Whole-Genome Sequencing for Resistance Prediction and Transmission Analysis of Mycobacterium tuberculosis Complex Strains from Namibia.

Namibia is among 30 countries with a high burden of tuberculosis (TB), with an estimated incidence of 460 per 100,000 population and around 800 new multidrug-resistant (MDR) TB cases per year. Still, data on the transmission and evolution of drug-resistant Mycobacterium tuberculosis complex (Mtbc) strains are not available. Whole-genome sequencing data of 136 rifampicin-resistant (RIFr) Mtbc strains obtained from 2016 to 2018 were used for phylogenetic classification, resistance prediction, and cluster analysis and linked with phenotypic drug susceptibility testing (pDST) data. Roughly 50% of the strains investigated were resistant to all first-line drugs. Furthermore, 13% of the MDR Mtbc strains were already pre-extensively drug resistant (pre-XDR). The cluster rates were high, at 74.6% among MDR and 85% among pre-XDR strains. A significant proportion of strains had borderline resistance-conferring mutations, e.g., inhA promoter mutations or rpoB L430P. Accordingly, 25% of the RIFr strains tested susceptible by pDST. Finally, we determined a potentially new bedaquiline resistance mutation (Rv0678 D88G) occurring in two independent clusters. High rates of resistance to first-line drugs in line with emerging pre-XDR and likely bedaquiline resistance linked with the ongoing recent transmission of MDR Mtbc clones underline the urgent need for the implementation of interventions that allow rapid diagnostics to break MDR TB transmission chains in the country. A borderline RIFr mutation in the dominant outbreak strain causing discrepancies between phenotypic and genotypic resistance testing results may require breakpoint adjustments but also may allow individualized regimens with high-dose treatment. IMPORTANCE The transmission of drug-resistant tuberculosis (TB) is a major problem for global TB control. Using genome sequencing, we showed that 13% of the multidrug-resistant (MDR) M. tuberculosis complex strains from Namibia are already pre-extensively drug resistant (pre-XDR), which is substantial in an African setting. Our data also indicate that the ongoing transmission of MDR and pre-XDR strains contributes significantly to the problem. In contrast to other settings with higher rates of drug resistance, we found a high proportion of strains having so-called borderline low-level resistance mutations, e.g., inhA promoter mutations or rpoB L430P. This led to the misclassification of 25% of the rifampicin-resistant strains as susceptible by phenotypic drug susceptibility testing. This observation potentially allows individualized regimens with high-dose treatment as a potential option for patients with few treatment options. We also found a potentially new bedaquiline resistance mutation in rv0678.

Thin-Layer-Agar-Based Direct Phenotypic Drug Susceptibility Testing on Sputum in Eswatini Rapidly Detects Mycobacterium tuberculosis Growth and Rifampicin Resistance Otherwise Missed by WHO-Endorsed Diagnostic Tests.

Xpert MTB/RIF rapidly detects resistance to rifampicin (RR); however, this test misses I491F-RR conferring rpoB mutation, common in southern Africa. In addition, Xpert MTB/RIF does not distinguish between viable and dead Mycobacterium tuberculosis (MTB). We aimed to investigate the ability of thin-layer agar (TLA) direct drug-susceptibility testing (DST) to detect MTB and its drug-resistance profiles in field conditions in Eswatini. Consecutive samples were tested in parallel with Xpert MTB/RIF and TLA for rifampicin (1.0 µg/ml) and ofloxacin (2.0 µg/ml). TLA results were compared at the Reference Laboratory in Antwerp with indirect-DST on Löwenstein-Jensen or 7H11 solid media and additional phenotypic and genotypic testing to resolve discordance. TLA showed a positivity rate for MTB detection of 7.1% versus 10.0% for Xpert MTB/RIF. Of a total of 4,547 samples included in the study, 200 isolates were available for comparison to the composite reference. Within a median of 18.4 days, TLA detected RR with 93.0% sensitivity (95% confidence interval [CI], 77.4 to 98.0) and 99.4% specificity (95% CI, 96.7 to 99.9) versus 62.5% (95% CI, 42.7 to 78.8) and 99.3% (95% CI, 96.2 to 99.9) for Xpert MTB/RIF. Eight isolates, 28.6% of all RR-confirmed isolates, carried the I491F mutation, all detected by TLA. TLA also correctly identified 183 of the 184 ofloxacin-susceptible isolates (99.5% specificity; 95% CI, 97.0 to 99.9). In field conditions, TLA rapidly detects RR, and in this specific setting, it contributed to detection of additional RR patients over Xpert MTB/RIF, mainly but not exclusively due to I491F. TLA also accurately excluded fluoroquinolone resistance.

Exercises for chronic low back pain: a clinical trial.

Different training models are effective for the treatment of chronic low back pain, but no consensus has been found. Earlier studies have emphasized training of spinal mobility and back strength. To evaluate if other physiological parameters, such as coordination, are of equal importance, we performed a randomized trial on 40 consecutive patients with chronic low back pain. Two training models were compared: 1) intensive training of muscle endurance and 2) muscle training, including coordination. In both groups, training was performed 1 hour twice a week for 3 months. Pain score, disability score, and spinal mobility improved in both training groups without differences between the two groups. Only intensive training of muscle endurance improved isokinetic back muscle strength. At study entry, we found a significant correlation between spinal mobility and dysfunction, but after the training, no correlation was found between improvement of spinal mobility or isokinetic back extension strength and improvement of function or pain level. We conclude that coordination training for patients with chronic low back pain is as equally effective as endurance training.

Supervised endurance exercise training compared to home training after first lumbar diskectomy: a clinical trial.

OBJECTIVE: We performed a randomised trial to evaluate if intensive supervised training of the back should be offered to all patients after a first lumbar diskectomy. METHODS: Forty consecutive patients were, after a first lumbar diskectomy, randomly allocated to 2 groups undergoing "supervised training" twice a week for 3 months in an outpatient clinic or "home training" after 2 hours of instruction. RESULTS: The two rehabilitation models both showed a significant effect on spinal mobility, isokinetic trunk flexion strength, isokinetic trunk extension strength and daily function. These improvements were unchanged at follow up 3 months later. The pain score remained unchanged, however, throughout the trial in both groups. No differences in effect between the two rehabilitation models could be found for any of the assessed parameters. Thirteen patients did not complete the trial, including 9 from the supervised endurance trained group, mainly because of increased pain and reprolaps (n = 4). Four patients dropped out of the home trained group, only one because of increased pain. The differences in drop-out rate and training side effects were, however, not statistically significant. CONCLUSION: We conclude that it is not worthwhile to implement 3 months of supervised intensive endurance training as opposed to home training in all cases of first lumbar diskectomy, although a beneficial effect and better compliance might be found for a selected group of such patients.

Different patterns of X inactivation in MZ twins discordant for red-green color-vision deficiency.

Two female identical twins who were clinically normal were obligatory heterozygotes for X-linked deuteranomaly associated with a green-red fusion gene derived from their deuteranomalous father. On anomaloscopy, one of the twins was phenotypically deuteranomalous while the other had normal color vision. The color vision-defective twin had two sons with normal color vision and one deuteranomalous son. X-inactivation analysis was done with the highly informative probe M27 beta. This probe detects a locus (DXS255) which contains a VNTR and which is somewhat differentially methylated on the active and inactive X chromosomes. In skin cells of the color vision-defective twin, almost all paternal X chromosomes with the abnormal color-vision genes were active, thereby explaining her color-vision defect. In contrast, a different pattern was observed in skin cells from the woman with normal color vision; her maternal X chromosome was mostly active. However, in blood lymphocytes, both twins showed identical patterns with mixtures of inactivated maternal and paternal X chromosomes. Deuteranomaly in one of the twins is explained by extremely skewed X inactivation, as shown in skin cells. Failure to find this skewed pattern in blood cells is explained by the sharing of fetal circulation and exchange of hematopoietic precursor cells between twins. These data give evidence for X inactivation of the color-vision locus and add another MZ twin pair with markedly different X-inactivation patterns for X-linked traits.

The first Danish chairs of ophthalmology.

In the last century German medical sciences made up the chief inspiration to the medical profession in Europe. The influence of German ophthalmology spread to Denmark, and accordingly the first Danish professor, Edmund Hansen Grut was trained in the Graefe clinic. His successor, Jannik Bjerrum grew up in southern Jutland, a district later on lost to the German Empire. The hitherto prevailing Danish sympathies with the neighbour in the south vanished after this. Bjerrum thus wrote all his papers in Danish and made no efforts to achieve an international reputation. In contrast, Marius Tscherning, received widespread recognition as a scientist. He spent many years in France. His scientific insights at last brought him to the Danish chair of ophthalmology. The history of the first three professors of ophthalmology, so different in their attitudes, has narrative value, but exemplifies as well the rapid development of the profession in the years 1886-1925.

Light microscopical and scanning electron microscopical examinations of deposits on disposable constant wear lenses.

An inexpensive, disposable soft contact lens for extended wear (DanaLens) has been developed. The lens is polymerized moulded in the wet state from hydroxyethyl methylacrylate and hydroxyethyl acrylate. Twenty-two pairs of the lens have in an open study been worn permanently from 1 to 43 days. Light microscopical and scanning electron microscopical examinations of the used lenses showed: superficial deposits on the front surfaces of the lenses of a mucous-like, easily removable material. Neither bacteria nor fungi were demonstrated.

Ergophthalmological studies in the electronic industry.

162 employees, the majority women, in an electronic industry were examined in a joint study involving several ergonomic aspects. Some results concerning visual skills are here extracted from a more comprehensive report. No natural selection of fitted workers could be demonstrated. The visual function was found to be only one component of a multifactorial system, which determines the psychological and physical well-being and productivity of industrial workers. The lack of a sufficient number of abnormal persons and comparable working conditions made it difficult to define limiting visual standards for job performance. Ordinary tests for visual acuity, near vision, heterophoria and stereopsis revealed few facts of importance. More intersting results were obtained when spectacles were evaluated as suitable for the job. 43% of the spectacles were considered insufficient. The use of bifocals did not seem to be related to the need of head movements, and 68% of all the spectacles had tinted glasses, in spite of the fact that the majority of persons wearing them considered the working illumination inadequate. An analysis of the working posture and the visual capacity of the worker should precede the prescription of spectacles for industrial workers.

Morphological, histochemical and X-ray microanalytical examination of deposits on soft contact lenses in extended wearing.

The deposits on 29 contact lenses of various water content from 20 wearers were analysed by the methods given in the title. Six lenses were used as bandage lenses, the remaining for optical correction. The age of the patients varied from 7 to 56 years, two-thirds being under 45 years. Wearing time had been from 1 week to 1 year, with an average of 13 weeks. The results obtained by the methods applied showed that calcium was present in just over two-thirds of the cases (20/29), other elements being infrequent. Mucopolysaccharides were found in just under two-thirds (18/29). Chlorine was present in one-fifth of the cases. No significant amounts of lipid were detected. Fungi were found in three cases (3/29). Bacteria were also found in these cases, but never without fungi. Evaluation of the methods applied showed that the methods of choice were macroscopical examination and scanning microscopy in combination with X-ray microanalysis, in a few cases combined with histochemistry. None of the methods applied is sufficient for protein analysis.

Zinc supplementation in alcoholic cirrhosis. A double-blind clinical trial.

A double-blind clinical trial with zinc sulfate, 0.2 g three times daily, and a placebo was performed in 30 patients with biopsy-proven alcoholic liver cirrhosis. The disease was in a stable phase, and none of the patients showed evidence of a decompensated liver function. Parameters of liver function, taste acuity, dark adaptation and of zinc and vitamin A metabolism were followed for six weeks. In the zinc-treated group of 16 patients, serum zinc rose from a normal mean value of 13.3 to 17.4 mumol/l, whereas the mean serum vitamin A level remained practically unaltered within the normal range, 1.89 at the entry and 1.83 mumol/l at the end of the study. Plasma prothrombin and serum alkaline phosphatase levels of the zinc group increased and serum bilirubin and serum carotene decreased significantly. The dark adaptation did not change, but the taste function was significantly improved during zinc treatment. The results indicate that zinc supplementation causes alleviation of certain abnormalities of cirrhotics, which deserves further attention.