Early Treatment Period Research Articles

An Observational Study on the Prediction of Range of Motion in Soldiers Diagnosed with Patellar Tendinopathy Using Ultrasound Shear Wave Elastography.

This study hypothesized that changes in the elasticity of the quadriceps and patellar tendons before and after the diagnosis of patellar tendinopathy would correlate with the range of motion (ROM) following conservative treatment. We aimed to prospectively assess post-treatment ROM using multinomial logistic regression, incorporating elasticity measurements obtained via shear wave elastography (SWE). From March 2023 to April 2024, 95 patients (86 men; aged 20-45 years, mean 25.62 ± 5.49 years) underwent SWE preoperatively and two days post-diagnosis of patellar tendinopathy. Elasticity measurements of the rectus femoris, vastus medialis, vastus lateralis, patellar tendon, and biceps tendon were obtained during full flexion and extension. Based on ROM 56 days post-treatment, patients were categorized into two groups: Group A (ROM > 120 degrees) and Group B (ROM < 120 degrees). A multinomial logistic regression algorithm was employed to classify the groups using patient information and tendon elasticity measurements both at diagnosis and 1-week post-diagnosis. The predictive accuracy using only patient information was 62%, while using only elasticity measurements yielded 68% accuracy. When combining patient information with elasticity measurements taken at diagnosis and two days post-diagnosis, the algorithm achieved an accuracy of 79%, sensitivity of 92%, and specificity of 56%. The combination of patient information and tendon elasticity measurements obtained via SWE at pre-conservative treatment and early post-conservative treatment periods effectively predicts post-treatment ROM. This algorithm can guide rehabilitation strategies for soldiers with patellar tendinopathy.

Late complications and long-term care of adult CAR T-cell patients.

The success of chimeric antigen receptor (CAR) T-cell therapy in adult patients with hematologic malignancies has resulted in a large number of long-term survivors who may experience late complications distinct from those in the early CAR T-cell treatment period. These late complications, defined as occurring more than 90 days after CAR T-cell infusion, include cytopenias, infections, secondary malignancies, and delayed neurotoxicities. Late cytopenias may be from prolonged recovery after lymphodepleting (LD) chemotherapy or arise anew, raising concerns for recurrent primary disease or a secondary malignancy. Cytopenias are treated with supportive care, hematopoietic cytokines, and, occasionally, hematopoietic stem cell support. LD chemotherapy profoundly affects B, T, and natural killer cells. CD19 and B-cell maturation antigen are expressed on normal B cells and plasma cells, respectively, and the targeting of these structures by CAR T-cell products can result in prolonged lymphopenias and hypogammaglobulinemia, making infection an ongoing risk. Late infections are predominantly due to respiratory viruses, reactivation of herpes viruses, and Pneumocystis jirovecii. Patients may require ongoing prophylaxis and immunoglobulin replacement therapy. Although responses may be blunted, vaccinations are generally recommended for most adult CAR T-cell patients. Both hematologic and solid secondary malignancies are a known risk of CAR T-cell therapy; retroviruses used to produce CAR T-cell products have resulted in T-cell cancers secondary to insertional oncogenesis. It is essential to monitor for late complications in adult patients receiving CAR T-cells by using a multidisciplinary approach between referring hematologist oncologists and cell therapy centers to improve the outcomes and quality of life for these patients.

Health-related quality of life among pediatric patients with acute lymphoblastic leukemia: An exploratory cross-sectional study.

Improved survival rates broadened the pediatric oncology focus to include health-related quality of life (HRQoL). This cross-sectional study aimed to examine HRQoL by treatment phase and disease risk level in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), including those in early survivorship. A subset of data from a larger prospective cohort study was analyzed. Data were collected from 73 patients (73 parent reports and 28 self-reports). Parent proxy and self-report PROMIS measures assessed HRQoL across treatment phases (early intensive, maintenance, and off treatment) and disease risk groups (standard vs high). Analyses assessed the relationship between parent proxy and patient self-reports and the differences in HRQoL among treatment phases and risk groups. Parent proxy reports generally indicated worse fatigue, pain interference, and mobility compared with patient self-reports. Self-reports in the early intensive treatment group suggested worse depressive symptoms, fatigue, mobility, and upper extremity function compared with those in later phases. Parent proxy reports showed worse fatigue and depressive symptoms in early intensive treatment group relative to those in later phases. Patient self-reports in the maintenance group demonstrated the best peer relationships scores. Parent proxy reports in the high-risk group reported significantly higher depressive symptoms and fatigue compared with the standard-risk group. Differences in HRQoL suggest targets for further assessment and intervention. The early treatment and immediate post-survivorship periods may represent particularly critical time points. Longitudinal studies with larger and diverse samples should further explore HRQoL trajectories in this population.

Clinical and molecular mechanisms for predicting the efficacy of immunotherapy for hepatocellular carcinoma based on gut microbiome.

e16222 Background: Hepatocellular carcinoma (HCC) is an aggressive malignant tumor, ranking as the fifth most common cancer and the third leading cause of cancer-related deaths globally, posing a significant global health issue. Increasing evidence suggests that the gut microbiome and their metabolites play a crucial role in the development and therapeutic processes of cancer. Immune checkpoint inhibitors (ICIs) have recently become a treatment option for unresectable advanced HCC. To further guide the selection of immunotherapy for clinical HCC patients, it is necessary to further elucidate the prediction of immunotherapy efficacy for HCC based on the microbiome. Methods: The study enrolled 26 unresectable advanced HCC patients and collected baseline clinical laboratory data. We administered ICIs therapy to HCC patients every three weeks. After 6 months of treatment, patients were divided the responsive group (R group) and the non-responsive group (NR group) based on imaging evaluation according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Prior to the application of anti-tumor treatment, fecal samples were collected from the patients for 16S rRNA microbiome sequencing analysis. Immunofluorescence was used to detect the expression of PD-L1 in tumor tissue, and immunohistochemistry was used to assess changes in lymphocyte subsets CD3+T cells, CD4+T cells, CD8+T cells and Treg cells, as well as the expression of TNF-α, γ-IFN, and GZMB. Additionally, the peripheral blood lymphocyte subsets CD3+T cells, CD4+T cells and CD8+T cells were analyzed by flow cytometry. Results: In our study, R group showed higher taxa richness and more gene counts than those of NR group. Comparing with NR group, the relative abundance of Firmicutes were significantly increased, whereas Proteobacteria and Bacteroidota were significantly decreased in R group at phylum level (all P &lt; 0.05). Our study showed that R group had high level of lymphocyte subsets CD3+T cells and CD8+T cells and low level of CD4+T cells and Treg cells compared to NR group (all P &lt; 0.05). And the expressions of PD-L1, TNF-α,γ-IFN and GZMB were upregulated in R group(all P &lt; 0.05). Conclusions: These findings suggested that the characteristics of gut-microbial diversity and composition at the early treatment period of ICIs therapy in HCC may have distinct implications on drug efficacy and disease prognosis. ICIs therapy reshaped HCC tumor microenvironment in parallel with regulating the gut microbiome and lymphocyte subsets immunity.

Treatment of unstable forearm fractures at the metaphyseal-diaphyseal junction in children: antegrade ESIN vs. transepiphyseal intramedullary K-wire fixation.

Treatment of unstable forearm fractures in the metaphyseal-diaphyseal junction (MDJ) zone is still a matter of debate. Major drawbacks of all types of fixations include either invasiveness, technical impracticality, or lack of acceptance by patients. This study reports results after antegrade ESIN (a-ESIN) compared to transepiphyseal intramedullary K-wire (TIK) for unstable MDJ forearm fractures. The MDJ of the forearm was defined as the square over the joints of both forearm bones subtracted with the square over the metaphysis of the radius alone. The data of 40 consecutive patients < 16 years of age who were treated either by a-ESIN (later treatment period) or TIK (early treatment period) for an unstable MDJ forearm fracture at a single high-volume pediatric trauma center were retrospectively analyzed. The average age was slightly lower in the first group (TIK = 7.42 years; a-ESIN = 10.5 years). An additional ulna fracture was found in 50% of cases and was treated with a classic antegrade ESIN in 10/20 (TIK) and 6/20 cases (a-ESIN). Additional plaster cast immobilization was performed in all cases with TIK and in three cases with a-ESIN. After TIK, no complication, malalignment, or functional limitation occurred. After a-ESIN, 19/20 patients had an event-free course with stable retention and healing without axial malalignment. In one case, a temporary sensor dysfunction occurred. The same patient suffered a refracture two months after the original trauma, which required a closed reduction. Metal removal was performed after 84 days (TIK) and 150 days (a-ESIN). The outcome in all patients was good. Both a-ESIN and TIK are minimally invasive procedures that are technically easy to perform. Both methods are safe and lead to a complete restoration of the forearm's range of motion. The decisive advantage of a-ESIN is the possibility of postoperative immobilization-free rehabilitation.

Novel peripheral blood mononuclear cell mRNA signature for IFN-beta therapy responsiveness prediction in multiple sclerosis

Interferon-beta (IFN- β ) is one of the classical drugs for immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS) patients, but the drug responsiveness of different patients varies. Currently, there is no valid model to predict IFN- β responsiveness. This research attempted to develop an IFN- β responsiveness prediction model based on mRNA expression in RRMS patient peripheral blood mononuclear cells. Peripheral blood mononuclear cell mRNA expression datasets including 50 RRMS patients receiving IFN- β treatment were obtained from GEO. Among the datasets, 24 cases from GSE24427 were included in a training set, and 18 and 9 cases from GSE19285 and GSE33464, respectively, were adopted as two independent test sets. In the training set, blood samples were collected immediately before first, second, month 1, 12, and 24 IFN- β injection, and the mRNA expression data at four time points, namely, two days, one month, one year and two years after the onset of IFN- β treatment, were compared with pre-treatment data to identify IFN-stimulated genes (ISGs). The ISGs at the one-month time point were used to construct the drug responsiveness prediction model. Next, the drug responsiveness model was verified in the two independent test sets to examine the performance of the model in predicting drug responsiveness. Finally, we used CIBERSORTx to estimate the content of cell subtypes in samples and evaluated whether differences in the proportions of cell subtypes were related to differences in IFN- β responsiveness. Among the four time points, one month was the time point when the training set GSE24427 and test set GSE33464 had the highest number of ISGs. Functional analysis showed that these one-month ISGs were enriched in biological functions such as the innate immune response, type-I interferon signalling pathway, and other IFN- β -associated functions. Based on these ISGs, we obtained a four-factor prediction model for IFN- β responsiveness including MX1, MX2, XAF1, and LAMP3. In addition, the model demonstrated favourable predictive performance within the training set and two external test sets. A higher proportion of activated NK cells and lower naive CD4/total CD4 ratio might indicate better drug responsiveness. This research developed a polygene-based biomarker model that could predict RRMS patient IFN- β responsiveness in the early treatment period. This model could probably help doctors screen out patients who would not benefit from IFN- β treatment early and determine whether a current treatment plan should be continued.

Effect of Low-dose Atropine on Myopia Control in Children Operated for Intermittent Exotropia

Purpose: To evaluate the effect of low-dose atropine on myopia control in children with a history of surgery for intermittent exotropia (IXT).Methods: We retrospectively reviewed the medical records of children who used 0.05% atropine for ≥ 1 year to control myopia progression. This group included 45 patients with a history of IXT surgery and 57 patients with no such history. The annual changes in spherical equivalent and axial length were compared 6 months before, 6 months after, and 1 year after atropine instillation between the IXT surgery group and myopia controls. In this comparison, the dominant eye was paired with the right eye and the non-dominant eye with the left eye. We also analyzed the difference between IXT surgery cases corrected within versus not within 10 prism diopters (PD) at the start of low-dose atropine treatment.Results: A total of 102 patients had an average of -3.81 ± 1.53 diopters (D) and used low-dose atropine for an average of 16.8 months from a mean age of 8.2 years. On average, the IXT surgery group underwent muscle surgery for 28.1 PD of IXT at 7.8 years. A year after instillation, the myopia progression rate was -0.52 ± 0.89 D/year and 0.27 ± 0.40 mm/year in the IXT surgery group compared to -0.47 ± 0.83 D/year and 0.31 ± 0.24 mm/year in the myopia control group with no significant differences. However, after 6 months of instillation, the dominant eye in the IXT surgery group exhibited a significantly faster myopia progression rate than the right eye in the myopia control group (-0.84 ± 1.61 D/year vs. -0.56 ± 0.80 D/year, &lt;i&gt;p&lt;/i&gt; = 0.04; 0.27 ± 0.33 mm/year vs. 0.22 ± 0.21 mm/year, &lt;i&gt;p&lt;/i&gt; = 0.02). No difference was found in the myopia control effect between corrected and uncorrected cases in the IXT surgery group.Conclusions: The effect of low-dose atropine on myopia control in children after IXT surgery was similar to that in myopia controls. However, it was less effective in the dominant eye during the early treatment period.

Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. Invitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.

Patterns of engagement in care during clients' first 12 months after HIV treatment initiation in South Africa: A retrospective cohort analysis using routinely collected data.

Retention on antiretroviral therapy (ART) during the early treatment period is one of the most serious challenges facing HIV programs, but the timing and patterns of early disengagement from care remain poorly understood. We describe patterns of engagement in HIV care during the first year after treatment initiation. We analysed retrospective datasets of routinely collected electronic medical register (EMR) data for ≥18-year-old clients who initiated ART at public sector clinics in South Africa after 01/01/2018 and had ≥14 months of potential follow-up. Using scheduled visit dates, we characterized engagement in care as continuous (no treatment interruption), cyclical (at least one visit >28 days late with a return visit observed) or disengaged (visit not attended and no evidence of return). We report 6- and 12-month patterns of retention in care and viral suppression. Among 35,830 participants (65% female, median age 33), in months 0-6, 59% were continuously in care, 14% had engaged cyclically, 11% had transferred to another facility, 1% had died, and 16% had disengaged from care at the initiating facility. Among disengagers in the first 6 months, 58% did not return after their initiation visit. By 12 months after initiation, the overall proportion disengaged was 23%, 45% were classified as continuously engaged in months 7-12, and only 38% of the cohort had maintained continuous engagement at both the 6- and 12-month endpoints. Participants who were cyclically engaged in months 0-6 were nearly twice as likely to disengage in months 7-12 as were continuous engagers in months 0-6 (relative risk 1.76, 95% CI:1.61-1.91) and were more likely to have an unsuppressed viral load by 12 months on ART (RR = 1.28; 95% CI1.13-1.44). The needs of continuous and cyclical engagers and those disengaging at different timepoints may vary and require different interventions or models of care.

The effect of anesthetic blockade of greater occipital nerve during the withdrawal period of the medication overuse headache treatment.

<p>Discontinua&shy;tion of medication still remains a key element in the treatment of medication overuse headache (MOH), but there is no consensus on the withdrawal procedure. We aimed to share the promising results of anesthetic blockade of greater occipital nerve (GON), which can be an alternative to existing treatments during the early withdrawal period of MOH treatment.</p>. <p>This study was conducted using regular electronic medical records and headache diaries of patients diagnosed with MOH and treated with anesthetic GON blockade with 0.5% bupivacaine solution in a specia&shy;lized headache outpatient clinic. A total of 86 patients who developed MOH while being followed up for chronic migraine were included in the study.</p>. <p>The treatment schemes for MOH are based on expert consensus and withdrawal strategies are the most challenging part of treatment. In our study, numerical rating scale for headache intensity, overused medication consumption per month, headache frequency (day/month) and the duration of each attack (hour/day) decreased significantly in the first month compared to pre-treatment (p &lt; 0.01).&nbsp;</p>. <p>Conclusion &ndash; Our study suggests that GON blockade can be used as a good alternative therapy in the treatment of MOH.</p>.

Final Analysis of the Randomized Phase II/III Study of Standard R-CHOP Versus CHOP Combined with Dose-Dense Weekly Rituximab for DLBCL: JCOG0601

Background: Despite several attempts of randomized phase III trial to overcome R-CHOP in overall survival (OS), R-CHOP has been continued to be a standard of care in previously untreated DLBCL. We conducted a randomized phase II/III study (JCOG0601, jRCTs031180139) that investigated the efficacy of dose-dense weekly rituximab combined with standard CHOP regimen (RW-CHOP) during the early treatment period for previously untreated DLBCL and published the results (Ohmachi K, et al. Blood Adv. 2021). Here in, we report the long-term efficacy and safety of the JCOG 0601 trial after 8 years follow-up from the end of accrual. Methods: Patients aged 20-79 years with previously untreated CD20-positive DLBCL (stage I-IV, performance status 0-2) were randomized to standard R-CHOP (CHOP-21 with eight doses of rituximab, once every 3 weeks) or RW-CHOP (CHOP-21 with eight doses of weekly rituximab). The primary endpoint of phase III part was progression-free survival (PFS). Required sample size was 422 patients, an accrual period of 7 years, and a follow-up period of 3 years with the primary analysis. An additional follow-up period was added to assess long-term outcomes, for a total of 8 years of follow-up. Results: Between December 2007 and December 2014, 422 patients were enrolled, but primary analysis was performed on 421 patients after one patient withdrew consent: 213 in the R-CHOP arm and 208 in the RW-CHOP arm. The baseline characteristics were as follows (R-CHOP arm vs. RW-CHOP arm): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and International Prognostic Index score ≤2, 77.0% vs. 87.5%. At a primary analysis, there was no significant difference in PFS between the arms. At the time of final analysis with a median follow-up of 9.6 years (range: 0.3-14.9) among all patients, meaningful differences were not found in PFS and OS as well as the primary analysist (hazard ratio [HR] in PFS of RW-CHOP against R-CHOP, 0.94; 95% confidence interval [CI], 0.67 to 1.32, one-sided log-rank, P = 0.36 and HR in OS, 0.94; 95% CI, 0.63 to 1.41). Median PFS and OS were not estimable in both arms. Estimated 10 years PFS and OS of all patients was 66.9% (95% CI, 62.1 to 71.3) and 78.0% (95% CI, 73.6 to 81.7). After the first relapse or refractoriness, 126 patients received post-protocol salvage therapy: 66 in the R-CHOP arm and 60 in the RW-CHOP arm. In each arm, 3 patients received high-dose chemotherapy followed by autologous stem cell transplantation. One patient in the R-CHOP arm proceeded to allogeneic stem cell transplantation from a sibling donor. Ann Arbor stage I to II disease tended to have more favor prognosis than Ann Arbor stage III to IV disease, and no sustained relapse was observed in either stage. Of the 401 patients who underwent central pathological review, 125 were diagnosed with germinal center B-cell-like (GCB) type and 216 with non-GCB type by immunohistochemistry analysis. There was no remarkable difference in PFS between the arms for GCB type and non-GCB type. Death occurred in 95 patients: 56 from DLBCL, 2 from treatment-related cardiac toxicity, 9 from treatment-related mortality caused by salvage treatment, 14 from secondary malignancies, and 11 from other diseases or reasons. There were 34 secondary malignancies in 31 patients (14.6%) in the R-CHOP arm, and 39 cases in 35 patients (16.8%) in the RW-CHOP arm. The most common secondary malignancies were lung cancer (2.6%), colon cancer (1.9%), prostate cancer (1.7%) and gastric cancer (1.9%). Three cases of acute myeloid leukemia (0.7%) and three of myelodysplastic syndromes (0.7%) were observed. The median age of patients who developed secondary malignancy was 72 years (range: 49-84) at the onset. The median time from study enrollment to the onset of secondary malignancy was 4.5 (range: 0.1-13.1) years and the incidence was time dependent. There were no unexpected adverse events, including late opportunistic infections. Conclusion: This final-follow up data demonstrated again no superiority of RW-CHOP in PFS and OS. Standard R-CHOP remains a standard of care for untreated DLBCL.

23 Tamoxifen Effects on Cognition and Language in Women with Breast Cancer

Objective:Cognitive changes following adjuvant treatment for breast cancer (BC) are well documented particularly following chemotherapy. However, limited studies have examined cognitive and/or language functions in chemotherapy-naive women with BC taking tamoxifen (TAM). While there is some compelling evidence TAM affects cognitive and language domains, language has not been studied beyond semantics (i.e., content of language), which is just one aspect of language. Using ambulatory cognitive assessment, we investigated the trajectory of cognitive and language changes during early period of adjuvant endocrine treatment (tamoxifen) in women with BC at two time periods (pre-treatment and two months after treatment begins).Participants and Methods:Four women with BC (mean age = 62.25 years, SD = 8.38) and 18 cognitively healthy age-matched controls (mean age = 59.77, SD = 7.45) completed 3 cognitive tasks using smartphones, during a short time period (5 days) and repeated at two time periods. Symbol search, dot memory and color dots tasks were used to measure the cognitive constructs - processing speed and working memory. Response times were recorded in milliseconds. To determine language ability, language samples were collected at two time periods, where the participants described two stories from two wordless picture books and samples were assessed using core lexicon analyses.Results:Wilcoxon-signed rank test was computed to identify cognitive and linguistic changes during early period of TAM administration in women with BC at two time periods. No significant within group or between group differences were seen on the cognitive and language tasks at the two time periods, however, a trend for decline in performance was seen in some BC participants across different tasks.Conclusions:This is the first study to our knowledge to use ambulatory cognitive assessment method and study discourse-level language function during this early period (pre-treatment and 2 months post-TAM). Findings from the current study advance our understanding of trajectories of cognition and language changes during the initial course of adjuvant endocrine treatment for women with BC with ER+ tumors. Using a measurement-burst design and ambulatory cognitive assessment, we were able to apply better precision measurement to identify distinct cognitive constructs affected by adjuvant endocrine treatment. In addition, insight into changes in discourse ability are impactful for numerous reasons: (1) better understanding of how adjuvant endocrine therapy impacts communication and (2) discernment into language domains that may require early behavioral intervention.

Trends in buprenorphine dosage and days supplied for new treatment episodes for opioid use disorder, 2010–2019

BackgroundBuprenorphine reduces risk of opioid overdose mortality. However, its benefits are limited by low retention, particularly in early treatment. Optimizing initial dosage may impact retention. However, little is known about the prescription characteristics of new buprenorphine treatment episodes. MethodsIn a US sample of commercial and employer-sponsored pharmacy claims, we identified new buprenorphine treatment episodes (days 1–30) from individuals ≥16 years following 90 days without buprenorphine from 2010 to 2019. Outcomes included first prescription average days supplied, first prescription average daily dosage, and average dosage on days 2, 8, 15 and 30. ResultsWe identified 117,793 new episodes among 96,451 unique individuals. Episodes per 10,000 person-years decreased slightly over time. Stratifying by age, sex and region demonstrated decreasing episodes among individuals ≤34 years and increasing episodes among individuals ≥35 years. From 2010–2019, first prescription average days supplied and daily dosage decreased from 17.1 to 15.3 days and 13.6mg to 11.6mg, respectively. Simultaneously, the proportion of episodes without possession and with dosages <16mg increased across all days and years. By day 30, episodes without buprenorphine possession grew from 27.9% to 30.8% and episodes involving dosages of <16mg grew from 26.4% to 33.4%. ConclusionsWe found that buprenorphine dosage and days supplied for new treatment episodes decreased from 2010 to 2019 while buprenorphine possession worsened. Further investigation examining the relationship between buprenorphine dosage and retention in the early treatment period is needed.

Streamflow decreases in response to acid deposition in a subtropical forest watershed in China

Streamflow reductions have been attributed to the impacts of soil nutrient availability on plant transpiration, connecting soil biogeochemical and hydrological processes. Here we conducted a plot-scale acid addition experiment and monitored long-term hydrology in a subtropical watershed to provide direct evidence for the underlying mechanisms of these connections. These results showed that acid deposition enhanced plant growth and thus increased plant transpiration in the early treatment period. It indicates that plants can increase their transport of water and nutrients to satisfy physiological demands under continuous acid deposition. Acid deposition mainly contributed to increased evapotranspiration and decreased streamflow at the watershed scale. These results provide complementary evidence of plants adjusting to acid deposition-induced changes in soil nutrient availability and these acclimations result in streamflow reductions at the watershed scale. Our results call for integrating forest biogeochemical feedback into watershed hydrology.

Individual-Level Risk Prediction of Return to Use During Opioid Use Disorder Treatment

No existing model allows clinicians to predict whether patients might return to opioid use in the early stages of treatment for opioid use disorder. To develop an individual-level prediction tool for risk of return to use in opioid use disorder. This decision analytical model used predictive modeling with individual-level data harmonized in June 1, 2019, to October 1, 2022, from 3 multicenter, pragmatic, randomized clinical trials of at least 12 weeks' duration within the National Institute on Drug Abuse Clinical Trials Network (CTN) performed between 2006 and 2016. The clinical trials covered a variety of treatment settings, including federally licensed treatment sites, physician practices, and inpatient treatment facilities. All 3 trials enrolled adult participants older than 18 years, with broad pragmatic inclusion and few exclusion criteria except for major medical and unstable psychiatric comorbidities. All participants received 1 of 3 medications for opioid use disorder: methadone, buprenorphine, or extended-release naltrexone. Predictive models were developed for return to use, which was defined as 4 consecutive weeks of urine drug screen (UDS) results either missing or positive for nonprescribed opioids by week 12 of treatment. The overall sample included 2199 trial participants (mean [SD] age, 35.3 [10.7] years; 728 women [33.1%] and 1471 men [66.9%]). The final model based on 4 predictors at treatment entry (heroin use days, morphine- and cocaine-positive UDS results, and heroin injection in the past 30 days) yielded an area under the receiver operating characteristic curve (AUROC) of 0.67 (95% CI, 0.62-0.71). Adding UDS in the first 3 treatment weeks improved model performance (AUROC, 0.82; 95% CI, 0.78-0.85). A simplified score (CTN-0094 OUD Return-to-Use Risk Score) provided good clinical risk stratification wherein patients with weekly opioid-negative UDS results in the 3 weeks after treatment initiation had a 13% risk of return to use compared with 85% for those with 3 weeks of opioid-positive or missing UDS results (AUROC, 0.80; 95% CI, 0.76-0.84). The prediction model described in this study may be a universal risk measure for return to opioid use by treatment week 3. Interventions to prevent return to regular use should focus on this critical early treatment period.

Preferences for services in a patient’s first six months on antiretroviral therapy for HIV in South Africa and Zambia (PREFER): research protocol for a prospective observational cohort study

Background For patients on HIV treatment in sub-Saharan Africa (SSA), the highest risk for loss from care consistently remains the first six months after antiretroviral (ART) initiation, when patients are not yet eligible for most existing differentiated service delivery (DSD) models. To reduce disengagement from care during this period, we must gain a comprehensive understanding of patients’ needs, concerns, resources, and preferences for service delivery during this period. The PREFER study will use a sequential mixed-methods approach to survey a sample of patients in South Africa and Zambia 0-6 months after ART initiation to develop a detailed profile of patient characteristics and needs. Protocol PREFER is an observational, prospective cohort study of adult patients on ART for ≤6 months at 12 public sector healthcare facilities in Zambia and 18 in South Africa that aims to inform the design of DSD models for the early HIV treatment period. It has four components: 1) survey of clients 0-6 months after ART initiation; 2) follow up through routinely collected medical records for &lt;12 or &lt;24 months after enrollment; 3) focus group discussions to explore specific issues raised in the survey; and 4) in South Africa only, collection of blood samples self-reported naïve participants to assess the prevalence of ARV metabolites indicating prior ART use. Results will include demographic and clinical characteristics of patients, self-reported HIV care histories, preferences for treatment delivery, and predictors of disengagement. Conclusions PREFER aims to understand why the early treatment period is so challenging and how service delivery can be amended to address the obstacles that lead to early disengagement from care and to distinguish the barriers encountered by naïve patients to those facing re-initiators. The information collected by PREFER will help respond to patients’ needs and design better strategies for service delivery and improve resource allocation going forward.

Diffusion-weighted imaging complements T2-weighted MRI for tumour response assessment in squamous anal carcinoma

ObjectivesA published tumour regression grade (TRG) score for squamous anal carcinoma treated with definitive chemoradiotherapy based on T2-weighted MRI yields a high proportion of indeterminate responses (TRG-3). We investigate whether the addition of diffusion-weighted imaging (DWI) improves tumour response assessment in the early post treatment period.Materials and methodsThis retrospective observational study included squamous anal carcinoma patients undergoing MRI before and within 3 months of completing chemoradiotherapy from 2009 to 2020. Four independent radiologists (1–20 years’ experience) scored MRI studies using a 5-point TRG system (1 = complete response; 5 = no response) based on T2-weighted sequences alone, and then after a 12-week washout period, using a 5-point DWI-TRG system based on T2-weighted and DWI. Scoring confidence was recorded on a 5-point scale (1 = low; 5 = high) for each reading and compared using the Wilcoxon test. Indeterminate scores (TRG-3) from each reading session were compared using the McNemar test. Interobserver agreement was assessed using kappa statistics.ResultsEighty-five patients were included (mean age, 59 years ± 12 [SD]; 55 women). T2-weighted TRG-3 scores from all readers combined halved from 24% (82/340) to 12% (41/340) with DWI (p < 0.001). TRG-3 scores changed most frequently (41%, 34/82) to DWI-TRG-2 (excellent response). Complete tumour response was recorded clinically in 77/85 patients (91%). Scoring confidence increased using DWI (p < 0.001), with scores of 4 or 5 in 84% (287/340). Interobserver agreement remained fair to moderate (kappa range, 0.28–0.58).ConclusionDWI complements T2-weighted MRI by reducing the number of indeterminate tumour responses (TRG-3). DWI increases radiologist’s scoring confidence.Clinical relevance statementDiffusion-weighted imaging improves T2-weighted tumour response assessment in squamous anal cancer, halving the number of indeterminate responses in the early post treatment period, and increases radiologists’ confidence.Key PointsTumour response based on T2-weighted MRI is often indeterminate in squamous anal carcinoma.Diffusion-weighted imaging alongside T2-weighted MRI halved indeterminate tumour regression grade scores assigned by four radiologists from 24 to 12%.Scoring confidence of expert and non-expert radiologists increased with the inclusion of diffusion-weighted imaging.

Prognostic value of baseline and early treatment response of neutrophil-lymphocyte ratio, C-reactive protein, and lactate dehydrogenase in non-small cell lung cancer patients undergoing immunotherapy.

Not all non-small cell lung cancer (NSCLC) patients will benefit from immune checkpoint therapy and use of these medications carry serious autoimmune adverse effects. Therefore, biomarkers are needed to better identify patients who will benefit from its use. Here, the correlation of overall survival (OS) with baseline and early treatment period serum biomarker responses was evaluated in patients with NSCLC undergoing immunotherapy. Patients diagnosed with NSCLC undergoing immunotherapy (n=597) at a tertiary academic medical center in South Korea were identified between January 2010 and November 2021. The neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels in the survival and non-survival groups were examined at baseline and early treatment periods. Additionally, aberrant laboratory parameters at each period were used to stratify survival curves and examine their correlation with one-year OS. In the non-survival group, the NLR, CRP, and LDH levels at the early treatment period were higher than those at the baseline (P<0.001). The survival curves stratified based on aberrant laboratory findings in each period varied (log-rank test P<0.001). Multivariate Cox regression analysis revealed that having prescribed more than 3rd line of chemotherapy [hazard ratio (HR) =3.19, 95% confidence interval (CI): 1.04-9.82; P=0.043] and early treatment period CRP (HR =3.88; 95% CI: 1.55-9.72; P=0.004) and LDH (HR =4.04; 95% CI: 2.01-8.12; P<0.001) levels were significant predictors of one-year OS. Early treatment period CRP and LDH levels were significant predictors of OS in patients with NSCLC undergoing immunotherapy.

Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods

While combination therapy completely suppresses HIV-1 replication in blood, functional virus persists in CD4+ Tcell subsets in non-peripheral compartments that are not easily accessible. To fill this gap, we investigated tissue-homing properties of cells that transiently appear in the circulating blood. Through cell separation and invitro stimulation, the HIV-1 "Gag and Envelope reactivation co-detection assay" (GERDA) enables sensitive detection of Gag+/Env+ protein-expressing cells down to about one cell per million using flow cytometry. By associating GERDA with proviral DNA and polyA-RNA transcripts, we corroborate the presence and functionality of HIV-1 in critical body compartments utilizing t-distributed stochastic neighbor embedding (tSNE) and density-based spatial clustering of applications with noise (DBSCAN) clustering with low viral activity in circulating cells early after diagnosis. We demonstrate transcriptional HIV-1 reactivation at any time, potentially giving rise to intact, infectious particles. With single-cell level resolution, GERDA attributes virus production to lymph-node-homing cells with central memory Tcells (TCMs) as main players, critical for HIV-1 reservoir eradication.

Tamoxifen Effects on Cognition and Language in Women with Breast Cancer.

Cognitive changes following adjuvant treatment for breast cancer (BC) are well documented following chemotherapy. However, limited studies have examined cognitive and/or language functions in chemotherapy-naive women with BC taking tamoxifen (TAM). Using ambulatory cognitive assessment, we investigated the trajectory of cognitive and language changes during early period of adjuvant endocrine treatment (TAM) in women with BC at two time periods (pretreatment and 2 months after treatment began). Four women with BC and 18 cognitively healthy age-matched controls completed three cognitive tasks using smartphones, during a short time period (5 days) and repeated them at two time periods. To determine language ability, language samples were collected at two time periods, where the participants described two stories from two wordless picture books and samples were assessed using core lexicon analyses. Wilcoxon-signed rank tests were computed to identify differences in linguistic and cognitive performances of both the groups at two time periods. No significant within-group or between-group differences were seen on the cognitive and language tasks at the two time periods; however, women with BC performed more poorly compared to the control group. We did see decline in some women with BC and not in others, in cognition and language during initial course of TAM treatment. However, the approach we used to assess these changes is valuable and innovative. This approach will help refine current research paradigms for determining cognitive and linguistic changes and will help determine if women with BC might require language intervention in the future.