Timing of dental development in relation to the treatment of maxillary canines: a retrospective register-based study

To investigate whether low-intensity pulsed ultrasound (US) has different protective effects on early and late rabbit osteoarthritis cartilage via the integrin/focal adhesion kinase (FAK)/mitogen-activated protein kinase (MAPK) signaling pathway. Thirty-six New Zealand White rabbits were divided into early control, early osteoarthritis, early treatment, late control, late osteoarthritis, and late treatment groups. The early and late osteoarthritis and treatment groups underwent anterior cruciate ligament transection. The remaining groups underwent sham operations with knee joint exposure. The early and late treatment groups were exposed to low-intensity pulsed US 4 and 8 weeks after surgery. After 6 weeks of US exposure, pathologic changes on the articular surface of the femoral condyle were assessed by modified Mankin scores. Expression of type II collagen, matrix metalloproteinase, integrin β1, phosphorylated FAK, and MAPKs (including extracellular signal-regulated kinase 1/2, MAPK 38, and c-Jun N-terminal kinase) was assessed by Western blot analysis. Cartilage damage was less severe in the early treatment group than the early osteoarthritis group. The Mankin score was significantly lower in the early treatment group than the early osteoarthritis group (P < .05). There was no significant difference in cartilage damage or Mankin score between the late treatment and late osteoarthritis groups. There was a significant increase in type II collagen expression but a significant decrease in matrix metalloproteinase 13 expression in the early treatment group compared to the early osteoarthritis group, whereas no significant difference was found between the late treatment and late osteoarthritis groups. Integrin β1 and phosphorylated FAK expression was significantly higher, and phosphorylated extracellular signal-regulated kinase 1/2 and phosphorylated MAPK 38 expression was significantly lower in the early treatment group than the early osteoarthritis group. Our findings indicate that low-intensity pulsed US protects cartilage from damage in early-stage osteoarthritis via the integrin/FAK/MAPK pathway.

Objective: We aimed to compare laboratory and outcome of the patients who were hospitalized in the intensive care unit with the diagnosis of Coronavirus Disease-19 (COVID-19) and transfused convalescent plasma based on timing of treatment. Methods: Patients administered 200 mL of convalescent plasma were analysed retrospectively. Based on symptoms’ onset, patients were divided into two groups as early (≤ 7 days) and late (&gt; 7 days) plasma treatment groups. Patients’ characteristics, comorbidities, treatments, laboratory (pre-transfusion, day 1 and day 3 after transfusion) and outcome were evaluated according to groups. Results: A total of 152 patients matched criteria. There was no difference between the early (n=82) and late (n=70) treatment groups in terms of demographic characteristics, comorbidities, treatments, outcomes. Ferritin levels were higher in the early treatment group than in the late treatment group on before transfusion and day 1 (p=0.023, p=0.015). C reactive protein value was lower in the late treatment group on day 3 (p=0.011). Comparing the rate of change between day 1 and day 3 of treatment, it was observed that the changes in ferritin and fibrinogen values were higher in the late group than in the early group (p=0.014, p=0.049). There was no difference between the groups in other laboratory values and outcome. Conclusion: In our study, we observed that the timing of convalescent plasma had no significant effect on outcome. However, more evidence was needed to prove the difference in laboratory results. Keywords: Intensive care unit, COVID-19, convalescent plasma, mortality

BackgroundPneumocystis jirovecii pneumonia (PCP) in non-human immunodeficiency virus (HIV) patients is associated with high morbidity and mortality. Although prior studies have linked delayed treatment to worse outcomes, they are often limited by small sample sizes and inadequate adjustment for confounders. Therefore, we evaluated whether early treatment after hospital admission improves mortality in non-HIV PCP, adjusting for patient characteristics.MethodsThis multi-center, retrospective, observational cohort study included non-HIV PCP patients treated between January 2006 and March 2021 at three institutions. Participants were divided into the early treatment (initiated within 2 days) and late treatment (initiated between days 3 and 7) groups. The primary endpoint was 30-day mortality, and the secondary endpoints were 180-day mortality. Propensity score weighting was used to adjust for patient background.ResultsNinety-four patients in the early treatment group and 43 in the late treatment group were evaluated. The average time-to-treatment for the early and late treatment groups was 0.13 days and 3.63 days, respectively. After adjusting for patient characteristics, there were no significant differences in 30-day mortality (14.0% vs. 8.2%, p = 0.307) or 180-day mortality (21.5% vs. 17.7%, p = 0.600) between the early and late treatment groups. In a subgroup analysis of cases requiring oxygen supplementation, 30-day and 180-day mortality also showed no significant differences between the two groups.ConclusionThis study emphasizes the importance of accurate diagnosis and tailored management based on disease severity rather than immediate empirical treatment, as early treatment initiation was not significantly associated with 30-day or 180-day mortality in non-HIV PCP.

The management of palatally displaced maxillary canines: Considerations and challenges

Objective: To analyze the treatment efficacy in the vertically impacted maxillary central incisors using cone-beam CT (CBCT) and explore the treatment timing and the influence of orthodontic traction on the root development and alveolar bone height in the mixed dentition. Methods: Twenty-two patients with vertically impacted maxillary central incisor who were admitted to the Department of Orthodontics, Stomatological Hospital affiliated to Nanjing Medical University from December 2012 to December 2017 were selected [12 males and 10 females, (9.2±0.9) years]. Based on the dental age, patients were classified as early treatment group (teeth ranging from a third to two thirds of root formation, n=12) and late treatment group (teeth with nearly or fully complete root formation, n=10). The contralateral maxillary central incisor was used as the control. Three-dimensional reconstruction of CBCT before treatment, after treatment and one year after treatment was carried out to measure root length, tooth surface area, tooth volume, labial and lingual apical alveolar bone thickness, the loss of labial alveolar bone height and intraosseous root ratio. The clinical crown length was measured in the mouth. The difference values of the measurement variables between the impacted teeth and the control teeth were calculated and analyzed(measurement values of impacted teeth were subtracted from control values). Results: The values of root length difference beween the impacted teeth and the control teeth in the early and late treatment group were (1.58±1.56) mm and (2.57±1.00) mm, respectively after the treatment and the values were significantly less than those corresponding values before treatment [(3.47±1.40) and (3.36±0.79) mm] (P<0.05). After the treatment, the values of the surface area and volume difference between the impacted teeth and the control teeth in the early treatment group [(0±34) mm(2) and (-10±44) mm(3)] were significantly less than those corresponding values before treatment [(38±31) mm(2) and (55±70) mm(3)] (P<0.05). The value differences of any measurement variables between the early and late treatment group were not significantly different after the treatment (P>0.05). The root length and intraosseous root ratio of the impacted teeth after the treatment in the early and late treatment group were significantly less than those of the control teeth after the treatment (P<0.05). The clinical crown length, the loss of labial alveolar bone height of the impacted teeth after the treatment were significantly larger than those of the control teeth after the treatment (P<0.05). Conclusions: Orthodontic traction promoted the root growth and development of the vertically impacted maxillary central incisors. However, the root length and alveolar bone height still cannot reach the normal level after treatment. Treatment timing had no effect on root development and alveolar bone height of vertically impacted maxillary central incisors in mixed dentition.

Background: We aimed to determine whether treatment with oseltamivir was associated with decreased mortality among patients admitted to intensive care units (ICUs) with severe influenza and whether early therapy (within 48 hours of symptoms onset) was associated with improved survival rates. Methods: This was a prospective observational study of patients with confirmed influenza who were admitted to 184 ICUs in Spain. The primary outcomes were to investigate the association of ICU mortality with oseltamivir therapy by comparing patients who are untreated (UT group) with those who are treated (all treated; AT group) and those in early treatment (ET) and late treatment (LT) groups. We also assessed the associations of both ET and LT with ICU mortality and compared the results. Findings: We enrolled 4,175 patients of whom 3,537 met the inclusion criteria. Most patients were diagnosed with influenza pneumonia (84·7%). When comparing the AT (n=3,439) and UT (n=98) groups, the former had higher survival after adjusting for severity and confounding factors (Hazard ratio [HR] 0·67; p=0·03). We included 3,388 patients to compare the ET and LT groups. In the multivariable analysis, ICU mortality was lower in the ET group, having an odds ratio of 0·7 (p=0·004). When propensity score matching was applied to a matched cohort (ET, n=790; LT, n=2,522), the ET group had lower ICU mortality (HR 0·78; p=0·008) compared with the LT group, even after a competing risks analysis (sub-HR 0·79; p=0·01). Interpretation: Oseltamivir treatment is associated with better survival rates in patients admitted to ICU with severe influenza, especially when initiated within 48 hours of illness onset. Funding Statement: SEMICYUC (Spanish Society of Critical Care) and Ricardo Barri Casanovas Foundation. Declaration of Interests: JSN-V-T has received research funding from F. Hoffman-La Roche for separate work. He is currently seconded to the Department of Health and Social Care, England (DHSC). The views expressed in this paper are those of the authors and not necessarily those of DHSC. CG-V has received the INTENSIFICACIO Grant- a grant supported by the Catalan Health Agency [PERIS (Pla estrategic de recerca i innovacio en salut – ‘Strategic Plan for Research and Innovation in HealthCare’)]. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the Joan XXIII University Hospital Ethics Committee (IRB#11809). All data were anonymised, allowing the requirement for informed consent to be waived.

Since December 2012, the prophylactic use of caffeine to treat AOP in preterm infants has been approved in China. This study aimed to investigate the relationship between early caffeine treatment initiation and the incidence of oxygen radical diseases in neonatology (ORDIN) in Chinese preterm infants. A retrospective study was conducted at two hospitals in South China, involving 452 preterm infants with gestational ages less than 37 weeks. The infants were divided into early (227 cases, initiating within 48 h after birth) and late (225 cases, initiating over 48 h after birth) caffeine treatment group. Logistic regression analysis and Receiver Operating Characteristic (ROC) curves were used to evaluate the association between early caffeine treatment and the incidence of ORDIN. The results showed that extremely preterm infants in early treatment group had a lower incidence of PIVH and ROP compared to those in the late treatment group (PIVH, 20.1% versus 47.8%, P = 0.02; ROP, 70.8% versus 89.9%, P = 0.025). Very preterm infants in the early treatment group had a lower incidence of BPD and PIVH compared to those in the late treatment group (BPD, 43.8% versus 63.1%, P = 0.002; PIVH, 9.0% versus 22.3%, P = 0.001). Moreover, VLBW infants who received early caffeine treatment exhibited a decreased incidence of BPD (55.9% versus 80.9%, P = 0.000), PIVH (11.8% versus 33.1%, P = 0.000), and ROP (69.9% versus 79.8%, P = 0.043) compared to those in the late treatment group. Infants in the early caffeine treatment showed a reduced likelihood of PIVH (adjusted odds ratio, 0.407; 95%CI, 0.188-0.846) but did not exhibit a significant association with other terms of ORDIN. ROC analysis revealed that early initiation of caffeine treatment was associated with lower risk of BPD, PIVH, and ROP in preterm infants. In conclusion, this study demonstrates that early initiation of caffeine treatment is associated with a decreased incidence of PIVH in Chinese preterm infants. Further prospective investigations are necessary to verify and elucidate the precise effects of early caffeine treatment on complications in preterm Chinese infants.

Although real-world studies have found that remdesivir is effective in preventing poor prognosis, more information is needed on the optimal timing of remdesivir administration in high-risk coronavirus disease 2019 (COVID-19) patients in the Omicron era. From February 2022 to January 2023, a single-center retrospective study was performed in Korea. We compared the clinical characteristics and treatment outcomes between early (remdesivir treatment within 0–3 days from symptom onset) and late (≥ 4 days from symptom onset) treatment groups of patients who received remdesivir monotherapy. Of 284 patients, 225 were classified into the early treatment group and 59 were classified into the late treatment group. The early treatment group had a lower rate of 28-day progression to severe disease than the late treatment group (1.4% vs 7.4%, P = .03). Delaying remdesivir treatment ≥ 4 days from symptom onset (adjusted odds ratio [aOR], 6.17; 95% CI, 1.18–32.44; P = .03) and Charlson comorbidity index ≥ 3 (aOR, 9.62; 95% CI, 1.65–56.10; P = .01) were independent risk factors for 28-day progression to severe disease. Our results suggest that early administration of remdesivir could be associated with better prognosis in COVID-19 patients with the Omicron variant, and within 3 days from symptom onset seems to be the appropriate timing.

Age-related hearing loss (ARHL) is a major public health concern, which is characterized by gradual, progressive sensorineural hearing loss and deterioration of sound localization, with no effective treatment available to date. The aim of the present study was to evaluate the efficacy of resveratrol to prevent and treat ARHL. For this purpose, 32 male C57BL/6 mice were assigned to four groups: Early treatment, late treatment, control and sham control. The experiment lasted for 15 months. Treatment was started at three months of age in the early treatment group and at sixth months in the late treatment group. The auditory brainstem response test was performed once every three months. At the end of the study period, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, NF-κB, Bcl-2, Bcl-xL, Bax, Bcl-2 homologous antagonist/killer (Bak), caspase-3 and caspase-9 levels in the cochlear tissues of the animals were analyzed by reverse transcription-quantitative PCR. Hearing thresholds of the mice in the early treatment group were better than those in the other groups (P<0.001) at the end of the study. However, hearing levels in the late treatment group were not significantly different from those in the control groups (P>0.05), although mean thresholds were lower. The threshold shift in the early treatment group was significantly lower at all frequencies when compared with those in the control groups (P<0.001). The mRNA expression levels of pro-apoptotic genes Bax and Bak were lower (P<0.05), anti-apoptotic genes Bcl-2 and Bcl-xL were higher (P<0.05), NF-κB, COX-2 and iNOS as genes that have a role in inflammation and caspase-3 and caspase-9 as genes with a vital role in apoptosis were lower (P<0.05) in the early treatment group when compared with the late treatment and control groups. These results suggested that resveratrol is effective in the prevention of ARHL, particularly when started prior to the beginning of hearing loss.

Tranexamic acid (TXA) is an antifibrinolytic pharmacological agent, but its use in gastrointestinal bleeding remains contentious. Moreover, studies on the timing of TXA administration are limited. We examined whether early TXA administration reduced the risk of mortality in patients with gastrointestinal bleeding in a Taiwanese population. We used the National Health Insurance Research Database to identify patients diagnosed with gastrointestinal bleeding with early and late TXA treatment. We defined early treatment as initial TXA treatment in an emergency department and late treatment as initial TXA treatment after hospitalization. Mortality within 52 weeks was the primary outcome. A multivariable analysis using a multiple Cox regression model was applied for data analysis. Propensity score matching (PSM) was performed to reduce the potential for bias caused by measured confounding variables. Of the 52,949 selected patients with gastrointestinal bleeding, 5127 were assigned to either an early or late TXA treatment group after PSM. The incidence of mortality was significantly decreased during the first and fourth weeks (adjusted HR (aHR): 0.65, 95% CI: 0.56–0.75). A Kaplan–Meier curve revealed a significant decrease in cumulative incidence of mortality in the early TXA treatment group (log-rank test: p < 0.0001). Multiple Cox regression analysis revealed significantly lower mortality in the early TXA treatment group compared with the late treatment group (aHR: 0.64, 95% CI: 0.57–0.73). Thromboembolic events were not significantly associated with early or late TXA treatment (aHR: 1.03, 95% CI: 0.94–1.12). A Kaplan–Meier curve also revealed no significant difference in either venous or arterial events (log-rank test: p = 0.3654 and 0.0975, respectively). In conclusion, early TXA treatment was associated with a reduced risk of mortality in patients with gastrointestinal bleeding compared with late treatment, without an increase in thromboembolic events. The risk of rebleeding and need for urgent endoscopic intervention require further randomized clinical trials.

Early versus late treatment of neonatal acidosis in low-birth-weight infants: Relation to respiratory distress syndrome

Objective To explore whether therapeutic dosing timing of proteasome inhibitor bortezomib(BZ) would impact its clinical efficacy. Methods From 2012 to 2018, 35 biopsy-confirmed cases of acute antibody-mediated kidney transplant rejection (AMR) were collected. They received intravenous immunoglobulin (IVIG) plus sirolimus (Sir) plus bortezomib (BZ). Three groups were assigned according to dosing timing of BZ. After a diagnosis of AMR, ET (early treatment) group began BZ dosing within 7 days (n=16) while DT (delayed treatment) group within 8-14 days (n=11) and LT (late treatment) group >14 days (n=8). Their clinical parameters and incidence of complications were analyzed. Results DSA reversal rate of ET, DT and LT groups was 87.5%, 45.5% and 25.0% (P=0.006) while DSA declining rate 93.8%, 90.9% and 50% respectively (P=0.019); recurrent rate of AMR was lower in ET/DT group than LT group (6.6% vs 10% vs 75%, P=0.042). No significant differences existed in blood perfusion score of allograft at 1 month post-dosing among three groups. In three groups, creatinine (Cr) of ET group was lower than DT group at month 1/3/12 while DT group was lower than LT group. No significant difference existed in the incidence of adverse reactions among 3 groups. Conclusions More likely to enter the window period, early dosing of BZ is more effective for treating acute AMR. An earlier intervention yields a better efficacy. Key words: Kidney transplantation; DSA; Rejection; Bortezomib

To investigate the efficacy of early surgical intervention in ameliorating aniseikonia among patients with epiretinal membrane. This prospective cohort study enrolled patients who underwent surgery for epiretinal membrane. Patients were divided into early (symptom onset within 1 year) and late (symptom onset ≥1 year) treatment groups. Changes in aniseikonia, best-corrected visual acuity, and tangential retinal displacement were assessed and compared at 6 and 12 months postoperatively. Of the 56 patients, 30 (53.6%) belonged to the early treatment group and 26 (46.4%) to the late treatment group. The early treatment group demonstrated a significant reduction in aniseikonia score at 6- and 12-month follow-up visits (-1.10 ± 1.50 [P = 0.002] and -1.18 ± 1.79 [P = 0.003], respectively); however, no improvement was observed in the late treatment group (0.98 ± 4.62 [P = 0.310] and 1.52 ± 4.35 [P = 0.124], respectively). The early treatment group showed larger tangential retinal displacement at the 12-month postoperative follow-up visit. In addition, the amount of tangential retinal displacement was associated with postoperative changes in aniseikonia. Early surgical intervention is helpful in improving aniseikonia in patients with epiretinal membrane. The degree of recovery in inner retinal displacement was associated with the improvement of aniseikonia.

Transforming growth factor (TGF)-β1 is associated with fibrosis in many organs. Recent studies demonstrated that delivery of TGF-β1 into chemically injured muscle enhances fibrosis. In this study, we investigated the effects of exogenous TGF-β1 on muscle regeneration and adipogenesis in glycerol-injured muscle of normal mice. Tibialis anterior (TA) muscles were injured by glycerol injection. TGF-β1 was either co-injected with glycerol, as an 'early treatment' group, or injected at day 4 after glycerol, as a 'late treatment' group and the TA muscles were collected at day 7 after initial injury. Myotube density was significantly lower in the early treatment group than in the glycerol-injured group (without TGF-β1 treatment). Moreover, the Oil red O-positive area was significantly smaller in the early treatment group than in the late treatment group and glycerol-injured group. Furthermore, TGF-β1 treatment increased endomysial fibrosis and induced immunostaining of α-smooth muscle actin. The greater inhibitory effects of early TGF-β1 treatment than that of late TGF-β1 treatment during regeneration in glycerol-injured muscle suggest a more potent effect of TGF-β1 on the initial stage of muscle regeneration and adipogenesis. Combination of TGF-β1 with glycerol might be an alternative to enhance muscle fibrosis for future studies.

Objective To discuss the maternal and neonatal outcomes in gestational diabetes patients given insulin therapy at different periods.Methods Clinical data of 52 cases of gestational diabetes patients admitted from May 2011 to June 2013 in The Central Hospital of Ningbo Development Zone were analyzed,among whom 28 cases accepted insulin therapy before 32 weeks of pregnancy(early diagnosis treatment group)and the rest 24 cases accepted insulin therapy after 32 weeks of pregnancy(late diagnosis treatment group).The pregnancy outcome,hemodynamic parameters,incidence of hypertension,and the outcome of neonates were compared.Results The blood glucose of the 52 patients was controlled in the normal range after insulin therapy.However,incidence of preterm and cesarean section was significantly higher in the early diagnosis treatment group than that in the late diagnosis treatment group (P ＜ 0.05).The incidence of neonatal ketosis,fetal distress,and the incidence of macrosomia was significantly lower in the early treatment group than that in late diagnosis treatment group (P ＜ 0.05).The incidence of pregnancy-induced hypertension had not statistical difference between the two groups of pregnant women(P ＞ 0.05).S/D value of the two groups of pregnant women had no statistical significance(P ＞ 0.05).RI and PI value was significantly higher in the late diagnosis treatment group than those in early diagnosis treatment group(P ＜0.05).Conclusions The blood glucose of patients was controlled in the normal range after insulin therapy.Insulin therapy before 32 weeks of pregnancy can improve pregnancy outcomes.However,further research is needed for specific treatment programs. Key words: Gestational diabetes ; Insulin therapy; Maternal and neonatal outcomes