Evolution of baseline characteristics and severe outcomes in COVID-19 inpatients during the first and second waves in Northeastern France.

OBJECTIVES: Two COVID-19 epidemic waves occurred in France in 2020. This single-center retrospective study compared patients' characteristics and outcomes. PATIENTS AND METHODS: We included all patients with confirmed COVID-19 admitted to Colmar Hospital in March (n=600) and October/November (n=205) 2020. RESULTS: Median ages, sex ratio, body mass index, and number of comorbidities were similar in wave 1 and 2 patients. Significant differences were found for temperature (38°C vs. 37.2), need for oxygen (38.6% vs. 26.8%), high-flow cannula (0% vs. 8.3%), and steroid use (6.3% vs. 54.1%). Intensive care unit (ICU) hospitalizations (25.5% vs. 15.1%, OR: 0.44, 95% CI [0.28; 0.68], P=0.002) and deaths (19.2% vs. 12.7%, OR: 0.61, 95% CI [0.37; 0.98], P=0.04) decreased during the second wave. Except for cardiovascular events (5.5% vs. 10.2%), no change was observed in extrapulmonary events. CONCLUSIONS: Deaths and ICU hospitalizations were significantly reduced during the second epidemic wave.

Predictors of mortality, ICU hospitalization, and extrapulmonary complications in COVID-19 patients.

OBJECTIVE: A major coronavirus disease 2019 (COVID-19) outbreak occurred in Northeastern France in spring 2020. This single-center retrospective observational cohort study aimed to compare patients with severe COVID-19 and those with non-severe COVID-19 (survivors vs. non-survivors, ICU patients vs. non-ICU patients) and to describe extrapulmonary complications. PATIENTS AND METHODS: We included all patients with a confirmed diagnosis of COVID-19 admitted to Colmar Hospital in March 2020. RESULTS: We examined 600 patients (median age 71.09 years; median body mass index: 26.9 kg/m2); 57.7% were males, 86.3% had at least one comorbidity, 153 (25.5%) required ICU hospitalization, and 115 (19.1%) died. Baseline independent factors associated with death were older age (>75 vs. ≤75 years), male sex, oxygen supply, chronic neurological, renal, and pulmonary diseases, diabetes, cancer, low platelet and hemoglobin counts, and high levels of C-reactive protein (CRP) and serum creatinine. Factors associated with ICU hospitalization were age <75 years, oxygen supply, chronic pulmonary disease, absence of dementia, and high levels of CRP, hemoglobin, and serum creatinine. Among the 600 patients, 80 (13.3%) had an acute renal injury, 33 (5.5%) had a cardiovascular event, 27 (4.5%) had an acute liver injury, 24 (4%) had venous thromboembolism, eight (1.3%) had a neurological event, five (0.8%) had rhabdomyolysis, and one had acute pancreatitis. Most extrapulmonary complications occurred in ICU patients. CONCLUSION: This study highlighted the main risk factors for ICU hospitalization and death caused by severe COVID-19 and the frequency of numerous extrapulmonary complications in France.

[Perforating and ruptured trichilemmal cyst with metaplastic ossification]. / Perforierende rupturierte Trichilemmalzyste mit metaplastischer Ossifikation.

Trichilemmal cysts can occur as multiple scalp lesions and may have a familial history. Metaplastic ossification, as seen in several traumatic, inflammatory or neoplastic conditions, however, seems to be an exceedingly rare event in trichilemmal cysts and might be associated with previous rupture.

The molecular phenotype of 6-week protocol biopsies from human renal allografts: reflections of prior injury but not future course.

We assessed the molecular phenotype of 107 6-week protocol biopsies from human renal allografts, using Affymetrix microarrays. Transcript changes were summarized as nonoverlapping pathogenesis-based transcript sets (PBTs) reflecting inflammation (T cells, macrophages, IFNG effects) and the injury-repair response of the parenchyma, stroma and microcirculation-increased ('injury-up') and decreased ('injury-down') transcripts. The molecular changes were highly correlated with each other, even when all rejection and borderline cases were excluded. Inflammation and injury-down PBTs correlated with histologic inflammation and tubulitis, and the inflammation transcripts were greater in kidneys diagnosed as T cell-mediated or borderline rejection. Injury-up PBTs did not correlate with histopathology but did correlate with kidney function: thus functional disturbances are represented in transcript changes but not in histopathology. PBT changes correlated with prior delayed graft function. However, there was little difference between live donor kidneys and deceased donor kidneys that had not shown delayed graft function. Molecular changes did not predict future biopsies for clinical indications, rejection episodes, functional deterioration or allograft loss. Thus while detecting T cell-mediated inflammation, the molecular phenotype of early protocol biopsies mostly reflects the injury-repair response to implantation stresses, and has little relationship to future events and outcomes.

Loss of solute carriers in T cell-mediated rejection in mouse and human kidneys: an active epithelial injury-repair response.

T cell-mediated rejection of kidney allografts causes epithelial deterioration, manifested by tubulitis, but the mechanism remains unclear. We hypothesized that interstitial inflammation triggers a stereotyped epithelial response similar to that triggered by other types of injury such as ischemia-reperfusion. We identified solute carrier transcripts with decreased expression in mouse allografts, and compared their behavior in T cell-mediated rejection to native kidneys with ischemic acute tubular necrosis (ATN). Average loss of solute carrier expression was similar in ATN (77%) and T cell-mediated rejection (75%) with high correlation of individual transcripts. Immunostaining of SLC6A19 confirmed loss of proteins. Analysis of human kidney transplant biopsies confirmed that T cell-mediated rejection and ATN showed similar loss of solute carrier mRNAs. The loss of solute carrier expression was weakly correlated with interstitial inflammation, but kidneys with ATN showed decreased solute carriers despite minimal inflammation. Loss of renal function correlated better with decreased solute carrier expression than with histologic lesions (r = 0.396, p < 0.001). Thus the loss of epithelial transcripts in rejection is not a unique consequence of T cell-mediated rejection but an active injury-repair response of epithelium, triggered by rejection but also by other injury mechanisms.

Alternative macrophage activation-associated transcripts in T-cell-mediated rejection of mouse kidney allografts.

Macrophages display two activation states that are considered mutually exclusive: classical macrophage activation (CMA), inducible by IFNG, and alternative macrophage activation (AMA), inducible by IL4 and IL13. CMA is prominent in allograft rejection and AMA is associated with tissue remodeling after injury. We studied expression of AMA markers in mouse kidney allografts and in kidneys with acute tubular necrosis (ATN). In rejecting allografts, unlike interferon gamma (IFNG) effects and T-cell infiltration that developed rapidly and plateaued by day 7, AMA transcripts (Arg1, Mrc1, Mmp12 and Ear1) rose progressively as tubulitis and parenchymal deterioration developed at days 21 and 42, despite persistent IFNG effects. AMA in allografts was associated with transcripts for AMA inducers IL4, IL13 and inhibin A, but also occurred when hosts lacked IL4/IL13 receptors, suggesting a role for inhibin A. Kidneys with ATN injured by ischemia/reperfusion also had increased expression of AMA markers and inhibin A. Thus kidneys undergoing T-cell-mediated rejection progressively acquire macrophages with alternative activation phenotype despite strong local IFNG effects, independent of IL4 and IL13. Although the mechanisms and causal relationships remain to be determined, high AMA transcript levels in rejecting allografts are strongly associated with and may be a consequence of parenchymal deterioration similar to ATN.

Fish, flesh and a good red herring: a case of ascending upper limb infection in a renal transplant patient.

While newly developed potent immunosuppressive agents have dramatically reduced the incidence of rejection of transplanted organs, they have increased the patients' susceptibility to opportunistic infections and cancer. Here we report a rare skin infection caused by atypical mycobacterium marinum in a 50-year-old female renal transplant recipient. The patient presented with localized skin lesion on the dorsum of her hand, which was misdiagnosed as gout. Only after the lesions spread in a sporotrichoid pattern, a cutaneous infection with atypical mycobacteria was suspected. The diagnosis was based on histopathological analysis as well as mycobacterial culture, both showing infection with atypical mycobacterium. Three months of antimycobacterial treatment led to a marked regression of the lesions. Sporotrichoid lesions in renal transplant patients are rare and a diagnostic challenge for the physician. A thorough history and a low threshold for skin biopsies could prevent painful and unnecessary surgical interventions.

Donor Fas is not necessary for T-cell-mediated rejection of mouse kidney allografts.

It is important to resolve whether T-cell-mediated rejection (TCMR) is mediated by contact-dependent cytotoxicity or by contact-independent inflammatory mechanisms. We recently showed that the cytotoxic molecules perforin and granzymes A and B are not required for TCMR of mouse kidney transplants. Nevertheless, TCMR could still be mediated by cytotoxicity via Fas on donor cells engaging Fas ligand on host T cells. We examined whether the diagnostic TCMR lesions would be abrogated if donor Fas was absent, particularly in hosts deficient in perforin or granzymes A and B. Kidneys from Fas-deficient donors transplanted into major histocompatibility complex (MHC)- mismatched hosts developed tubulitis and diffuse interstitial infiltration indistinguishable from wild-type (WT) allografts, even in hosts deficient in perforin and granzymes A and B. Gene expression analysis revealed similar molecular disturbances in Fas-deficient and WT allografts at day 21 transplanted into WT, perforin and granzyme A/B-deficient hosts, indicating epithelial injury and dedifferentiation. Thus, donor Fas is not necessary for TCMR diagnostic lesions or molecular changes, even in the absence of perforin-granzyme mechanisms. We propose that in TCMR, interstitial effector T cells mediate parenchymal injury by inflammatory mechanisms that require neither the perforin-granzyme nor the Fas-Fas ligand cytotoxic mechanisms.

Chemical substances and contact allergy--244 substances ranked according to allergenic potency.

From 1985 to 2001 a group consisting of thirty experts including dermatologists from universities, representatives from the chemical industry and from regulatory authorities elaborated and consequently decided on the potency ranking of chemicals with contact allergenic properties. These chemicals were defined either as synthetic chemicals or as chemicals identified as ingredients in natural products. On 244 substances clinical and experimental data on humans and results of animal tests as documented in the scientific literature were carefully collected and evaluated. This careful evaluation and assessment of these chemicals clearly demonstrate that ranking of substances according to their allergenic potency is possible and justified. It was decided to rank the most potent contact allergens in Category A of substances having significant allergenic properties. Substances with a solid-based indication of a contact allergenic potential and substances with the capacity of cross-reactions were listed in Category B and substances with insignificant or questionable allergenic effects were listed in Category C. An assessment of these compiled data is published here. Three Appendices give a comprehensive overview of the 98 substances listed in Category A, the 77 substances listed in Category B and the 69 substances listed in Category C.

[Comparison of mechanical properties of orthodontic nickel-titanium wires]. / Vergleich mechanischer Eigenschaften orthodontischer Nickel-Titan-Drähte.

Two packages each, containing 10 wires per package, of different batches of 25 different types of orthodontic archwires made of super-elastic nickel-titanium alloys measuring 0.41 x 0.56 mm2, were investigated. The wires were characterized by obtaining the following measurements at an ambient temperature of 37 degrees: a three-point bending test with the supporting points spaced 10 mm apart, and determination of the torque/bending angle curves using a pure bending test. The force/deflection curves provided the parameters characterizing the super-elastic unloading plateau: average force, slope and endpoint. From the torque/bending angle curves, the parameters average torque, plateau endpoint and the elasticity parameters were determined. Average force (0.8-4.5 N), endpoint (0.2-0.9 mm) and the slope of the unloading plateau (0.2-2.1 N/mm) of the three-point bending test clearly differed for individual wires. Significant differences were also seen for average torque (1.5-11.5 Nmm), unloading plateau endpoint (2.7-20.0 degrees) and elasticity parameters epsilon 4, E4, E5 and E6 in the pure bending test. Individual batches showed only minor differences. The results permit the conclusion to be drawn that super-elasticity is applicable to only a small portion of the wires examined. Although other wires showed super-elastic behaviour, the unloading plateaus has a force level of up to 6 N, and cannot be recommended for orthodontic application. The super-elastic plateau is often of use only for deflections greater than 1.5 mm. The use of super-elastic archwires made of nickel-titanium alloys makes sense only when the elastic properties of the respective wires are known. This makes the provision by the manufacturer of relevant data on the elastic properties of wires a necessity.

[Delivery of desflurane by a Tec 6 vaporizer at a concentration superior to that posted on the regulating valve]. / Libération par un vaporisateur Tec 6 de desflurane à une concentration supérieure à celle affichée sur le bouton de réglage.

We report the case of a defective Tec 6 vaporizer (Datex-Ohmeda) which delivered higher concentrations of desflurane (end-tidal concentration: 3.5 vol%) than indicated by the vaporizer dial setting (2 vol%), at a fresh gas flow of 1 L.min-1. This condition was caused by a defective rotary control valve. Therefore it is essential to administer desflurane only in presence of a vapour analyser.

The dermal acute toxic class method: test procedures and biometric evaluations.

A dermal acute toxic class (ATC) method is presented with the use of significantly fewer animals in comparison with the classical dermal 50% lethal dose (LD50) test. The principle of the dermal ATC method is based on the oral and the inhalation ATC method. The method was developed for three fixed starting doses. Depending on the dermal LD50, the slope, the classification system and the starting dose on average 40 to 90% fewer animals will be used in comparison to at least 30 animals with the dermal LD50 test. The method was biometrically evaluated by using the Probit model for dose-response relationships. At present, there are eight different international classification systems based on dermal LD50 values. The test procedures and the calculations of the classification probabilities demonstrate that the dermal ATC method is a reliable alternative to the dermal LD50 test with the use of significantly fewer animals. Classification probabilities are presented for all classification systems currently in use, and expected numbers of experimental and of moribund/dead animals are demonstrated for the system of chemicals in the European Union for all three starting doses. The conclusion is justified that, similarly to the inhalation ATC method, there is no need to validate the dermal ATC method with the use of experimental animals.

The inhalation acute toxic class method: test procedures and biometric evaluations.

A method of inhalation acute toxic (ATC) classification is presented with the use of significantly fewer animals in comparison with the classical LC50 test. The principle of the inhalation ATC method is based on the oral ATC method, which has been adopted in 1996 as an official test guideline of the OECD and the European Union. The inhalation ATC method, like the oral ATC method, is a stepwise procedure; three animals of each sex are used simultaneously for each tested concentration, and not, as in the oral ATC method, three animals of each sex separately for each dose. The method was developed for three starting concentrations and two reference systems (based on ppm and mg/l). Depending on the LC50, slope, classification system and starting concentration, on average 50 to 80% fewer animals will be used in comparison to at least 30 animals with the classical LC50 test. The method was biometrically evaluated with the use of the probit model for dose-response relationships. At present, there are 12 different international classification systems based on LC50 values: 6 systems referring to mg/litre and 6 systems based on ppm values, and exposure time varying from 1 to 4 h. The test procedures and the calculations of the classification probabilities demonstrate that the inhalation ATC method is a reliable alternative to the classical LC50 test with the use of significantly fewer animals. Classification probabilities are presented for all classification systems currently in use, and expected numbers of experimental and of moribund/dead animals are demonstrated for one system of each reference system and for all three starting concentrations. The conclusion is justified that there is no need to validate the inhalation ATC method with the use of experimental animals.

The international validation study of the acute toxic class method (oral).

An alternative to the oral LD50 test, the acute toxic class (ATC) method (oral), was validated with 20 substances in an international collaborative study with nine laboratories in five countries. The ATC method is a stepwise procedure with the use of three animals per step. It has been designed with three fixed doses (25, 200 and 2000 mg/kg). In general, this testing is sufficient for allocation to the toxicity classes of the majority of the international classification systems currently in use. The selection of testing at additional fixed doses (5, 50 and 500 mg/kg) may be considered if further refinement is necessary or for specific allocation to those international classification systems with a cut-off value of 5 mg/kg. On average, two to four steps are necessary to complete a test. With the ATC method substances can be ranked in a similar or even better manner than with an LD50 test but it uses up to 90% fewer animals, the average being 70% fewer. This also results in substantially fewer moribund/dead animals. The ATC method is based on biometric evaluations that, together with the experimental results, demonstrate that this method is a sensitive and reliable alternative to the LD50 test.

The biometric evaluation of the acute-toxic-class method (oral).

The acute toxic class method (ATC method) is an alternative to the LD50 test, with the use of substantially fewer animals needed for the classification of substances. Like the classical LD50 test the biometry of the ATC method is based on the probit model. The biometric calculations of the ATC method were carried out not only for the classification categories of the European Union but also for the classification criteria of various countries and organizations, currently in use. It is demonstrated that in comparison with the LD50 test in general the same classification is obtained with the ATC method and with the use of substantially fewer animals. Substances with high slopes are likely to be allocated to the predicted toxicity class in comparison with substances having low slopes, with both the ATC method and the LD50 test. Substances are more likely to be allocated into a lower toxicity class with the LD50 test than with the ATC method.

A national validation study of the acute-toxic-class method--an alternative to the LD50 test.

In a national collaborative study an alternative to the classical LD50 test--the acute-toxic-class method--was validated. With this testing procedure mortality ranges are determined between defined dose levels that are used for classification and labelling in the European Community. The results were compared with LD50 data obtained from the literature which were categorized according to the defined dose levels. The results of this collaborative study have shown that the acute-toxic-class method allows allocation to the toxicity classes of very toxic, toxic, harmful and unclassified in the same manner as on the basis of the classical LD50 tests. The acute-toxic-class method uses fewer animals and subjects fewer animals to pain and distress than the LD50 test and yields the same information on toxic signs in the treated animals. Identical classifications were obtained by the six participating laboratories in 86% of the tests. This demonstrates that the acute-toxic-class method results in excellent reproducibility in comparison to the classical LD50 test and that this new method is a reliable alternative to the LD50 test.

[Long-term results following surgery or radioiodine treatment of solitary autonomous adenoma of the thyroid gland]. / Langzeitergebnisse nach Operation oder Radiojodbehandlung des solitären autonomen Adenoms der Schilddrüse.

128 patients were investigated after surgery (n = 72) or 131-iodine therapy (n = 56) of a scintigraphically solitary, hyperfunctioning adenoma of the thyroid gland. The median follow-up period amounted to 10.6 years. Recurrent hyperthyroidism was observed in six patients after surgery and in one patient after 131-iodine therapy. Hypothyroidism occurred in one patient after 131-iodine therapy. The percentage of 131-iodine treated patients with a normal TSH-response to TSH-releasing hormone (TRH) increased during the follow-up period from 57 to 90%, whereas after surgery the percentage of patients showing a normal TSH-response to TSH decreased from 58 to 31%. This latter observation points to persistent hyperfunctioning tissue areas inducing late recurrent hyperthyroidism in 8.3% of the patients who underwent surgery.