-hospital acute kidney injury, as well as increased mortality due to large infarction areas. Thus, early revascularization is warranted in such cases.

What can heart failure trialists learn from oncology trialists?

Globally, there has been little change in mortality rates from cardiovascular (CV) diseases or cancers over the past two decades (1997-2018). This is especially true for heart failure (HF) where 5-year mortality rates remain as high as 45-55%. In the same timeframe, the proportion of drug revenue, and regulatory drug approvals for cancer drugs, far out paces those for CV drugs. In 2018, while cancer drugs made 27% of Food and Drug Administration drug approvals, only 1% of drug approvals was for a CV drug, and over this entire 20 year span, only four drugs were approved for HF in the USA. Cardiovascular trialists need to reassess the design, execution, and purpose of CV clinical trials. In the area of oncology research, trials are much smaller, follow-up is shorter, and targeted therapies are common. Cardiovascular diseases and cancer are the two most common causes of death globally, and although they differ substantially, this review evaluates whether some elements of oncology research may be applicable in the CV arena. As one of the most underserved CV diseases, the review focuses on aspects of cancer research that may be applicable to HF research with the aim of streamlining the clinical trial process and decreasing the time and cost required to bring safe, effective, treatments to patients who need them. The paper is based on discussions among clinical trialists, industry representatives, regulatory authorities, and patients, which took place at the Cardiovascular Clinical Trialists Workshop in Washington, DC, on 8 December 2019 (https://www.globalcvctforum.com/2019 (14 September 2020)).

Vaccine for Diabetes-Where Do We Stand?

Diabetes is an endocrinological disorder with a rapidly increasing number of patients globally. Over the last few years, the alarming status of diabetes has become a pivotal factor pertaining to morbidity and mortality among the youth as well as middle-aged people. Current developments in our understanding related to autoimmune responses leading to diabetes have developed a cause for concern in the prospective usage of immunomodulatory agents to prevent diabetes. The mechanism of action of vaccines varies greatly, such as removing autoreactive T cells and inhibiting the interactions between immune cells. Currently, most developed diabetes vaccines have been tested in animal models, while only a few human trials have been completed with positive outcomes. In this review, we investigate the undergoing clinical trial studies for the development of a prototype diabetes vaccine.

Results from a 2018 cross-sectional survey in Tokyo, Osaka and Sendai to assess tobacco and nicotine product usage after the introduction of heated tobacco products (HTPs) in Japan.

BACKGROUND: For novel tobacco products that potentially reduce the risk of tobacco harm, post-market surveillance is important to observe population usage and behaviours associated with everyday use. This pilot study was performed to examine the use of tobacco products in three Japanese urban regions. METHODS: This study was a cross-sectional epidemiological survey administered in Sendai, Tokyo and Osaka, Japan, from May 19th to June 25th, 2018. Participants were selected with a three-stage probability random sampling process that first identified primary sampling units, then households and finally individuals. Eligible participants were aged at least 20 years who were willing to participate after information about the study was provided. People younger than 20 years and those living in institutions were excluded. Questionnaires were paper based and administered door to door. RESULTS: Responses were obtained from 4154 participants. Sixty-five percent self-reported being never, 19% current and 16% former users of any tobacco product at the time of the survey. Combustible tobacco products (almost all being cigarette) were used most (16%) followed by HTPs (5%). In the categories of combustible tobacco users and HTP users, 70% and 16%, respectively, used these products exclusively. Dual use was reported by 11% of respondents. Compared with 12 months before the survey, 12% of sole combustible tobacco products users were using HTPs exclusively or as dual users and 6% had quit tobacco products completely; 94% of sole HTP users remained sole users and 4% had quit tobacco products completely; and amongst dual users 12% had reverted to exclusive use of combustible tobacco products, 14% had switched to sole use of HTPs and 4% had quit tobacco products completely. CONCLUSION: HTPs seem to be accepted as an alternative tobacco product amongst combustible tobacco users. Given complex findings for dual use, improved understanding of the motivations underlying this behaviour would be of interest.

Genotype × environment interactions for grain iron and zinc content in rice.

BACKGROUND: Nutrient deficiency in humans, especially in children and lactating women, is a major concern. Increasing the micronutrient concentration in staple crops like rice is one way to overcome this. The micronutrient content in rice, especially the iron (Fe) and zinc (Zn) content, is highly variable. The identification of rice genotypes in which there are naturally high Fe and Zn concentrations across environments is an important target towards the production of biofortified rice. RESULTS: Phenotypic correlations between grain Fe and Zn content were positive and significant in all environments but a significant negative association was observed between grain yield and grain Fe and Zn. Promising breeding lines with higher Zn or Fe content, or both, were: IR 82475-110-2-2-1-2 (Zn: 20.24-37.33 mg kg-1 ; Fe: 7.47-14.65 mg kg-1 ); IR 83294-66-2-2-3-2 (Zn: 22-37-41.97 mg kg-1 ; Fe: 9.43-17.16); IR 83668-35-2-2-2 (Zn: 27.15-42.73 mg kg-1 ; Fe: 6.01-14.71); IR 68144-2B-2-2-3-1-166 (Zn: 23.53-40.30 mg kg-1 ; Fe: 10.53-17.80 mg kg-1 ) and RP Bio 5478-185M7 (Zn: 22.60-40.07 mg kg-1 ; Fe: 7.64-14.73 mg kg-1 ). Among these, IR82475-110-2-2-1-2 (Zn: 20.24-37.33 mg kg-1 ; Fe: 7.47-14.65 mg kg-1 ) is also high yielding with 3.75 t ha-1 . Kelhrie Cha (Zn: 17.76-36.45 mg kg-1 ; Fe: 7.17-14.77 mg kg-1 ), Dzuluorhe (Zn: 17.48-39.68 mg kg-1 ; Fe: 7.89-19.90 mg kg-1 ), Nedu (Zn: 18.97-43.55 mg kg-1 Fe: 8.01-19.51 mg kg-1 ), Kuhusoi-Ri-Sareku (Zn: 17.37-44.14 mg kg-1 ; Fe: 8.99-14.30 mg kg-1 ) and Mima (Zn: 17.10-45.64 mg kg-1 ; Fe: 9.97-17.40 mg kg-1 ) were traditional donor genotypes that possessed both high grain Fe and high Zn content. CONCLUSION: Significant genotype × location (G × L) effects were observed in all traits except Fe. Genetic variance was significant and was considerably larger than the variance of G × L for grain Zn and Fe content traits, except grain yield. The G × L × year variance component was significant in all cases. © 2020 Society of Chemical Industry.

Clinicopathological spectrum of solitary Plasmacytoma: a single center experience from coastal India.

BACKGROUND: Plasma cell disorders are a rare group of hematological malignancies that accounts for 10% of all hematological neoplasms. Solitary plasmacytomas are rarer entities accounting for less than 5% of all the plasma cell dyscrasias. They encompass three subtypes - Solitary Plasmacytoma of Bone (SPB) and Solitary Extramedullary Plasmacytoma (SEP) and multiple solitary plasmacytomas (MSP). In this study, we discuss the clinical, histopathological and immunohistochemical characteristics of solitary plasmacytomas. METHODS: A 13 year retrospective analysis of solitary plasmacytomas was performed from a single tertiary care center. Bone marrow evaluation was done concurrently at the time of diagnosis to rule out the presence of multiple myeloma. RESULTS: A total of 29 cases fulfilled the diagnostic criteria for SP during the study period. SPB accounted for 55.2%, SEP for 44.4% and MSP for 3.4% of the cases. The most common sites involved were the paranasal sinuses and vertebrae. Other infrequent sites included lymph node, tonsil and lungs. The mean age of presentation of SPB was a decade later than SEP. A male preponderance was observed in both subtypes. CONCLUSION: Solitary plasmacytoma is a rare entity, the diagnosis of which requires a systematic approach. There is limited data available in the literature on the clinico-pathological characteristics of SP from India.

Assessment of tobacco heating product THP1.0. Part 4: Characterisation of indoor air quality and odour.

The tobacco heating product THP1.0, which heats but does not burn tobacco, was tested as part of a modified-risk tobacco product assessment framework for its impacts on indoor air quality and residual tobacco smoke odour. THP1.0 heats the tobacco to less than 240 °C ± 5 °C during puffs. An environmentally controlled room was used to simulate ventilation conditions corresponding to residential, office and hospitality environments. An analysis of known tobacco smoke constituents, included CO, CO2, NO, NO2, nicotine, glycerol, 3-ethenyl pyridine, sixteen polycyclic aromatic hydrocarbons, eight volatile organic compounds, four carbonyls, four tobacco-specific nitrosamines and total aerosol particulate matter. Significant emissions reductions in comparison to conventional cigarettes were measured for THP1.0. Levels of nicotine, acetaldehyde, formaldehyde and particulate matter emitted from THP1.0 exceeded ambient air measurements, but were more than 90% reduced relative to cigarette smoke emissions within the laboratory conditions defined Residual tobacco smoke odour was assessed by trained sensory panels after exposure of cloth, hair and skin to both mainstream and environmental emissions from the test products. Residual tobacco smoke odour was significantly lower from THP1.0 than from a conventional cigarette. These data show that using THP1.0 has the potential to result in considerably reduced environmental emissions that affect indoor air quality relative to conventional cigarettes.

Assessment of tobacco heating product THP1.0. Part 8: Study to determine puffing topography, mouth level exposure and consumption among Japanese users.

A four-arm study was undertaken in Japan to determine the puffing topography, mouth level exposure and average daily consumption by consumers of the tobacco heating products (THPs): the non-mentholated THP1.0(T), the mentholated THP1.0(M) and a tobacco heating system (THS). The extent of lip blocking of air inlet holes while using THP1.0(T) was also assessed. Groups 1, 2, and 4 included smokers, and group 3 included regular THP users. Smokers of 7-8 mg ISO nicotine free dry particulate matter (NFDPM) non-mentholated cigarettes took on average larger mean puff volumes from THPs than from conventional cigarettes, but puff numbers and durations were similar. Mouth level exposure to NFDPM and nicotine levels were significantly lower when using THPs than conventional cigarettes. Similar trends were observed among smokers of 7-8 mg ISO NFDPM mentholated cigarettes who used mentholated cigarettes and THP1.0(M). Regular users of commercial THS had similar puffing behaviours irrespective of whether they were using THS or THP1.0(T), except for mean puff volume which was lower with THP1.0(T). No smokers blocked the air inlet holes when using THP1.0(T). The puffing topography results support the machine puffing regime used to generate toxicant emissions data and in vitro toxicology testing.

Assessment of tobacco heating product THP1.0. Part 9: The placement of a range of next-generation products on an emissions continuum relative to cigarettes via pre-clinical assessment studies.

This series of nine papers described the operation and pre-clinical assessment of a tobacco heating product THP1.0. This last paper contextualises the pre-clinical assessment data on THP1.0 with data from other next generation products relative to cigarette smoke. The tobacco and nicotine risk continuum is a concept that ranks products according to their potential harm, with cigarettes at the highest risk extreme and Nicotine Replacement Therapy at the least risky extreme. Data generated in pre-clinical studies on THP1.0 and a range of Next Generation Products (NGPs) may provide some initial indication of potential ranking of these products, although importantly, data from such studies are limited and cannot take into consideration several important aspects for risk such as long term product use patterns. In each of the studies, the responses to the emissions from THP1.0 were substantially reduced relative to cigarette smoke. Additionally, responses from THP1.0 were very similar to those from the other NGP emissions. A comparison of the results clearly showed the emissions from all the NGPs were considerably lower than those from cigarettes and all in around the same emissions level. These results show that THP1.0 could have the potential to be a reduced risk product compared to cigarettes, though further studies assessing the exposure, individual and population risk reduction profile would be required to substantiate this potential.

Reconstruction for chronic Achilles tendinopathy: comparison of flexor hallucis longus (FHL) transfer versus V-Y advancement.

BACKGROUND: Several operative techniques exist for Achilles tendinopathy. The purpose of our study was to compare the clinical and functional outcomes of flexor hallucis longus (FHL) transfer and V-Y advancement for the treatment of chronic insertional Achilles tendinopathy. METHODS: Retrospective chart review from 2010 to 2016 of patients that underwent FHL transfer or V-Y advancement for chronic insertional Achilles tendinopathy. Outcome measures were compared for these two procedures. RESULTS: In total, 46 patients (49 ankles) with a mean age of 55.0 (range 33-73) years. Mean follow-up time 44.7 +/- 25.5 months. FHL group had 21 patients (21 ankles) with 89% satisfaction, 14% complication rate, final VAS of 0.4, final VISA-A of 89.1, subjective strength improvement following surgery of 78%, and 94% would recommend the procedure. V-Y group had 25 patients (28 ankles) with 74% subjective satisfaction, 21% complication rate, final VAS of 1.4, final VISA-A of 78.4, subjective strength improvement following surgery of 67%, and 84% would recommend the procedure. There was no significant difference in any of the results rates between the two groups (p > .05). CONCLUSION: V-Y advancement is comparable to FHL transfer for the operative management of insertional Achilles tendinopathy. Though our results trend towards less satisfactory results following V-Y advancement, we found high satisfaction rates with similar functional outcomes and complication rates in both operative groups. We suggest considering V-Y advancement as a viable option for the primary treatment of chronic insertional Achilles tendinopathy in patients who may not be an ideal candidate for FHL transfer.

Effect of Type II Diabetes Mellitus, Candida Albicans and Streptococcus Mutans on the Biofilm Formation on Prosthetic Materials.

AIM: To investigate the biofilm formation on Prosthetic materials as affected by type II diabetes mellitus, Candida albicans and Streptococcus mutans. MATERIALS AND METHODS: Two types of saliva, natural saliva, and artificial saliva were collected and prepared respectively. The natural saliva was divided into diabetic and non-diabetic saliva. The artificial saliva was further divided into two groups, one inoculated with Streptococcus mutans and the second with Candida albicans. The 150 samples of various prosthetic materials were prepared using nickel-chromium alloy, ceramic, soft liner, tooth molding powder; heat cured the acrylic resin. The samples were then immersed in natural saliva and artificial saliva and studied for biofilm formation. RESULTS: Diabetic saliva formed more biofilm than non-diabetic saliva. Streptococcus mutans were able to form more biofilm than Candida albicans in artificial saliva on constitutive androstane receptor (hCAR) and spinal length (SL). In Diabetic saliva, there was a significant difference in the biofilm formation seen between MC and NCA (p < 0.05). No biofilm was formed on hCAR in natural saliva (diabetic or non-diabetic). In artificial saliva inoculated with Candida albicans and streptococcus mutans there is a significant difference in the biofilm formation in all the materials except NCA. CONCLUSION: Diabetic saliva has more potential to form biofilm than non-diabetic saliva. Also, Candida albicans and Streptococcus mutans both can form a biofilm on materials used with the maximum formation on hCAR. Smoother materials formed less biofilm than rougher surfaces like hCAR, PCM, SL. CLINICAL SIGNIFICANCE: It is desirable for dental restorative materials to have a low susceptibility for accumulation and formation of biofilm as it may lead to pathologies such as dental caries, periodontal disease, peri-implantitis, etc. which are plaque-related. The most commonly used materials in prosthodontics have been used in the study to establish a direct relationship with the formation of biofilm, this, in turn, helps us to take the right call in choosing a material for a patient with an already compromised systemic condition.

Assessing modified risk tobacco and nicotine products: Description of the scientific framework and assessment of a closed modular electronic cigarette.

Cigarette smoking causes many human diseases including cardiovascular disease, lung disease and cancer. Novel tobacco products with reduced yields of toxicants compared to cigarettes, such as tobacco-heating products, snus and electronic cigarettes, hold great potential for reducing the harms associated with tobacco use. In the UK several public health agencies have advocated a potential role for novel products in tobacco harm reduction. Public Health England has stated that "The current best estimate is that e-cigarettes are around 95% less harmful than smoking" and the Royal College of Physicians has urged public health to "Promote e-cigarettes widely as substitute for smoking". Health related claims on novel products such as 'reduced exposure' and 'reduced risk' should be substantiated using a weight of evidence approach based on a comprehensive scientific assessment. The US FDA, has provided draft guidance outlining a framework to assess novel products as Modified Risk Tobacco Products (MRTP). Based on this, we now propose a framework comprising pre-clinical, clinical, and population studies to assess the risk profile of novel tobacco products. Additionally, the utility of this framework is assessed through the pre-clinical and part of the clinical comparison of a commercial e-cigarette (Vype ePen) with a scientific reference cigarette (3R4F) and the results of these studies suggest that ePen has the potential to be a reduced risk product.

Influence of cigarette filter ventilation on smokers' mouth level exposure to tar and nicotine.

Cigarette filter ventilation allows air to be drawn into the filter, diluting the cigarette smoke. Although machine smoking reveals that toxicant yields are reduced, it does not predict human yields. The objective of this study was to investigate the relationship between cigarette filter ventilation and mouth level exposure (MLE) to tar and nicotine in cigarette smokers. We collated and reviewed data from 11 studies across 9 countries, in studies performed between 2005 and 2013 which contained data on MLE from 156 products with filter ventilation between 0% and 87%. MLE among 7534 participants to tar and nicotine was estimated using the part-filter analysis method from spent filter tips. For each of the countries, MLE to tar and nicotine tended to decrease as filter ventilation increased. Across countries, per-cigarette MLE to tar and nicotine decreased as filter ventilation increased from 0% to 87%. Daily MLE to tar and nicotine also decreased across the range of increasing filter ventilation. These data suggest that on average smokers of highly ventilated cigarettes are exposed to lower amounts of nicotine and tar per cigarette and per day than smokers of cigarettes with lower levels of ventilation.

Need for streamlined use of DPP-4 inhibitors in the treatment of type 2 diabetes.

Regulatory agencies request an assessment of cardiovascular safety for all "new" oral anti-diabetic drugs in order to avoid possible negative effects on cardiovascular events. Dipeptidyl peptidase 4 inhibitors have emerged as a new therapeutic alternative for the treatment of type 2 diabetes mellitus, but the several large post-marketing clinical trials have shown only a modest effect in glycaemic control and, more importantly, a neutral effect on total and cardiovascular events. Conversely a recent trial with empagliflozin, a sodium-glucose co-transporter 2 inhibitor, has shown significant effect on overall and cardiovascular mortality. Although glycaemic control is an important aspect of diabetes management, the results of the EMPA-REG outcome trial suggest that it is possible to develop anti-diabetic drugs that may exert an overall beneficial effect beyond the mere improvement of glycaemic control. While the regulatory hurdles should not be increased, there is the need for evaluation of the net clinical impact and cost effectiveness of all anti-diabetic agents. Therefore, a better collaboration among all stakeholders is needed in order to develop studies with endpoints that will be both clinically meaningful including appropriate follow-up, and economically relevant in patients with type 2 diabetes mellitus.

Maxillary sinus augmentation using sinus membrane elevation without grafts - A Systematic Review.

Implants have a predictable outcome and are the foremost treatment modality for prosthetic rehabilitation of edentulous patients. Due to loss of bone after extraction and pneumatization of maxillary sinus, there is insufficient bone volume for implant placement. The direct maxillary sinus lift procedure has been performed with different grafting materials (autogenous bone grafts, alloplasts, allografts, and xenografts) and without grafting material, having new bone formation around the implant. There is no evidence to prove the need for grafting material in all direct sinus lift procedures, hence the need for this review. Previous meta-analysis showed that survival rates of implants placed in grafted maxillary sinuses had similar survival rates whether autogenous, allogenous, or alloplastic grafts were used. This paper aims to review scientific data on the direct sinus elevation technique without use of any grafting material, volume of new bone formed, and also mechanism behind this technique. Articles were searched from 1997 to October 2014 in PubMed, Google Scholar, and Cochrane CENTRAL. The study eligibility criteria were (1) direct sinus lift procedure without any graft material during implant placement and (2) human or animal studies with a minimum follow-up of 6 months or more. Two authors independently scrutinized the literature and if any controversy was raised, third author's opinion was sought to arrive at a mutual consensus for including the study in the review. Due to the heterogeneity across all studies in all study designs, the data were not pooled and a meta-analysis was not performed. Taking into consideration all factors reviewed in this regard along with the outcomes, the direct sinus lift technique without grafting can be suggested as a viable treatment option keeping in mind the limitations involved. The average bone gain was seen across all studies ranging from 2.37 to 10 mm and with an implant survival rate ranging from 79.9% to 100% across studies.

A longitudinal study of smokers' exposure to cigarette smoke and the effects of spontaneous product switching.

A challenge in investigating the effect of public health policies on cigarette consumption and exposure arises from variation in a smoker's exposure from cigarette to cigarette and the considerable differences between smokers. In addition, limited data are available on the effects of spontaneous product switching on a smoker's cigarette consumption and exposure to smoke constituents. Over 1000 adult smokers of the same commercial 10mg International Organization for Standardization (ISO) tar yield cigarette were recruited into the non-residential, longitudinal study across 10 cities in Germany. Cigarette consumption, mouth level exposure to tar and nicotine and biomarkers of exposure to nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were measured every 6months over a 3 and a half year period. Cigarette consumption remained stable through the study period and did not vary significantly when smokers spontaneously switched products. Mouth level exposure decreased for smokers (n=111) who switched to cigarettes of 7mg ISO tar yield or lower. In addition, downward trends in mouth level exposure estimates were observed for smokers who did not switch cigarettes. Data from this study illustrate some of the challenges in measuring smokers' long-term exposure to smoke constituents in their everyday environment.

Unrecognized catatonia as a cause for delayed weaning in Intensive Care Unit.

The cause of altered sensorium in critical care settings includes metabolic derangements, drug and toxin overdose, central nervous system infections, neurodegenerative disorders, vascular events, hypo-perfusion states, and septic encephalopathy. Here, we present a case of an elderly woman who presented to us with altered sensorium with respiratory failure requiring mechanical ventilation. Her metabolic parameters, imaging, and cerebrospinal fluid study were all normal despite that she continued to remain in altered sensorium and had an unrecognized behavioral state that delayed her weaning.

Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.

The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study.

Longitudinal study of long-term smoking behaviour by biomarker-supported determination of exposure to smoke.

BACKGROUND: Long-term studies of smokers who switch to lower nicotine yield cigarettes have been identified by the World Health Organization Study Group TobReg and the US Food and Drug Administration as one key area where new knowledge is required to guide science based regulation. The limited number of long-term switching studies have concluded that smokers who switch to lower nicotine yield cigarettes show evidence of partial compensation. Since the European Union tobacco product directive of 2001 introduced tar and nicotine yield ceilings, there has been no long-term observational switching study. To address the limitations of previous studies where smokers were forced switched for relatively short durations, we plan to undertake a long-term study of spontaneous switching which is appropriately powered and includes non-switchers as a control group. METHODS/DESIGN: Healthy adult smokers aged 21-64 years will be enrolled into this 5-year non-residential, multicentre study across 10 cities in Germany. They will be assessed at 10 timepoints with 6 month intervals during which inclusion criteria will be reassessed and spent cigarette filter tips, saliva and 24 h urine samples will be collected. These samples will be used to determine average daily cigarette consumption, estimate mouth-level exposure to tar and nicotine and measure selected biomarkers of exposure, respectively. Spontaneous changes in subjects' preferred cigarette products and any consequent change in tar or nicotine yield will be monitored. Subjects will be required to complete questionnaires on quality of life, smoking behaviours, smoking-related sensory attributes and recent life changes. DISCUSSION: The planned study is anticipated to contribute to understanding smokers' behaviours and their consequent exposure to smoke constituents. It will also allow assessment of compensatory changes in their behaviour following spontaneous switching of cigarette product smoked. Data from this study are expected to provide insights into study design and conduct for non-clinical assessment of smokers' exposure as part of post marketing surveillance programmes. TRIAL REGISTRATION: Current Controlled Trials Database reference ISRCTN95019245.