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In the context of mitochondrial genome heteroplasmy that causes defective oxidative phosphorylation in C. elegans , the ATFS-1-mediated mitochondrial unfolded protein response maintains the deleterious mitochondrial DNA in an attempt to recover oxidative phosphorylation activity and avoid cellular dysfunction. Mitochondrial mutations tolerated — up to a point A eukaryotic cell contains a single copy of the nuclear genome, but hundreds of mitochondrial genomes (mtDNA), encoding proteins essential for oxidative phosphorylation. The cell can tolerate a number of mutations or deletions in mitochondrial genes, but beyond a toxic threshold, further mutations can cause inborn mitochondrial diseases. Cole Haynes and colleagues examined the mechanism by which mtDNA mutations are tolerated by focusing on the role of the mitochondrial unfolded protein response (UPR mt ), a process mediated by the transcription factor ATFS-1 that promotes the recovery of defective mitochondria. They compare normal Caenorhabditis elegans roundworms to a heteroplasmic strain carrying a deletion mutation in four mitochondrial-encoded genes in 60% of the mitochondria. The heteroplasmic strain displayed constant UPR mt activation and only modest mitochondrial dysfunction. In worms with impaired UPR mt activity, there was a tenfold reduction in the number of mutated mtDNAs. The authors infer that ATFS-1-mediated UPR mt maintains the deleterious mtDNA in an attempt to recover oxidative phosphorylation activity, to avoid the possible alternative scenario of the demise of the cell. Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OXPHOS declines, resulting in cellular dysfunction. For example, Kearns–Sayre syndrome is caused by a single heteroplasmic mtDNA deletion. More broadly, mtDNA deletion accumulation has been observed in individual muscle cells 1 and dopaminergic neurons 2 during ageing. It is unclear how mtDNA deletions are tolerated or how they are propagated in somatic cells. One mechanism by which cells respond to OXPHOS dysfunction is by activating the mitochondrial unfolded protein response (UPR mt ), a transcriptional response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria 3 , 4 . Here we investigate the role of ATFS-1 in the maintenance and propagation of a deleterious mtDNA in a heteroplasmic Caenorhabditis elegans strain that stably expresses wild-type mtDNA and mtDNA with a 3.1-kilobase deletion ( ∆ mtDNA) lacking four essential genes 5 . The heteroplasmic strain, which has 60% ∆ mtDNA, displays modest mitochondrial dysfunction and constitutive UPR mt activation. ATFS-1 impairment reduced the ∆ mtDNA nearly tenfold, decreasing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPR mt activation caused by OXPHOS defects propagates or maintains the deleterious mtDNA in an attempt to recover OXPHOS activity by promoting mitochondrial biogenesis and dynamics.

Background: Penile cancer is a relatively rare genital malignancy whose incidence and mortality are rising in many countries. Objective: This study aims to assess the recent incidence and mortality patterns and incidence trends of penile cancer. Methods: The age-standardized incidence and mortality rates (ASIR and ASMR, respectively) of penile cancer in 2020 were estimated from the Global Cancer Registries (GLOBOCAN) database. Incidence trends of penile cancer from 1973 to 2012 were assessed in 44 populations from 43 countries using the Cancer Incidence in Five Continents plus (CI5plus) and the Nordic Cancer Registries (NORDCAN) databases. Average annual percentage change was calculated to quantify trends in ASIR using joinpoint regression. Results: Globally, the estimated ASIR and ASMR of penile cancer were 0.80 (per 100,000) and 0.29 (per 100,000) in 2020, equating to 36,068 new cases and 13,211 deaths in 2020, respectively. There was no significant correlation between the ASIR (P=.05) or ASMR (P=.90) and Human Development Index. In addition, 15 countries saw increasing ASIR for penile cancer, 13 of which were from Europe (United Kingdom, Lithuania, Norway, Estonia, Finland, Sweden, Cyprus, Netherlands, Italy, Croatia, Slovakia, Russia, and the Czech), and 2 from Asia (China and Israel). Conclusions: Although the developing countries still bear the higher incidence and mortality of penile cancer, the incidence is on the rise in most European countries. To mitigate the disease burden resulting from penile cancer, measures to lower the risk for penile cancers, including improving penile hygiene and male human papillomavirus vaccination, may be warranted.

Since May 2022, large numbers of human mpox (previously known as monkeypox) cases have been reported in non-endemic regions. We conducted a systematic review and meta-analysis to elucidate clinical characteristics of the current mpox outbreak. Our systematic review and meta-analysis were undertaken according to PRISMA and MOOSE guidelines. We searched PubMed, EMBASE, and Web of Science for publications between 1 January and 11 November 2022. Random-effects models were used to pool results. Heterogeneity was assessed using I2. This study is registered with PROSPERO, CRD42022355590. Skin lesions (95.2%, 95% CI [93.3–96.9%]), fever (58.4%, [54.9–61.8%]) and lymphadenopathy (53.0%, [48.7–57.3%]) were the most common symptoms. The most common dermatological manifestations were anogenital lesions (65.7%, [57.8–73.0%]), and the most common lymphadenopathy was inguinal (46.8%, [40.6–53.0%]). There were no differences in symptoms including malaise, fever, headache, and genital, anal, and oropharyngeal lesions according to HIV infection status. Median age of patients varied from 15 to 57.5 years (median, 35 years). The median proportion of men who had sex with men (MSM) was 100.0% (20.6–100.0%). The median proportion of patients who reported recent sexual exposure was 99.2% (14.3–100.0%). The median proportion of PLHIV was 42.2% (0.0–100.0%). Skin lesions, fever, inguinal lymphadenopathy, and anogenital lesions were the most common symptoms of mpox reported in the current outbreak. Existing guidelines should be updated to reflect these clinical manifestations and groups at highest risk of infection, MSM in particular.

Background Previous studies have examined the associations of baseline smartphone dependence (SPD) with depressive symptoms and anxiety symptoms, ignoring changes in SPD over time. Especially, it is unclear whether individuals quitting SPD remain at high risk for depressive symptoms and anxiety symptoms. This study aimed to investigate the longitudinal associations of changes in SPD with depressive symptoms and anxiety symptoms among adolescents. Methods From September to December 2021 (wave 1), we recruited adolescents in grades 4 and 7 in five public primary schools and nine public junior high schools in Shenzhen, China, and collected information on SPD using the Smartphone Addiction Scale-Short Version. The cut-off values of ≥ 31 and ≥ 33 were used in boys and girls, respectively, to identify adolescents with SPD. From September to December 2022 (wave 2), in addition to SPD, we collected the information on depressive symptoms and anxiety symptoms using the 9-item version of Patient Health Questionnaire and the 7-item version of General Anxiety Disorder Scale, respectively. The cut-off values for clinically significant symptoms were both ≥ 10. Four patterns of changes in SPD during waves 1–2 were defined: none, quitting, new-onset, and persistent. From September to December 2023 (wave 3), we assessed depressive symptoms and anxiety symptoms again. Results Of the 3088 adolescents included, the mean age was 12.5 (standard deviation [SD], 1.4) years and 54.3% were boys. Compared with adolescents without SPD, those with new-onset SPD (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.06 to 2.31) or persistent SPD (OR, 2.37; 95% CI, 1.56 to 3.61) showed a higher risk of depressive symptoms, but those quitting SPD did not (OR, 1.33; 95% CI, 0.83 to 2.12). We have observed a similar association between changes in SPD and anxiety symptoms. Several sensitivity analyses confirmed the robustness of the results. Conclusions Our findings suggest that adolescents with SPD might be a high-risk group for depressive symptoms and anxiety symptoms, and quitting SPD might help prevent them from developing depressive symptoms and anxiety symptoms.

Background Among people living with HIV (PLHIV) on antiretroviral therapy (ART), the mortality of immunological non-responders (INRs) is higher than that of immunological responders (IRs). However, factors associated with immunological non-response following ART are not well documented. Methods We obtained data for HIV patients from the National Free Antiretroviral Treatment Program database in China. Patients were grouped into IRs (CD4 cell count ≥ 350 cells/μl after 24 months’ treatment), immunological incomplete responders (ICRs) (200–350 cells/μl) and INRs (< 200 cells/μl). Multivariable logistic regression was used to assess factors associated with immunological non-response. Results A total of 3900 PLHIV were included, among whom 2309 (59.2%) were IRs, 1206 (30.9%) ICRs and 385 (9.9%) INRs. In multivariable analysis, immunological non-response was associated with being male (2.07, 1.39–3.09), older age [40–49 years (vs. 18–29 years): 2.05, 1.29–3.25; 50–59 years: 4.04, 2.33-7.00; ≥ 60 years: 5.51, 2.84–10.67], HBV co-infection (1.63, 1.14–2.34), HCV co-infection (2.01, 1.01–4.02), lower CD4 + T cell count [50–200 cells/μl (vs. 200–350 cells/μl): 40.20, 16.83–96.01; < 50 cells/μl: 215.67, 85.62-543.26] and lower CD4/CD8 ratio (2.93, 1.98–4.34) at baseline. Compared with patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) based regimens, those receiving protease inhibitors (PIs) based regimens were less likely to be INRs (0.47, 0.26–0.82). Conclusions We found a sizable immunological non-response rate among HIV-infected patients. Being male, older age, coinfection with HBV and HCV, lower CD4 + T cell count and lower CD4/CD8 ratio are risk factors of immunological non-response, whereas PIs-based regimens is a protective factor.

A cardiac injury study in zebrafish reveals the plasticity of heart cell lineages as shown by a Notch-dependent transdifferentiation of atrial to ventricular cardiomyocytes, regenerating a cell type that is damaged in human heart failure. Heart cells with regenerative potential Obstacles to the use of stem-cell therapy in heart failure patients include the difficulty of ensuring the differentiation of cardiac progenitor cells into functional ventricular cardiomyocytes, and the delivery and integration of differentiated cells into the patient's ventricular myocardium. Neil Chi and colleagues studied the ability of specific cardiac muscle cell types to differentiate into closely related but distinct cell types in embryonic zebrafish hearts. They find that differentiated atrial cardiomyocytes can transform into ventricular cardiomyocytes when the heart is injured and that the Notch signalling pathway induces the regeneration. This work identifies an endogenous population of cardiac cells as a potential source for cardiac ventricular regeneration. Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct 1 , 2 . Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium 3 . Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles 4 , 5 , 6 ; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration 3 . Here we have developed, in the zebrafish ( Danio rerio ), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.

The health and economic benefits of human papillomavirus (HPV) vaccination targeted at men who have sex with men (MSM) in developing settings have been rarely assessed. This study aimed to evaluate the effectiveness and cost-effectiveness of different HPV vaccination strategies among MSM in China. A Markov model was developed to simulate HPV transmission dynamics among a total of 30.73 million MSM in China. The corresponding natural history included 6 states: susceptible, infected with low-risk subtypes, high-risk subtypes, anogenital warts and anal cancer, and deaths from anal cancer. MSM were divided into three age groups with cut-off points of 27 and 45 years. Alternative vaccination strategies were built by allocating bivalent, quadrivalent, nine-valent, or no vaccine to each of the groups. We generated the prevented infections and deaths by vaccination compared with baseline (no vaccination) and calculated incremental cost-effectiveness ratios (ICERs) to determine the optimal strategy. The model showed that in 10 years, at baseline, the existing cases of anogenital warts would reach 5,464,225 (IQR, 4,685,708-6,174,175); that of anal cancer would reach 1,922.95 (1,716.56-2,119.93), resulting in 940.55 (732.27-1,141.87) deaths. Under 50% vaccination coverage among one age group, the prevented cases of anogenital warts were maximized with quadrivalent vaccines allocated to MSM aged 27-45 years; that of anal cancer were maximized when offering nine-valent vaccines to the same group. Under 50% vaccination coverage among all groups, the lowest ICER (34,098.09 USD/QALY, 31,146.54-37,062.88) was reached when only quadrivalent vaccines were provided. Based on this strategy, when the annual vaccination rate increased by 30%, the ICER (33,521.75 USD/QALY, 31,040.73-36,013.92) would fall below three times China's per capita GDP. When the vaccine price decreased by 60%, the ICER was reduced to 7,344.44 USD/QALY (4,392.89-10,309.23), indicating good cost-effectiveness taking China's per capita GDP as a threshold. HPV vaccination can effectively reduce the prevalence and mortality of related diseases among MSM in China, especially quadrivalent vaccines for anogenital warts and nine-valent vaccines for anal cancer. MSM aged 27-45 years were the optimal group for vaccination. Annual vaccination and appropriate adjustment of vaccine price are necessary to further improve the cost-effectiveness.

Human papillomavirus (HPV) infection among men who have sex with men (MSM) in China is underreported. We performed a systematic review and meta-analysis to clarify site-specific HPV prevalence among MSM in China. We searched both English and Chinese databases for all studies published before April 1, 2020, that reported HPV prevalence among MSM in China. Random-effects meta-analysis was used to calculate summary estimates. Thirty-four articles were eligible, where 32, 5, and 2 articles reported HPV prevalence at the anus, penis, and oral cavity, respectively. The estimated prevalence of anal HPV among MSM in China was 85.1% (HIV-positive), 53.6% (HIV-negative), and 59.2% (unknown HIV status), with HPV genotypes being predominated by HPV 6, 11, 16, 18, 52, and 58. Any HPV and high-risk (HR) HPV was more common in northern China, while low-risk HPV was more common in southern China. HPV prevalence increased with age among HIV-negative MSM, from 40.5% (aged < 20 years) to 57.2% (aged ≥ 40 years). High prevalence of any HPV (HIV+: 95.1%; HIV−: 97.7%) and multiple infections (HIV+: 75.9%; HIV−: 41.7%) was found in anogenital warts among MSM. HPV is common among MSM in China. MSM living with HIV and/or anogenital warts were at disproportionate risk for HR HPV. Younger MSM were found to have a lower HPV prevalence. HPV vaccines would have prevented the majority of infections if given before sex debut. HPV at anatomical sites other than the anus, incident HPV infection, and the cost-effectiveness of HPV vaccination in this population are worth further investigation.

Background Meeting the 24-hour movement behavior (24-HMB) guideline helps enhance quality of life (QOL) of adolescents. This study aimed to assess the associations between the 24-HMB (physical activity, screen time, sleep) and QOL among adolescents with idiopathic scoliosis. Methods A cross-sectional study was conducted between September 2021 and September 2023. 24-HMB, QOL and demographic variables were collected through a self-reported questionnaire. Linear regression models and stratified analyses were used to explore statistical associations between the 24-HMB and QOL. Results A total of 1073 participants aged 10–18 years with a spinal Cobb angle between 10° and 40° were included. Overall, 20 participants (1.9%) met all three behavioral guidelines, and 272 participants (25.3%) met none. Compared to those who did not meet any of the guidelines, adolescents meeting both screen time and sleep duration ( β  = 4.10, 95% CI: 2.02–6.18, P  < 0.001) and all 3 guidelines ( β  = 4.39, 95% CI: 0.27–8.51, P  = 0.037) had higher QOL scores. Stratified analyses showed that the above associations were more pronounced in adolescents without back pain or with good self-image. Conclusions These findings highlight the importance of adopting and maintaining healthy behavioral habits in order to improve QOL among adolescents with idiopathic scoliosis, especially in those without back pain or with good self-image.

The spinal health of teenagers is adversely affected by the effects of COVID-19, and large-scale scoliosis screening for teenagers after the pandemic has not been reported. This study aimed to explore the prevalence of incorrect posture among Chinese adolescents after the COVID-19 pandemic. This was a large-scale cross-sectional study based on school scoliosis screening. Each student underwent visual inspection, Adam's forward bending test, and trunk rotation angle measurement. A scoliometer was used for posture assessment. The participants were subgrouped based on sex, age, and ethnicity to compare the prevalence of suspected scoliosis. Univariate and multivariate logistic regression (LR) models were used to evaluate factors associated with suspected scoliosis. During the post-COVID-19 pandemic period, 1,793,787 students participated. The overall prevalence of incorrect postures among Chinese adolescents was 79.92%, and the most common incorrect postures were high and low shoulders (74.18%) and scapular tilt (70.46%). A total of 97,529 students (5.44%) were suspected to have scoliosis. More females (7.5%) than males (3.7%) and more students aged > 15 years (15.12%) than those aged 10-15 years (7.58%) and < 10 years (0.88%) were suspected to have scoliosis. Univariate LR analysis showed that sex, age, grade, and various incorrect postures were significantly associated with suspected scoliosis. Multivariate LR analysis showed that being female (OR = 2.54, 95% CI: 1.68-3.85), age of 10-15 years (OR = 30.34, 95% CI: 4.99-12.64), and ages of > 15 years (OR = 22.30, 95% CI: 10.84-45.87), and incorrect posture, especially the lumbar eminence and right rib hump were high risk factors for suspected scoliosis. The prevalence of incorrect posture and suspected scoliosis among Chinese adolescents increased significantly after the COVID-19 pandemic. Early screening of high-risk populations for suspected scoliosis and effective interventions should be implemented to prevent adolescent idiopathic scoliosis during the post-COVID-19 period.