Regorafenib in patients with relapsed advanced or metastatic chordoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study.

BACKGROUND: REGOBONE multicohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the cohort of patients with relapsed advanced or metastatic chordoma. METHODS: Patients with relapsed chordoma progressing despite 0-2 prior lines of systemic therapy, were randomised (2 : 1) to receive regorafenib (160 mg/day, 21/28 days) or placebo. Patients on placebo could cross over to receive regorafenib after centrally-confirmed progression. The primary endpoint was the progression-free rate at 6 months (PFR-6) (by RECIST 1.1). With one-sided α of 0.05, and 80% power, at least 10/24 progression-free patients at 6 months (PFR-6) were needed for success. RESULTS: From March 2016 to February 2020, 27 patients were enrolled. A total of 23 patients were assessable for efficacy: 7 on placebo, 16 on regorafenib, 16 were men, median age was 66 (32-85) years. At 6 months, in the regorafenib arm, 1 patient was not assessable, 6/14 were non-progressive (PFR-6: 42.9%; one-sided 95% CI = 20.6) 3/14 discontinued regorafenib due to toxicity; and in the placebo arm, 2/5 patients were non-progressive (PFR-6: 40.0%; one-sided 95% CI = 7.6), 2 were non-assessable. Median progression-free survival was 8.2 months (95% CI 4.5-12.9 months) on regorafenib and 10.1 months (95% CI 0.8 months-non evaluable [NE]) on placebo. Median overall survival rates were 28.3 months (95% CI 14.8 months-NE) on regorafenib but not reached in placebo arm. Four placebo patients crossed over to receive regorafenib after centrally-confirmed progression. The most common grade ≥3 regorafenib-related adverse events were hand-foot skin reaction (22%), hypertension (22%), pain (22%), and diarrhoea (17%), with no toxic death. CONCLUSION: This study failed to show any signal of benefit for regorafenib in patients with advanced/metastatic recurrent chordoma.

Reduced and stable feature sets selection with random forest for neurons segmentation in histological images of macaque brain.

In preclinical research, histology images are produced using powerful optical microscopes to digitize entire sections at cell scale. Quantification of stained tissue relies on machine learning driven segmentation. However, such methods require multiple additional information, or features, which are increasing the quantity of data to process. As a result, the quantity of features to deal with represents a drawback to process large series or massive histological images rapidly in a robust manner. Existing feature selection methods can reduce the amount of required information but the selected subsets lack reproducibility. We propose a novel methodology operating on high performance computing (HPC) infrastructures and aiming at finding small and stable sets of features for fast and robust segmentation of high-resolution histological images. This selection has two steps: (1) selection at features families scale (an intermediate pool of features, between spaces and individual features) and (2) feature selection performed on pre-selected features families. We show that the selected sets of features are stables for two different neuron staining. In order to test different configurations, one of these dataset is a mono-subject dataset and the other is a multi-subjects dataset to test different configurations. Furthermore, the feature selection results in a significant reduction of computation time and memory cost. This methodology will allow exhaustive histological studies at a high-resolution scale on HPC infrastructures for both preclinical and clinical research.

Protuberant fibro-osseous lesion of the temporal bone: report of four cases and review of the literature.

'Bullough lesions', also referred to as protuberant fibro-osseous lesions (PFOL), are rare temporal bone lesions initially described in 1999. Since only 12 cases have been reported, several key issues, such as their origin and recommended management strategies, remain unresolved. This article reports the largest cohort included in the literature to date, comprising four patients with PFOL. PFOL appears to be characterized by female and right-side predominance. These lesions were consistently located regarding the mastoid, generally diagnosed in early adulthood, without functional symptoms, and were always fibro-osseous. Invasive/malignant features were not found on imaging or histology. The main differential diagnosis was malignant low-grade parosteal osteosarcoma. Clinical examination and computed tomography images provided strong elements supporting the diagnosis of PFOL. Biopsy allowed molecular biology investigations (MDM2 and CDK4 amplification), in order to rule out low-grade parosteal osteosarcoma.

Percutaneous cryoablation of osteoblastoma in the proximal femur.

A 37-year-old man presented with a 2-year history of left hip pain. Pretherapeutic imaging demonstrated a 4 cm osteoblastoma located in the intertrochanteric region of the proximal femur, surrounded by extensive bone marrow edema. After multidisciplinary meeting, percutaneous cryoablation was decided and performed under computed tomography guidance using three cryoprobes to match the exact size and shape of the tumor, resulting in complete resolution of symptoms. Magnetic resonance imaging follow-up demonstrated resolution of the bone marrow edema pattern and ingrowth of fat at the periphery of the ablation zone consistent with long-term healing of the tumor.

[Therapeutic education in primary cardiovascular prevention]. / Éducation thérapeutique en prévention primaire cardiovasculaire.

BACKGROUND: As primary prevention against cardiovascular diseases, Patient Therapeutic Education helps to develop a protective lifestyle within a socioeconomic context where risk factors abound. PATIENTS AND METHODS: Patient Therapeutic Education offers those eager to protect their cardiovascular health a program of six workshops. Upon enrolment, a Program aide conducts an educational diagnosis with the patient, specific to each workshop theme, so that he might understand the clinical, socio-professional, cognitive and psycho-affective dimensions. An evaluation of each workshop is requested from participants in the form of open and closed questions. RESULTS: The study comprised 2225people, majority women (79%), relatively old (age 63.9for women, 66.3for men), most often retired (65%). An analysis of the educational diagnosis notes a great frequency of classic risk factors; a good knowledge of the factors favoring them contrasting with the weak means implemented in everyday life to reduce their impact; the great majority of participants (68%) believe they have a well balanced diet; patients are greatly involved in their own health, with a slight external locus involving the general practitioner, the immediate entourage and society. The notes of the evaluation are usually maximum. CONCLUSION: Patient Therapeutic Education arouses strong interest in the public, allows a personalized approach that optimizes learning, increases knowledge and facilitates the use of new protective practices.

[Ability of French General Practitioners to detect common mental disorders identified using the Patient Health Questionnaire: Has this changed with the introduction of gatekeeping and registration with a chosen doctor?] / Détection par le médecin généraliste des troubles psychiatriques courants selon l'auto-questionnaire diagnostique le Patient Health Questionnaire : dix ans après, le dispositif du médecin traitant a-t-il modifié la donne ?

OBJECTIVES: The general practitioner (GP) is the most frequently consulted health professional by patients with common mental disorders (CMD). Yet approximately half of cases are not detected by the GP. Many factors linked to the patient, the doctor and the health care system influence detection. For example, detection rates are higher when patients are better known to their GP. On the other hand, patients visiting a different GP for reasons of dissatisfaction with previous care are more likely to be detected on the survey-day. In France, a form of gatekeeping was introduced in 2005 to encourage patients to register with a doctor (most often a GP) of their choice (known as the Preferred Doctor), responsible for care coordination and referral if necessary to secondary care. Visiting a different GP, other than for non-avoidable reasons (for e.g. GP unreachable, patient on holiday), is still possible but financially sanctioned with lower reimbursement rates. We aimed to compare GP detection rates before and after the introduction of this gatekeeping scheme. Patient service use behaviour such as doctor-shopping and GP referral to secondary care were also compared. METHODS: Two cross-sectional surveys using the same study methods were carried out 10 years apart. In 2003, 46 GPs and 1151 patients participated (approximately 25 patients per GP), with a 32.7% GP participation rate. In 2013, 38 GPs participated (of which 29 had participated in the previous study, with a 85.3% "recapture" rate) and 1133 patients (approximately 30 patients per GP). Patient participation rates were 89.8% and 67%, respectively. Patients completed self-report questionnaires in the waiting room of which the DSM-IV diagnostic criteria Patient Health Questionnaire (PHQ) and an adapted version of the Client Service Receipt Inventory (CSRI) on contacts with health care services in the previous six months. For each patient, the GP completed a questionnaire giving his rating of psychiatric illness on a five-point scale with his/her diagnosis for cases, and action undertaken. RESULTS: Of the patients, 27% and 25.4% had a CMD according to the PHQ (defined as a diagnosis of minor or major depression, panic attack, anxiety or somatoform disorder) in 2003 and 2013 respectively. Corresponding detection rates were 51% and 52.6%. Rates were highest for threshold disorders: panic disorder (69.4% and 79.9% in 2003 and 2013, respectively), major depression (75% and 63.3% in 2003 and 2013, respectively) and other anxiety disorders (69.1% and 78.8% in 2003 and 2013, respectively). In 2003, the GPs declared seeing 15.5% for the first time on the survey-day, compared to 9.6% in 2013 (P=0.006). Doctor-shopping declined between the two studies, from 18.4% to 12.1% for practical and mostly unavoidable reasons, and from 9.8% to 4.2% for dissatisfaction reasons (P<0.0001). Referral to specialist doctors increased from 9.7% in 2003 to 14.7% in 2013 (P=0.014). In 2013, on the survey-day, 94.8% of patients had registered with a Preferred Doctor and 81.2% were seeing this Preferred Doctor. In 2003, 93.5% of patients declared having a usual GP and 79.9% were visiting this GP on the survey-day. CONCLUSIONS: This is one of the first studies to report data from two repeated surveys carried out before and after a change in the health service organisation, with data collected from both the patient and the GP. We report relatively high GP detection rates for the two periods, with about 50% of CMDs, including subsyndromic conditions, detected by the GP. Rates are considerably higher for the threshold disorders. The overall detection rate did not increase as expected between the two studies. Detection is a complex topic, involving issues such as the suitability of applying categorical DSM-IV criteria diagnoses to primary care, the relevance of detecting subthreshold conditions and the ability of cross-sectional studies to correctly assess the ability of GPs to recognise cases. The introduction of gatekeeping with the choice of a Preferred Doctor has led to a decline in the frequency of doctor-shopping, whatever its reason, with patients no doubt being better known to the GP. Yet it appears most patients had already chosen a GP they were loyal to before the scheme, with a similar proportion of patients consulting their chosen GP or Preferred Doctor on both survey-days in 2003 and 2013, suggesting the scheme may to some extent only have officialised what already existed with respect to having a usual GP. The French reform still allows for doctor-shopping which can be considered as a positive aspect of the scheme: patients either dissatisfied with previous care or needing to change GP are thus able to "test" and choose the doctor that best suits their needs.

Captive bottlenose dolphins and killer whales harbor a species-specific skin microbiota that varies among individuals.

Marine animals surfaces host diverse microbial communities, which play major roles for host's health. Most inventories of marine animal surface microbiota have focused on corals and fishes, while cetaceans remain overlooked. The few studies focused on wild cetaceans, making difficult to distinguish intrinsic inter- and/or intraspecific variability in skin microbiota from environmental effects. We used high-throughput sequencing to assess the skin microbiota from 4 body zones of 8 bottlenose dolphins (Tursiops truncatus) and killer whales (Orcinus orca), housed in captivity (Marineland park, France). Overall, cetacean skin microbiota is more diverse than planktonic communities and is dominated by different phylogenetic lineages and functions. In addition, the two cetacean species host different skin microbiotas. Within each species, variability was higher between individuals than between body parts, suggesting a high individuality of cetacean skin microbiota. Overall, the skin microbiota of the assessed cetaceans related more to the humpback whale and fishes' than to microbiotas of terrestrial mammals.

Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

BACKGROUND: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. PATIENTS AND METHODS: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. RESULTS: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. CONCLUSION: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells.

Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1high states, characterized by highly active cell proliferation, and EWSR1-FLI1low states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.

Primary subacute epiphyseal osteomyelitis caused by Mycobacterium species in young children: a modern diagnostic approach.

Primary epiphyseal subacute osteomyelitis (PESAO) caused by Mycobacterium species in young children is poorly recognized. We aimed to define the spectrum of this uncommon condition and to propose a novel diagnostic approach. We performed a systematic review of the literature on the PubMed website by selecting all reports of isolated infantile PESAO caused by Mycobacterium species since 1975. We identified 350 citations, of which 174 were assessed for eligibility based on title and abstract. The full text of 81 eligible citations was screened, and relevant data of 15 children under 4 years of age with mycobacterial PESAO were extracted. These data were pooled with those from our Institution. Data from 16 children were reviewed. The median age was 16 ± 7 months and the male:female ratio 1.7. The knee was the most common infection site (94%). The diagnosis of mycobacterial disease was delayed in all cases (range, 2 weeks to 6 months), and initially presumed by histology in 15 children (94%). Microbiologically proven diagnosis was confirmed by bone cultures in 8 of the 15 children (53%), and by specific PCR in 2 of the 3 culture-negative bone specimens (67%). Three children experienced long-term orthopedic complications despite surgical drainage and prolonged antimycobacterial regimens. All recently reported cases came from high-burden tuberculosis areas. Mycobacterium species contribute to the burden of infantile PESAO in endemic tuberculosis areas and may cause growth disturbances. We argue in favor of the early recognition of mycobacterial disease by specific molecular assays in children with infantile PESAO living in high-burden areas.

"Giant cell reparative tumor: An exceptional differential diagnosis for a lytic lesion of the temporal bone".

BACKGROUND AND IMPORTANCE: Giant cell reparative granuloma is a very rare benign osteolytic lesion. It typically arises in the mandible and rarely involves the skull. CLINICAL PRESENTATION: A 25-year-old male was admitted in August 2002 for a painless left preauricular mass of several months duration. CT scan revealed an osteolytic extradural lesion located in the temporal bone, with extension to infratemporal fossa. We performed a surgical partial resection of the tumour via a frontotemporal approach. At 36 months after surgery, the lesion continued growth and subsequently we decided to perform a preauricular infratemporal approach. After a ten year-follow-up, the patient remained asymptomatic and a small tumour remnant was visible and stable. CONCLUSION: Giant cell reparative granulomas that originate from the temporal bone are exceptional. There are no typical radiological features of this disease. Diagnosis is confirmed by analysis of the surgical specimen. Tumor growth requires surgical resection.

Linking the lytic and lysogenic bacteriophage cycles to environmental conditions, host physiology and their variability in coastal lagoons.

Changes in environmental conditions and prokaryote physiology can strongly affect the dynamics of both the lysogenic and lytic bacteriophage replication cycles in aquatic systems. However, it remains unclear whether it is the nature, amplitude or frequency of these changes that alter the phage replication cycles. We performed an annual survey of three Mediterranean lagoons with contrasting levels of chlorophyll a concentration and salinity to explore how these cues and their variability influence either replication cycle. The lytic cycle was always detected and showed seasonal patterns, whereas the lysogenic cycle was often undetected and highly variable. The lytic cycle was influenced by environmental and prokaryotic physiological cues, increasing with concentrations of dissolved organic carbon, chlorophyll a, and the proportion of respiring cells, and decreasing with the proportion of damaged cells. In contrast, lysogeny was not explained by the magnitude of any environmental or physiological parameter, but increased with the amplitude of change in prokaryote physiology. Our study suggests that both cycles are regulated by distinct factors: the lytic cycle is dependent on environmental parameters and host physiology, while lysogeny is dependent on the variability of prokaryote physiology. This could lead to the contrasting patterns observed between both cycles in aquatic systems.

Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution.

BACKGROUND: Pilocytic astrocytomas (PAs) are characterized by an excellent prognosis although several factors of adverse outcome have been reported. The mitogen-activated protein kinase pathway plays a major role in their tumorigenesis. AIM: To report a series of 148 PAs in children to define clinicopathological and biological prognostic factors. METHODS: Clinical data were collected from patient files and mail inquiry. Pathological specimens were centrally reviewed. The three major KIAA1549:BRAF fusion subtypes were analysed by reverse transcription - polymerase chain reaction (RT-PCR) in a subset of 47 frozen cases and by fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue in 23 cases. Tumour location, age at surgery, extent of surgical removal, histological subtype and KIAA1549:BRAF fusion by RT-PCR were searched for prognostic significance. RESULTS: Pilomyxoid astrocytoma (PMA) and the hypothalamo-chiasmatic (H/C) location were associated with a worse prognosis [P < 0.001 for overall survival (OS) and P = 0.001 for progression-free survival (PFS)]. Patients who underwent complete surgical excision had a better OS (P = 0.004) and a longer PFS (P < 0.001) than the others. Age was also a strong prognostic factor for OS but not for PFS. Infants (<1 year) and young children (<3 years) had a much worse outcome than the others (P < 0.001 and P = 0.004 respectively). KIAA1549:BRAF fusion status was not predictive of outcome. CONCLUSION: This study highlights the good prognostic factors of PAs but H/C PA remains a subgroup with dismal prognosis associated with young age, PMA variant and incomplete surgery. Search for KIAA1549:BRAF fusion in tumours with PA pattern is recommended even though the prognostic impact is still unclear.

Value of diffusion-weighted images in differentiating mid-course responders to chemotherapy for osteosarcoma compared to the histological response: preliminary results.

BACKGROUND: Preoperative diffusion-weighted MRI (DW-MRI) has been described as an efficient method to differentiate good and poor responders to chemotherapy in osteosarcoma patients. A DW-MRI performed earlier during treatment could be helpful in monitoring chemotherapy. OBJECTIVE: To assess the accuracy of DW-MRI in evaluating response to chemotherapy in the treatment of osteosarcoma, more specifically at mid-course of treatment. MATERIALS AND METHODS: This study was carried out on a prospective series of adolescents treated for long-bone osteosarcoma. MR examinations were performed at diagnosis (MRI-1), at mid-course of chemotherapy (MRI-2), and immediately before surgery (MRI-3). A DW sequence was performed using diffusion gradients of b0 and b900. The apparent diffusion coefficients (ADC1, ADC2, ADC3, respectively), their differentials (ADC2 - ADC1 and ADC3 - ADC1), and their variation (ADC2 - ADC1/ADC1 and ADC3 - ADC1/ADC1) were calculated for each of these three time points. RESULTS: Fifteen patients were included. Patients with no increase in ADC showed a poor response to chemotherapy on their histology results. At mid-course, the three calculated values were significantly different between good and poor responders. ADC2 - ADC1 enabled us to detect, with 100% specificity, four out of seven of the poor responders. There was no significant difference in the values at MRI-3 between the two groups. CONCLUSION: DW-MRI performed both at baseline and mid-course of neoadjuvant chemotherapy is an efficient method to predict further histological response of osteosarcoma. This method could be used as an early prognostic factor to monitor preoperative chemotherapy.

Histomolecular classification of adult diffuse gliomas: the diagnostic value of immunohistochemical markers.

Adult gliomas are most often infiltrative. The World Health Organization (WHO) has classed them into three major groups according to the presomptive cell of origin: astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Depending on the presence or absence of a small number of signs of anaplasia (mitosis, nuclear atypia, cell density, microvascular proliferation and necrosis) the WHO distinguishes grade II (LGG), III (anaplastic), and IV (glioblastomas, GBM). Mutation in the isocitrate deshydrogenase I and II (IDH1 and 2) genes distinguishes grade II, III and secondary GBM from primary GBM. Moreover two additional genetic alterations are recorded in grade II and III gliomas: TP53 mutations that characterize astrocytomas and 1p19q codeletion (as the result of t(1;19)(q10;p10) translocation) recorded in oligodendrogliomas. Mixed gliomas, the most non-reproducible category, share with astrocytomas and oligodendrogliomas the same genetic alterations. Interestingly TP53 mutation (p53+) and 1p19q codeletion (1p19q+) are mutually exclusive and involve IDH mutated (IDH+) glial precursor cells. According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Interestingly, p53 expression and internexin alpha (INA) expression can replace to some extent TP53 mutation and 1p19 codeletion, respectively. Moreover the antibody directed against the IDH1R132H isoform is highly specific. Because this mutation is the most frequent it is sufficient to assess IDH status in more than 80% of grade II and III gliomas. Taken together these three immunohistochemical markers are contribute greatly to the classification of gliomas and should be tested routinely as diagnostic markers. Finally, although GBM are genetically heterogeneous, the vast majority display EGFR amplification, often associated with EGFR expression, which can be helpful for diagnosis in certain cases.

Phytoplankton distribution and productivity in a highly turbid, tropical coastal system (Bach Dang Estuary, Vietnam).

Phytoplankton diversity, primary and bacterial production, nutrients and metallic contaminants were measured during the wet season (July) and dry season (March) in the Bach Dang Estuary, a sub-estuary of the Red River system, Northern Vietnam. Using canonical correspondence analysis we show that phytoplankton community structure is potentially influenced by both organometallic species (Hg and Sn) and inorganic metal (Hg) concentrations. During March, dissolved methylmercury and inorganic mercury were important factors for determining phytoplankton community composition at most of the stations. In contrast, during July, low salinity phytoplankton community composition was associated with particulate methylmercury concentrations, whereas phytoplankton community composition in the higher salinity stations was more related to dissolved inorganic mercury and dissolved mono and tributyltin concentrations. These results highlight the importance of taking into account factors other than light and nutrients, such as eco-toxic heavy metals, in understanding phytoplankton diversity and activity in estuarine ecosystems.

Trophic interactions between viruses, bacteria and nanoflagellates under various nutrient conditions and simulated climate change.

Population dynamics in the microbial food web are influenced by resource availability and predator/parasitism activities. Climatic changes, such as an increase in temperature and/or UV radiation, can also modify ecological systems in many ways. A series of enclosure experiments was conducted using natural microbial communities from a Mediterranean lagoon to assess the response of microbial communities to top-down control [grazing by heterotrophic nanoflagellates (HNF), viral lysis] and bottom-up control (nutrients) under various simulated climatic conditions (temperature and UV-B radiations). Different biological assemblages were obtained by separating bacteria and viruses from HNF by size fractionation which were then incubated in whirl-Pak bags exposed to an increase of 3°C and 20% UV-B above the control conditions for 96 h. The assemblages were also provided with an inorganic and organic nutrient supply. The data show (i) a clear nutrient limitation of bacterial growth under all simulated climatic conditions in the absence of HNF, (ii) a great impact of HNF grazing on bacteria irrespective of the nutrient conditions and the simulated climatic conditions, (iii) a significant decrease in burst size (BS) (number of intracellular lytic viruses per bacterium) and a significant increase of VBR (virus to bacterium ratio) in the presence of HNF, and (iv) a much larger temperature effect than UV-B radiation effect on the bacterial dynamics. These results show that top-down factors, essentially HNF grazing, control the dynamics of the lagoon bacterioplankton assemblage and that short-term simulated climate changes are only a secondary effect controlling microbial processes.