| 1. |
- Diessl, Jutta, 1989-, et al.
(författare)
-
Manganese-driven CoQ deficiency
- 2022
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species. Across phylae, excess manganese disrupts energy metabolism by unclear mechanisms. Here, Diessl et al. report that failure of mitochondrial bioenergetics upon manganese overload is due to mismetallation of a diiron enzyme crucial for CoQ biosynthesis
|
|
| 2. |
- Kohler, S, et al.
(författare)
-
Programme costs of longer and shorter tuberculosis drug regimens and drug import: a modelling study for Karakalpakstan, Uzbekistan
- 2022
-
Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- The introduction of new and often shorter tuberculosis (TB) drug regimens affects the cost of TB programmes.MethodsWe modelled drug purchase and import costs for 20-month, 9-month and 4- to 6-month TB drug regimens based on 2016–2020 treatment numbers from a TB programme in Karakalpakstan, Uzbekistan, and 2021 Global Drug Facility prices.ResultsOn average, 2225±374 (±sd) people per year started TB treatment, 30±2.1% of whom were diagnosed with drug-resistant forms of TB. Transitioning from a 6-month to a 4-month drug-susceptible (DS)-TB drug regimen increased the TB programme's annual DS-TB drug cost from USD 65±10 K to USD 357±56 K (p<0.001) and its drug import cost from USD 6.4±1.0 K to USD 9.3±1.4 K (p=0.008). Transitioning from a 20-month all-oral multidrug-resistant (MDR)-TB drug regimen to a 9-month MDR-TB drug regimen with an injectable antibiotic decreased the TB programme's annual MDR-TB drug cost from USD 1336±265 K to USD 266±53 K (p<0.001) and had no significant effect on the drug import cost (USD 28±5.5 KversusUSD 27±5.4 K; p=0.88). Purchasing (USD 577±114 K) and importing (USD 3.0±0.59 K) the 6-month all-oral MDR-TB drug regimen cost more than procuring the 9-month MDR-TB drug regimen but less than the 20-month all-oral MDR-TB drug regimen (both p<0.01).ConclusionIntroducing new and shorter TB drug regimens could increase the cost of TB programmes with low drug resistance rates and decrease the cost of TB programmes with high drug resistance rates.
|
|
| 3. |
- Kohler, S, et al.
(författare)
-
The contribution of drug import to the cost of tuberculosis treatment: A cost analysis of longer, shorter, and short drug regimens for Karakalpakstan, Uzbekistan
- 2022
-
Ingår i: PLOS global public health. - : Public Library of Science (PLoS). - 2767-3375. ; 2:8, s. e0000567-
-
Tidskriftsartikel (refereegranskat)abstract
- Tuberculosis (TB) programs depend on a continuous supply of large amounts of high-quality TB drugs. When TB programs procure TB drugs from international suppliers, such as the Global Drug Facility, they can incur import costs for international transport, customs clearance, and national transport. We assessed the drug costs and import costs of 18 longer (≥18 months), 10 shorter (9–12 months), and 8 short (≤6 months) drug regimens for drug-sensitive (DS) and multidrug-resistant (MDR)-TB treatment. Costs per regimen were estimated by multiplying recommended drug amounts with 2021 Global Drug Facility prices and drug import costs of a TB program in Karakalpakstan, Uzbekistan. The standard short-course treatment of DS-TB requires taking 730 fixed-dose combination tablets, which weigh 0.79 kg and cause an import cost of $4.19 (9.8% of the regimen’s drug cost of $43). A new 4-month DS-TB regimen requires taking 1358 tablets, which weigh 1.1 kg and cause an import cost of $6.07 (2.6% of the regimen’s drug cost of $233). MDR-TB regimens that last between 24 weeks and 20 months involve 546–9368 tablets and injections. The drugs for these MDR-TB regimens were estimated to weigh 0.42–96 kg and cause an import cost of $2.26–507 per drug regimen (0.29–11% of a regimen’s drug cost of $360–15,028). In a multivariable regression analysis, an additional treatment month increased the import cost of a drug regimen by $5.45 (95% CI: 1.65 to 9.26). Use of an injectable antibiotic in a regimen increased the import cost by $133 (95% CI: 47 to 219). The variable and potentially sizable import costs of TB regimens can affect the financial needs of TB programs. Drug regimens that are shorter and all-oral tend to reduce import costs compared to longer regimens and regimens including an injectable drug.
|
|
| 4. |
- Waterink, L, et al.
(författare)
-
Changes in Brain-Health Related Modifiable Risk Factors in Older Adults After One Year of COVID-19-Restrictions
- 2022
-
Ingår i: Frontiers in psychiatry. - : Frontiers Media SA. - 1664-0640. ; 13, s. 877460-
-
Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic has major influence on lifestyle and mental health, which might affect brain-health and increase the risk of cognitive decline, particularly in older adults. We aimed to describe changes in modifiable risk factors related to brain-health in older adults after one year of COVID-19 restrictions.MethodsAn online survey was disseminated between February and March 2021 to 17,773 registrants of the Dutch Brain Research Registry, aged ≥50, without a self-reported diagnosis of mild cognitive impairment or dementia. Participants were asked to report potential changes in behaviors during the COVID-19 pandemic, compared to pre-pandemic, in eight domains related to brain health: physical activity, sleep, feeling of memory decline, perceived stress, feeling of loneliness, diet, alcohol consumption, and smoking. We used negative binomial regression analyses to relate (socio)demographics, subjective memory complaints and COVID-19 related aspects (fear of, or current/past COVID-19 infection) to the number of reported detrimental and beneficial changes as dependent variable.Results3,943 participants (66 ± 8 years old; 76% female; 71% highly educated) completed the survey. After one year of COVID-19-restrictions, 74% reported at least one detrimental lifestyle change unfavorable for their brain health, most frequently reported were feelings of loneliness, sleep problems, and less physical activity. 60% of participants reported at least one beneficial change, which were most often more physical activity, healthier dietary habits, and less alcohol consumption. Individuals who are younger [incidence rate ratio (IRR) = 0.99, 95% CI = 0.98–0.99], female (1.20, 1.11–1.30), living alone (1.20, 1.11–1.28) and in urban environments (1.18, 1.08–1.29), who are less satisfied with their income (1.38, 1.17–1.62), experiencing subjective memory complaints (1.40, 1.28–1.52) and those with a past or current (1.19, 1.06–1.34) or fear of a COVID-19 infection (1.33, 1.25–1.42) reported higher numbers of detrimental changes.DiscussionThe COVID-19 pandemic has influenced lifestyle in both positive and negative ways. We identified (socio)demographic factors associated with more detrimental changes in modifiable risk factors related to brain health, suggesting that some individuals are more vulnerable for the impact of the COVID-19 pandemic. These findings provide an opportunity for targeted prevention and education to promote a healthy lifestyle during and after the pandemic.
|
|
