The impact of the COVID-19 lockdown on drug service provision in European prisons.

PURPOSE: This paper aims to describe the impact of the COVID-19 containment measures on the provision of drug treatment and harm reduction services in European prisons in15 countries during the early phase of the pandemic (March -June 2020). DESIGN/METHODOLOGY/APPROACH: The paper is based on a mixed method research approach that triangulates different data sources, including the results of an on-line survey, the outcome of a focus group and four national case studies. FINDINGS: The emergence of COVID-19 led to a disruption in prison drug markets and resulted in a number of challenges for the drug services provision inside prison. Challenges for health services included the need to maintain the provision of drug-related interventions inside prison, while introducing a range of COVID-19 containment measures. To reduce contacts between people, many countries introduced measures for early release, resulted in around a 10% reduction of the prison population in Europe. Concerns were expressed around reduction of drug-related interventions, including group activities, services by external agencies, interventions in preparation for release and continuity of care. PRACTICAL IMPLICATIONS: Innovations aimed at improving drug service provision included telemedicine, better partnership between security and health staff and an approach to drug treatment more individualised. Future developments must be closely monitored. ORIGINALITY/VALUE: The paper provides a unique and timely overview of the main issues, challenges and initial adaptations implemented for drug services in European prisons in response to the COVID-19 pandemic.

Epigenetic modifiers as new immunomodulatory therapies in solid tumours.

Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described. Results: Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations. Conclusion: In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.

Targeting chromatin defects in selected solid tumors based on oncogene addiction, synthetic lethality and epigenetic antagonism.

Background: Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors. Material and methods: We reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. Experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described. Results: The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1-deficient malignant rhabdoid tumors and SMARCA4-deficient ovarian small cell carcinomas. Clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between EZH2 inhibitors and deficiencies in components of the Polycomb or SWI/SNF chromatin-remodeling complexes (including BAP1, ARID1A and PBRM1 subunits), as well as between the CREBBP and EP300 histone acetylases. Further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs. Conclusion: Epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly selected patient populations have facilitated recent successes in proof-of-concept studies in solid tumors. Appropriate clinical trial design and molecular patient selection will be key for the success of epigenetic modifiers in solid tumours.

Effects of whole body vibration exercises on bone mineral density of women with postmenopausal osteoporosis without medications: novel findings and literature review.

OBJECTIVES: The aim of this study was to review the literature about the effect of whole body vibration exercise in the BMD in patients with postmenopausal osteoporosis without medications. METHODS: A systematic review was performed. RESULTS: The frequency of the mechanical vibration used in the protocols has varied from 12 to 90 Hz. The time used in the protocols varied from 2 up to 22 months. Techniques with X-rays were used in nine of the twelve publications analyzed, the Dual energy X-ray absorptiometry (DEXA) in eight studies and the High resolution peripheral quantitative computed tomography (HR-pQCT) in one publication. The concentration of some biomarkers was determined, as the sclerostin, the bone alkaline phosphatase, N-telopeptide X and 25-hydroxyvitamin D. Among the twelve articles analyzed, seven of them have shown an improvement of the BMD of some bone of postmenopausal women exposed to whole body vibration exercises not associated to medications; as well as modifications in biomarkers.

Pertinence of the Sysmex XE-5000™ parameters: rule of slide review in a context of 'normal' lymphocyte count (defined from control and mantle cell lymphoma blood specimens).

INTRODUCTION: As most hematology cell analyzers, the different parameters of Sysmex XE-5000™ are little informative in the qualitative analysis of lymphoid cells, and especially when the lymphocyte count is below 4 × 10(9) /L (i.e., 'normal'). The aim of our study was to investigate whether some parameters and/or 'flags' not routinely provided by this analyzer, but reachable by operator could be reliable to define rules of slide review in absence of common qualitative and quantitative alarms particularly in case of 'normal' lymphocyte count. METHODS: Blood samples from 13 mantle cell lymphoma fully annotated cases, and 180 control specimens were studied with Sysmex XE-5000™ analyzer. All cases did not present any anomalies in common quantitative and structural parameters. RESULTS: Using the method of area under the curve and ROC curve analysis, we described a novel threshold of alarm VAL_ABN LYMPH (≥40 instead of 100 defined by Sysmex), as well as a pertinent LyX threshold (≥89). The combination of these thresholds allowed defining a rule of slide review in context of 'normal' lymphocyte count. CONCLUSION: Among the parameters provided by the Sysmex XE-5000™ analyzer, the combination of the alarm VAL_ABN LYMPH and the LyX value, routinely available on a simple blood analysis appears particularly informative to trigger slide review in a context of 'normal' lymphocyte count with a good sensitivity (85%) to detect circulating lymphoma cells and with <1% of false positive results.

Interobserver concordance in the assessment of features used for the diagnosis of cervical atypical squamous cells and squamous intraepithelial lesions (ASC-US, ASC-H, LSIL and HSIL).

OBJECTIVES: Given the well-known poor reproducibility of cervical cytology diagnosis, especially for atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL), this study surveyed reproducibility in the assessment of individual cytomorphological features. METHODS: One hundred and fifty cells or groups of cells, with a variety of morphological appearances, including normal cells, high-grade squamous intraepithelial lesion (HSIL), LSIL, ASC-US and ASC cannot exclude HSIL (ASC-H), were precisely marked on 150 different liquid-based cytological preparations. They were analysed by 17 observers who assessed 17 cytological features including nuclear features (chromatin texture, nuclear outline, nuclear shape, etc.), cytoplasmic features (cell shape, cytoplasmic staining, cytoplasmic clearing, etc.) and group characteristics (nuclear polarity, cellular density, etc.). A total of 43,350 data scores were collected in a database using a web-based survey. Kendall's W and relative entropy indexes were utilized to compute concordance indexes of respectively ordinal and nominal variables. RESULTS: Nuclear features have significantly lower reproducibility (0.46) compared with other cytological features (0.59). The feature with least agreement is assessment of chromatin texture. A small but significant difference in concordance was found between two subsets of observers with different levels of experience. CONCLUSION: Most previous studies assessing reproducibility of cytological diagnoses show, at best, moderate reproducibility among observers. This study focused on agreement regarding the presence of constituent morphological features used to recognize dyskaryosis and various grades of squamous intraepithelial lesions. A map of reproducibility indexes is presented that highlights, for daily practice or teaching, the robustness of features used for cytological assessment, recognizing that diagnosis is always based on a combination of features.

Preemptive therapy versus valgancyclovir prophylaxis in cytomegalovirus-positive kidney transplant recipients receiving antithymocyte globulin induction.

International consensus guidelines on the management of cytomegalovirus (CMV) infections in kidney transplantation recommend the use of universal prophylaxis over preemptive therapy for the highest risk kidney transplant recipients (KTR), namely donor+/recipient - CMV serostatus. However, no universal recommendations have been made for R+ KTR undergoing antithymocyte globulin (ATG) induction. In this retrospective study, we compared 1-year outcomes among 24 R+ KTR who received 3 months of valgancyclovir prophylaxis with 72 R+ KTR who were subjected to a preemptive strategy. All subjects received ATG induction. The incidence of CMV infection was significantly higher among the preemptive subjects versus the prophylaxis group (78% versus 38%, respectively; P = .0003), whereas the incidence of CMV disease was low and did not differ significantly between the cohorts (8% versus 7% respectively, P = .8). Late-onset CMV infections were only observed in the prophylaxis group (25% versus 0%, P = .0001). Finally, the rate of opportunistic infections, acute rejection episodes, and graft/patient survivals at 1 year were also similar between the two groups. In light of this study, preemptive therapy and universal prophylaxis were almost equally effective to prevent CMV infection among R+ KTR receiving ATG induction.

High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy.

Anti-cytomegalovirus (CMV) prophylaxis is recommended in D+R- kidney transplant recipients (KTR), but is associated with a theoretical increased risk of developing anti-CMV drug resistance. This hypothesis was retested in this study by comparing 32 D+R- KTR who received 3 months prophylaxis (valganciclovir) with 80 D+R- KTR who received preemptive treatment. The incidence of CMV infections was higher in the preemptive group than in the prophylactic group (60% vs. 34%, respectively; p = 0.02). Treatment failure (i.e. a positive DNAemia 8 weeks after the initiation of anti-CMV treatment) was more frequent in the preemptive group (31% vs. 3% in the prophylactic group; p = 0.001). Similarly, anti-CMV drug resistance (UL97 or UL54 mutations) was also more frequent in the preemptive group (16% vs. 3% in the prophylactic group; p = 0.05). Antiviral treatment failures were associated with anti-CMV drug resistance (p = 0.0001). Patients with a CMV load over 5.25 log(10) copies/mL displayed the highest risk of developing anti-CMV drug resistance (OR = 16.91, p = 0.0008). Finally, the 1-year estimated glomerular filtration rate was reduced in patients with anti-CMV drug resistance (p = 0.02). In summary, preemptive therapy in D+R- KTR with high CMV loads and antiviral treatment failure was associated with a high incidence of anti-CMV drug resistance.

[Functional insulin therapy courses adapted to the patient's reality]. / Cours d'insulinothérapie fonctionnelle adaptés au vécu du patient.

Therapeutic education was initially developed in the field of diabetology. In this chronic disease, it is the patient who is the major decision-maker. R. K. Bernstein is probably the first patient to have practised self glucose monitoring. He developed the basal-bolus technique for himself, which prompted the creation of functional insulin therapy courses by European physicians. This experiential approach has been adapted and simplified for patients in order to facilitate their management of uncertainty. The ASKAR method offers a frame of reference for the development of teaching-learning sequences. The acronym ASKAR refers to the five components of a person's experience: Action, Situation, Knowledge, Attitude and Resource. Working on these five components is a way for patients to improve their management of uncertainty.

Relevance of a scoring system including CD11c expression in the identification of splenic diffuse red pulp small B-cell lymphoma (SRPL).

'Splenic red pulp lymphoma with numerous basophilic villous lymphocytes' (SRPL), recently described, is characterized by clinical, morphologic, immunologic, cytogenetic and molecular features distinct from SMZL/SLVL and HCL. In particular, the intensity of CD11c staining (expressed as fluorescence intensity -RFI-) in SRPL is significantly different from the RFI in SMZL/SLVL and HCL. Moreover the use of a scoring system based on the expression of CD11c, CD22, CD76, CD38 and CD27 appears to improve the differential diagnosis between SRPL and SMZL/SLVL and emphasizes that SRPL is an entity closed to but distinct from SMZL/SLVL.

An acquired inhibitor to the GPVI platelet collagen receptor in a patient with lupus nephritis.

BACKGROUND: GPVI is a major platelet collagen signaling receptor. In rare cases of immune thrombocytopenic purpura (ITP), autoantibodies to GPVI result in receptor shedding. OBJECTIVES: To investigate a possible pathogenic role of plasma anti-GPVI antibody located in a woman with lupus nephritis. METHODS: Measured were (i) platelet aggregation to collagen and convulxin, (ii) platelet GPVI expression (flow cytometry and western blotting), (iii) plasma soluble GPVI (sGPVI, dual antibody ELISA), and (iv) plasma anti-GPVI antibody (ELISA using recombinant sGPVI). RESULTS: In 2006 and early 2007, the patient had a normal platelet count but a virtual absence of platelet aggregation to collagen and convulxin. Her platelets responded normally to other agonists including cross-linking ITAM-dependent FcgammaRIIA by monoclonal antibody, IV.3. Flow cytometry and western blotting showed a platelet deficiency of GPVI. Plasma sGPVI levels were undetectable whereas ELISA confirmed the presence of anti-GPVI antibody. Sequencing revealed a normal GPVI cDNA structure. The patient's plasma and the isolated IgG3 fraction activated and induced GPVI shedding from normal platelets. A deteriorating clinical condition led to increasingly strict immunosuppressive therapy. This was globally associated with a fall in plasma anti-GPVI titres, the restoration of platelet GPVI and the convulxin response, and the loss of her nephrotic syndrome. CONCLUSIONS: Our results show that this patient acquired a potent anti-GPVI IgG3 antibody with loss of GPVI and collagen-related platelet function. Further studies are required to determine whether anti-GPVI antibodies occur in other lupus patients with nephritis.

Synergetic bitherapy in mice with xenografts of human prostate cancer using a methional mimic (METLICO) and an aldehyde dehydrogenase 3 inhibitor (MATE): systemic intraperitoneal (IP) and targeted intra-tumoral (IT) administration.

An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.

In vivo myocardial infarct area at risk assessment in the rat using manganese enhanced magnetic resonance imaging (MEMRI) at 1.5T.

The aim of this study was to measure the myocardial area at risk in rat, using MRI and manganese injection during a coronary occlusion/reperfusion model at 1.5T. A sequential protocol with occlusion and MnCl2 injection immediately followed by MRI was used with the assumption that MnCl2-induced contrast persistence is enough to accurately image the area at risk 90 min after occlusion. A total of 15 adult rats underwent a single 30-min episode of coronary occlusion followed by reperfusion. MnCl2 was injected (25 micromol/kg) at the beginning of the occlusion for 11 rats (group 1) and 6 h after reperfusion for four animals (group 2). A deficit of signal enhancement was observed in all rats. Hypoenhancement area in group 1 was correlated to the area at risk delineated by methylene blue (r=0.96, P<0.0001) whereas in group 2 it was correlated to the infarct area given by triphenyltetrazolium chloride (TTC) solution (r=0.98, P=0.003). The area at risk size was significantly correlated with left ventricle ejection fraction (LVEF), end-systolic volume and anterolateral wall thickening. This work demonstrates that hypoenhanced zone obtained after manganese injection during occlusion represents the area at risk and not only the infarct zone.

Implication of dipeptidylpeptidase IV activity in human bronchial inflammation and in bronchoconstriction evaluated in anesthetized rabbits.

BACKGROUND: Decreased dipeptidylpeptidase IV (DPPIV) activity within the human nasal mucosa has previously been shown to contribute to the severity of chronic inflammatory rhinosinusitis. OBJECTIVE: To investigate and correlate the role of DPPIV activity with regard to bronchial inflammation. METHODS: DPPIV/CD26 activity/concentration was investigated in the bronchial tissue of human subjects suffering from chronic bronchial inflammation. In addition, the effect of a recombinant Aspergillus fumigatus DPPIV (fuDPPIV) was investigated on histamine-induced bronchoconstriction in anesthetized rabbits. RESULTS AND CONCLUSIONS: DPPIV/CD26 was present in submucosal seromucous glands, in leukocytes and to a very low degree in endothelial cells of human bronchi. DPPIV activity was correlated with tissue CD26 content measured by immunoassay. As previously reported for the nasal mucosa, DPPIV/CD26 activity was inversely correlated with the degree of airway inflammation. Systemic pretreatment with recombinant fuDPPIV markedly reduced the increase in histamine-induced airway resistance in rabbits. In conclusion, DPPIV activity modulates lower airway tone by degrading unknown peptidic substrates released by histamine in response to an allergen. Contrasting with our observations in the nose, this modulation is apparently not mediated via a neurokinin (NK1) receptor.

Protective effects of volatile agents against acetylcholine-induced bronchoconstriction in isolated perfused rat lungs.

BACKGROUND: Bronchoactive properties of volatile agents against lung constriction are well established. The purpose of this study was to investigate the ability of halothane (Hal), isoflurane (Iso), sevoflurane (Sev) and desflurane (Des) to alter the lung mechanics in the absence of an airway tone and during acetylcholine (Ach)-induced bronchoconstriction. METHODS: Low-frequency pulmonary impedance data (ZL) were collected from isolated, normo-perfused rat lungs under baseline conditions and following the injection of Ach (0.1 mg/kg) into the pulmonary artery. Measurements were performed without the administration of any anaesthetic agent in the first phase of the experiments and during inhalation without any volatile agent (control group, n = 6) or during inhalation of Hal (n = 6), Iso (n = 9), Sev (n = 6) or Des (n = 8) at 1 minimum alveolar concentration (MAC). The airway resistance (Raw) and parenchymal damping and elastance were estimated from the Z(L) data by model fitting. RESULTS: Under baseline conditions, the basic value of Raw was significantly decreased by Des (- 31.2 +/- 3.8%) and Sev (- 18.0 +/- 4.5%) administration, whereas Hal and Iso did not have a statistically significant effect on Raw (- 3.3 +/- 5.1% and - 8.6 +/- 2.4%, respectively). Moreover, all four inhalation anaesthetics prevented the increase in Raw following Ach administration, the findings ranging between - 14.3 +/- 11.4% for Hal and - 37.5 +/- 10.9% for Sev. CONCLUSIONS: Our results on a denervated isolated perfused lung model demonstrate the potential of Des and Sev to decrease the basal airway tone, whereas Iso and Hal are ineffective in this regard. All of these volatile agents markedly protect against Ach-induced bronchoconstriction.

Optimization of cardiac cine in the rat on a clinical 1.5-T MR system.

OBJECT: The overall goal was to study cardiovascular function in small animals using a clinical 1.5-T MR scanner optimizing a fast gradient-echo cine sequence to obtain high spatial and temporal resolution. MATERIALS AND METHODS: Normal rat hearts (n = 9) were imaged using a 1.5-T MR scanner with a spiral fast gradient-echo (fast field echo for Philips scanners) sequence, three Cartesian fast gradient-echo (turbo field echo for Philips scanners) sequences with different in-plane resolution, and with and without flow compensation and half-Fourier acquisition. The hearts of four rats were then excised and left-ventricle mass was weighed. Inter- and intra-observer variability analysis was performed for magnetic resonance imaging (MRI) measurements. RESULTS: Half-Fourier acquisition with flow compensation gave the best sequence in terms of image quality, spatial as well as temporal resolution, and suppression of flow artifact. Ejection fraction was 71 +/- 4% with less than 5% inter- and intra-observer variability. A good correlation was found between MRI-calculated left-ventricular mass and wet weight. CONCLUSIONS: Using optimized sequences on a clinical 1.5-T MR scanner can provide accurate quantification of cardiac function in small animals and can promote cardiovascular research on small animals at 1.5-T.

Identification of circulating CD10 positive T cells in angioimmunoblastic T-cell lymphoma.

In most cases of lymphomas with blood dissemination, the careful cytological analysis of peripheral blood smears provides a rapid orientation to diagnosis, even if the final subtyping is achieved by histology and eventually other techniques. Here, we evaluated if the analysis of blood smears may suggest the blood dissemination of angioimmunoblastic T-cell lymphoma (AITL) and if CD10 expression on neoplastic T cells, as recently reported on AITL, may contribute to the diagnosis. In all, 11 lymph nodes and six peripheral blood samples from 12 patients with AITL were studied using four-colour flow cytometry associated to histological, cytological and molecular data. According to previous results, a fraction of T cells expressed CD10 in 10/11 lymph nodes. Interestingly, all blood smears showed atypical lymphoid cells and a fraction of T cells expressed CD10 with a mean percentage of 18.75% (range 5.00-47.00%), regardless of lymphocytosis level and of rate of CD10 T cells in corresponding lymph node. In contrast, in all control samples (100), none CD10-positive T cell was identified. This is to our knowledge the first description of circulating CD10 neoplastic T cells in AITL. Therefore, they ought to be explored in further studies when aggressive lymphoma, in particular with lymphopenia and circulating atypical cells, is suspected.

Time and tidal volume-dependent ventilator-induced lung injury in healthy rats.

BACKGROUND AND OBJECTIVE: We evaluated the effect of duration of mechanical ventilation with different tidal volumes (VT) on ventilator-induced lung injury in healthy rats. METHODS: Anaesthetized rats were ventilated with VT between 9 and 45 mL kg[-1] for 1 or 7 h with a positive end-expiratory pressure of 2.5 cmH2O. RESULTS: After 1 h, rats ventilated even with the highest applied VT (36 and 45 mL kg[minus sign]1, resulting in average peak airway pressures of 30 +/-3 and 37 +/- 4 cmH2O), had no detectable alterations in dynamic or static lung mechanics, gas exchange or pulmonary permeability, but a moderate degree of lung inflammation (neutrophil accumulation in broncho-alveolar lavage) observed in all groups. In contrast, after 3 h of ventilation, rats ventilated with the highest VT (36 and 45 mL kg[minus sign]1) died from progressive circulatory failure and high-permeability pulmonary oedema, manifested by hypoxaemia, an increased alveolar-arterial protein concentration ratio and a reduced static lung compliance (mortality rate at 7 h, 62.5% and 100%). Animals with lower VT all survived and presented no changes in the measured variables. CONCLUSION: These results in normal rats demonstrate the preponderant effect of the duration (>3 h) of 'aggressive' ventilation and the cut-off value of the level of VT applied (>27 mL kg[minus sign]1).