Medium-term exposure to size-fractioned particulate matter and asthma exacerbations in China: A longitudinal study of asthmatics with poor medication adherence.

BACKGROUND: Studies have shown that short- and long-term exposure to particulate matter (PM) can increase the risk of asthma morbidity and mortality. However, the effect of medium-term exposure remains unknown. We aim to examine the effect of medium-term exposure to size-fractioned PM on asthma exacerbations among asthmatics with poor medication adherence. METHODS: We conducted a longitudinal study in China based on the National Mobile Asthma Management System Project that specifically and routinely followed asthma exacerbations in asthmatics with poor medication adherence from April 2017 to May 2019. High-resolution satellite remote-sensing data were used to estimate each participant's medium-term exposure (on average 90 days) to size-fractioned PM (PM1, PM2.5, and PM10) based on the residential address and the date of the follow-up when asthma exacerbations (e.g., hospitalizations and emergency room visits) occurred or the end of the follow-up. The Cox proportional hazards model was employed to examine the hazard ratio of asthma exacerbations associated with each PM after controlling for sex, age, BMI, education level, geographic region, and temperature. RESULTS: Modelling results revealed nonlinear exposure-response associations of asthma exacerbations with medium-term exposure to PM1, PM2.5, and PM10. Specifically, for emergency room visits, we found an increased hazard ratio for PM1 above 22.8 µg/m3 (1.060, 95 % CI: 1.025-1.096, per 1 µg/m3 increase), PM2.5 above 38.2 µg/m3 (1.032, 95 % CI: 1.010-1.054), and PM10 above 78.6 µg/m3 (1.019, 95 % CI: 1.006-1.032). For hospitalizations, we also found an increased hazard ratio for PM1 above 20.3 µg/m3 (1.055, 95 % CI: 1.001-1.111) and PM2.5 above 39.2 µg/m3 (1.038, 95 % CI: 1.003-1.074). Furthermore, the effects of PM were greater for a longer exposure window (90-180 days) and among participants with a high BMI. CONCLUSION: This study suggests that medium-term exposure to PM is associated with an increased risk of asthma exacerbations in asthmatics with poor medication adherence, with a higher risk from smaller PM.

Autologous microfragmented adipose tissue treatment of knee osteoarthritis demonstrates effectiveness in 68% of patients at 4-year follow-up.

BACKGROUND: Adipose tissue-derived stem cells are an interesting therapeutic option for early knee osteoarthritis (OA) treatment due to their high plasticity, easiness of harvesting and rapidity of administration. The aim of this study was to evaluate the medium-term effectiveness and safety of Microfragmented Autologous Fat Tissue (MFAT) injection treatment at 4-year follow-up and to investigate potential correlations among patients' pre-treatment clinical condition and clinical outcomes to identify possible predicting factors for procedure success or failure. PATIENTS AND METHODS: This is a prospective trial enrolling 46 patients with diagnosis of symptomatic knee OA and failure of previous conservative measures who underwent diagnostic arthroscopy and single autologous MFAT injection between June 2017 and July 2018. Patients were assessed with repeated clinical scoring systems at baseline, 6 months, 1 and 4 years after surgery. The evaluation included demographic characteristics, arthroscopic findings, and stem cell number from injected tissue. RESULTS: No major complications were reported during follow-up period and there was a significant increase of Lysholm knee score from baseline value of 61.7 ± 13.8 to 79.5 ± 16.9 at 4 years (p < 0.001). The WOMAC score increased from a baseline value of 66.5 ± 14.7 to 82.8 ± 15.7 at 4 years (p < 0.001) and there was a significant decrease of VAS pain score from baseline value of 6.3 ± 1.5 to 3.5 ± 2.6 at 4-year follow-up (p < 0.001). ROM improved significantly from 118.4 ± 2.6 to 122.5 ± 2.5 at 12 months (p < 0.001), but did not improve at 4 years (p > 0.05). 15 patients (32.6%) were considered treatment failures, because they required secondary surgery, further injection therapy or experienced symptoms persistence. Patient with synovitis had 75% failure rate, although synovitis did not result as a statistically significant factor influencing clinical outcome up to 4-year follow-up (p = 0.058). Age, cartilage defects severity, BMI, concomitant procedures, and stem cell number from injected MFAT did not show any significant correlation with the results. CONCLUSIONS: MFAT intra-articular injection is a safe procedure with positive improvements up to 4-year follow-up in patients with early knee OA. These findings suggest MFAT could be a minimally invasive treatment of early knee OA with durable benefits at mid-term evaluation. TRIAL REGISTRATION: IRB number ID-3522.

Effects of Short- And Medium-Term Exposures to Lower Air Temperature on 71 Novel Biomarkers of Subclinical Inflammation: Results from the KORA F4 Study.

Increasing evidence has revealed that exposure to low temperatures is linked to a higher risk of chronic diseases and death; however, the mechanisms underlying the observed associations are still poorly understood. We performed a cross-sectional analysis with 1115 participants from the population-based KORA F4 study, which was conducted in Augsburg, Germany, from 2006 to 2008. Seventy-one inflammation-related protein biomarkers were analyzed in serum using proximity extension assay technology. We employed generalized additive models to explore short- and medium-term effects of air temperature on biomarkers of subclinical inflammation at cumulative lags of 0-1 days, 2-6 days, 0-13 days, 0-27 days, and 0-55 days. We found that short- and medium-term exposures to lower air temperature were associated with higher levels in 64 biomarkers of subclinical inflammation, such as Protein S100-A12 (EN-RAGE), Interleukin-6 (IL-6), Interleukin-10 (IL-10), C-C motif chemokine 28 (CCL28), and Neurotrophin-3 (NT-3). More pronounced associations between lower air temperature and higher biomarker of subclinical inflammation were observed among older participants, people with cardiovascular disease or prediabetes/diabetes, and people exposed to higher levels of air pollution (PM2.5, NO2, and O3). Our findings provide intriguing insight into how low air temperature may cause adverse health effects by activating inflammatory pathways.

Replacement of long-segment ureteral defect with tapered demucosalized ileum: medium-term outcomes of 4 patients.

PURPOSE: Repair of long-segment ureteral defect (LSUD) is challenging. Currently available procedures carry some potential complications. We modified the ileal graft by tapering the wall and stripping the mucosa to combat associated pitfalls and first reported the medium-term outcomes of 4 patients. MATERIAL AND METHODS: From September 2019 to October 2020, tapered demucosalized ileum (TDI) was used for LSUD reconstruction in 4 patients on the right (2 males and 2 females). Two patients were with panureteral avulsion and 2 with high-risk urothelial carcinoma in the distal ureter. TDI was made by tapering 1/2-2/3 of the antimesenteric ileal wall and stripping the mucosa with a blunt/blunt operating scissor. Follow-up modalities included serum creatinine, electrolytes, ultrasonography, CT urogram, renal scintigraphy, and ureteroscopy. RESULTS: Mean operation time was 443 min (range 360-550) and blood loss was negligible. The mean follow-up period was 29 months (range 23-36). Vesicoureteral reflux and related pyelonephritis occurred in 1 patient, necessitating a repair operation (Clavien-Dindo grade IIIb). No strictures, obstructions, metabolic disorders, or electrolyte imbalances were observed in the remaining patients. In carcinoma patients, ureteroscopy in month 18 post-operation revealed ileal mucosal regrowth in the form of dwarf isolated islands. All renal units maintained adequate drainage and function during the follow-up. CONCLUSIONS: Ileal wall tapering and mucosa stripping confined to the muscularis mucosae level will not result in shrinkage, fibrosis, or stricture formation of the ileal ureter. The present work provides evidence for further application of TDI in the replacement of LSUD in patients.

Sustainability capacity and health worker normalisation of a successful non-communicable disease (NCD) health systems intervention within primary care settings in Uganda: a quantitative approach to a qualitative question.

BACKGROUND: Interventions for non-communicable diseases are increasingly implemented and evaluated in sub-Saharan Africa, but little is known about their medium- to long-term sustainability beyond the end of research funding. A cluster randomised trial conducted between 2013 and 2016 in Uganda and Tanzania showed that an intervention package to improve hypertension (HT) and type-2 diabetes mellitus (DM) care was highly effective in increasing service readiness and quality of care. The present study assesses the sustainability of the intervention 4 years after the trial in Uganda. METHODS: The study was conducted in 2020 in 22 primary care health facilities (HFs) (3 referrals and 19 lower-level units) that had received the intervention package until trial end (2016), to assess their current capacity and practice to sustain ongoing intervention activities for HT and DM care. Through a cross-sectional survey, 4 pre-defined domains (i.e., cognitive participation, coherence, collective action, and reflexive monitoring) were examined with regard to health worker (HW) normalization and 8 pre-defined domains for intervention sustainability (i.e., organisational capacity, local environment, funding stability, partnerships, communication, evaluation, adaptation, and strategic planning), using the normalisation tool and the program sustainability tool (PSAT). Summary scores were assessed by domains and facility level. RESULTS: Overall normalization strength was adequate at 4.0 (IQR: 3.8, 4.2) of a possible 5 with no evidence of association with HF level (p = 0.40); cognitive participation (buy-in) and reflexive monitoring (appraisal) were strongest at > 4 across all HF levels. All HF levels were weak (< 4) on collective action (teamwork) and coherence (sense-making). Only collective action differed by level (p < 0.002). Overall intervention sustainability was suboptimal at 3.1 [IQR: 1.9, 4.1] of a possible 7 with weak scores on funding stability (2.0), supportive partnerships (2.2), and strategic planning (2.6). Domain differences by HF level were significant for environmental support (p = 0.02) and capacity in organisation (p = 0.01). Adequate strength at a cut-off mean of ≥5 did not differ by HF level for any domain. CONCLUSIONS: Four years after their introduction, practice-dependent intervention elements e.g., local organisational context, HW knowledge or dedication were sustained, but external elements e.g., new funding support or attracting new partners to sustain intervention efforts were not. Whenever new interventions are introduced into an existing health service, their long-term sustainability including the required financial support should be ensured. The quality of services should be upheld by providing routine in-service training with dedicated support supervision.

Medium-to-long term sustainability of a health systems intervention to improve service readiness and quality of non-communicable disease (NCD) patient care and experience at primary care settings in Uganda.

BACKGROUND: With the double burden of rising chronic non-communicable diseases (NCDs) and persistent infectious diseases facing sub-Saharan Africa, integrated health service delivery strategies among resource-poor countries are needed. Our study explored the post-trial sustainability of a health system intervention to improve NCD care, introduced during a cluster randomised trial between 2013 and 2016 in Uganda, focusing on hypertension (HT) and type-2 diabetes mellitus (DM) services. In 2020, 19 of 38 primary care health facilities (HFs) that constituted the trial's original intervention arm until 2016 and 3 of 6 referral HFs that also received the intervention then, were evaluated on i) their facility performance (FPS) through health worker knowledge, and service availability and readiness (SAR), and ii) the quality-of-patient-care-and-experience (QoCE) received. METHODS: Cross-sectional data from the original trial (2016) and our study (2020) were compared. FPS included a clinical knowledge test with 222 health workers: 131 (2016) and 91 (2020) and a five-element SAR assessment of all 22 HFs. QoCE assessment was performed among 420 patients: 88 (2016) and 332 (2020). Using a pair-matched approach, FPS and QoCE summary scores were compared. Linear and random effects Tobit regression models were also analysed. RESULTS: The mean aggregate facility performance (FPS) in 2020 was lower than in 2016: 70.2 (95%CI = 66.0-74.5) vs. 74.8 (95%CI = 71.3-78.3) respectively, with no significant difference (p = 0.18). Mean scores declined in 4 of 5 SAR elements. Overall FPS was negatively affected by rural or urban HF location relative to peri-urban HFs (p < 0.01). FPS was not independently predicted but patient club functionality showed weak association (p = 0.09). QoCE declined slightly to 8.7 (95%CI = 8.4-91) in 2020 vs 9.5 (95%CI = 9.1-9.9) in 2016 (p = 0.02) while the proportion of patients receiving adequate quality care also declined slightly to 88.2% from 98.5% respectively, with no statistical difference (p = 0.20). Only the parent district weakly predicted QoCE (p = 0.05). CONCLUSIONS: Four years after the end of research-related support, overall facility performance had declined as expected because of the interrupted supplies and a decline in regular supervision. However, both service availability and readiness and quality of HT/DM care were surprisingly well preserved. Sustainability of an NCD intervention in similar settings may remain achievable despite the funding instability following a trial's end but organisational measures to prepare for the post-trial phase should be taken early on in the intervention process.

Persistent morbidity in Clade IIb mpox patients: interim results of a long-term follow-up study, Belgium, June to November 2022.

While mpox was well characterised during the 2022 global Clade IIb outbreak, little is known about persistent morbidity. We present interim results of a prospective cohort study of 95 mpox patients assessed 3-20 weeks post-symptom onset. Two-thirds of participants had residual morbidity, including 25 with persistent anorectal and 18 with genital symptoms. Loss of physical fitness, new-onset/worsened fatigue and mental health problems were reported in 36, 19 and 11 patients, respectively. These findings require attention by healthcare providers.

Oncological monitoring after transanal total mesorectal excision (TaTME) for rectal neoplasia.

BACKGROUND: The surgical treatment of choice for rectal neoplasia is total mesorectal excision (TME). The transanal approach enables a better approach in male and obese patients and/or those with a narrow pelvis and in patients with small tumors. Short-term results are comparable with those for laparoscopy or the open approach, but the medium- and long-term oncological data are sparse. The aim of the present study was to evaluate our early experience with transanal TME (TaTME). METHODS: This was a retrospective study conducted on patients who underwent TaTME at our center between August 2013 and April 2017 with a follow-up ≥ 3 years. Histopathology, complications, mortality, neoplastic recurrence and disease-free survival were analyzed. RESULTS: One hundred patients (68 men and 32 women,, median age 66.8 years [range 29.6-91.2 years]) were included. There were 67 T3 cases (67%) with 74 N0 cases (74%), the mesorectal quality was graded optimal for 87.6% and only 2 cases of radial margin involvement were detected (2%). The median follow-up period was 47.6 months (range 11.8-78.9 months). Eighteen cases of recurrence were diagnosed, of which 3 (3%) recurred locally with an average disease-free period of 43.1 months. Overall survival was 80% and mortality due to progression of disease was 13%. CONCLUSIONS: TaTME is a safe surgical procedure with surgical, anatomopathological and oncological results at 3 years (medium-term) comparable with those for the laparoscopic and open approaches. Better monitoring is required with studies of the long-term functional and quality of life outcomes, i.e., at 5 or 10 years.

Combined Bankart and SLAP repair: patient-reported outcome measurements after a minimum 5-year follow-up.

BACKGROUND: Anterior shoulder instability is typically characterized by detachment of the anteroinferior labrum (Bankart lesion). Some patients also sustain a superior labrum anterior-to-posterior (SLAP) injury. The purpose of this study was to compare the medium-term clinical results of isolated anterior Bankart repairs (ABR) with those of combined Bankart and SLAP repair (ABR + SLAP). METHODS: Data on all patients treated surgically for recurrent anterior shoulder instability between 2006 and 2011 were retrospectively collected from medical charts. The minimum follow-up was 5 years. Patients were interviewed to assess patient-reported outcome measurements (PROM) as determined by the American Shoulder and Elbow Surgeons Score (ASES), the Subjective Shoulder Score (SSV), and the Disabilities of the Arm, Shoulder, and Hand Score (DASH), as well as their quality of life (QOL: SF12 questionnaire). Information on complications, re-operations, and recurrent instability was recorded and evaluated as well. RESULTS: A total of 150 patients (88% males) with a mean age 23.7 years (range 15-40) were included. Forty-two patients following ABR + SLAP repair were compared to 108 patients following ABR alone, with a mean follow-up of 7.8 years (range 5-10.7). The rate of re-dislocation was similar in both groups (26% for ABR + SLAP vs 20% for ABR, p = .44). There were no significant differences in functional outcome between the ABR + SLAP and the ABR alone groups (SSV 86.7 vs 86.5, p = .93, ASES 89.6 vs 86.5, p = .11, and DASH 4.9 vs 7, p = .17), or in QOL outcome (SF12 physical 95.6 vs 93.3, p = .27, SF12 mental 84.4 vs 85.7, p = .63). CONCLUSION: Surgical repair for anterior shoulder instability and a coexisting SLAP lesion yields clinical results as good as those of isolated ABR, as evidenced by similar PROM and re-dislocation rates after medium-term follow-up. LEVEL OF EVIDENCE: III.

Evaluation of high intensity focused ultrasound treatment for different types of adenomyosis based on magnetic resonance imaging classification.

OBJECTIVE: To evaluate the mid-term symptom improvement of patients with different types of adenomyosis based on magnetic resonance imaging (MRI) classification after ultrasound-guided high intensity focused ultrasound (USgHIFU) treatment. MATERIALS AND METHODS: A total of 321 patients with adenomyosis who underwent HIFU and completed 18-month follow-up were retrospectively reviewed. Based on the relationship between the adenomyotic lesion and the uterine structural components on T2-weighted imaging (T2WI), adenomyotic lesions were classified as internal, external, full thickness and intramural adenomyosis. Based on the extent of the myometrial involvement, these lesions were further subclassified as asymmetric and symmetric adenomyosis. RESULTS: All patients completed HIFU ablation in one session. The range of median menstrual pain score in patients with asymmetric internal, symmetric internal, asymmetric external, asymmetric full thickness, symmetric full thickness, and intramural adenomyosis was between 6 and 8 points before HIFU, the median menstrual pain score decreased to 2-4 points 18-month post-HIFU (p < .005). The menstrual pain relief rate was 68.3%, 62.1%, 54.7%, 64.1%, 60%, and 100%, respectively. The median menstrual blood volume score range was between 2 and 4 points in the different groups of patients before HIFU, it decreased to 1-3 points 18-month after HIFU with a relief rate of 68.3%, 51.6%, 51.0%, 55.5%, 57.2%, and 100%, respectively. No serious complication occurred in any of these patients. CONCLUSIONS: Based on our results, USgHIFU is safe and effective in the treatment of patients with different subtypes of adenomyosis with mid-term sustained improvement in symptoms of menstrual pain and menstrual blood volume.

Ultralight type I transvaginal mesh: an alternative for recurrent severe posterior vaginal prolapse.

OBJECTIVE: This study aimed to analyze the medium-term outcomes of ultralight type I mesh for postmenopausal women with recurrent severe posterior vaginal prolapse (PVP). METHODS: All participants underwent transvaginal ultralight type I mesh repair between April 2016 and April 2021 and were followed until May 2022. Pelvic Organ Prolapse Quantification System (POP-Q) staging, mesh-related complications, Patient Global Impression of Improvement (PGI-I) scale and quality of life questionnaire responses were evaluated. The primary outcome was composite surgical success rate at the last follow-up, composite success being defined as no vaginal bulge symptoms, no POP-Q point at or beyond the hymen and no re-treatment for POP. Secondary outcomes included anatomic outcomes (POP-Q score), symptomatic relief and complications. RESULTS: The median follow-up was 37.3 months. At the last follow-up, the composite success rate was 75%, and POP-Q scores for the vault and posterior wall and quality of life questionnaire scores were significantly improved (p < 0.01). The subjective satisfaction (PGI-I ≤ 2) rate was 83.3%. There were no mesh-related complications. CONCLUSIONS: Ultralight mesh can achieve good clinical outcomes and substantially improve the quality of life of patients with severe recurrent PVP in the medium term, and may thus be a viable alternative for treating this condition.

Medium-term follow-up of autologous pericardial patches for pediatric aortic arch reconstruction.

OBJECTIVES: Direct anastomosis, like end-to-end anastomosis or end-to-side anastomosis, is commonly employed to repair aortic coarctation or interrupted aortic arch. Direct anastomosis of the aorta, however, may result in restenosis or bronchial compression. To circumvent these complications, we have applied a technique consisting of aortic reconstruction using glutaraldehyde-fixed autologous pericardial patches. METHODS: Our database was queried for infants who underwent aortic arch reconstruction using autologous pericardial patches from 2007 to 2019. Medical records, including echography imaging, were reviewed, and Z-scores of aortic arch diameters were retrospectively assessed at baseline, immediately after surgery, and at follow-up end. RESULTS: Overall, 58 patients met the inclusion criteria, with a median age of 9.8 days at surgery and median postoperative follow-up of 46 months. Re-coarctation requiring re-intervention by either surgery or percutaneous angioplasty was documented in 14.7% of patients. Overall, 9% of patients died of all-cause mortality. The Z-scores evolved favorably from baseline, which clearly indicated hypoplastic aortic arch, to early postoperative status, which clearly showed values close to those obtained in normal infants, with likewise normal values obtained at median 46-month follow-up. CONCLUSIONS: Glutaraldehyde-fixed autologous pericardial patches were shown to provide correct medium-term results for aortic arch reconstruction. The incidence of restenosis requiring re-intervention was shown to be low. Autologous pericardial patches can be considered as an acceptable and easily available solution for aortic arch repair surgery.

Medium-term outcomes 2 years after laparoscopic sacrocolpopexy: a retrospective cohort study in Japan.

This study was performed to investigate medium-term outcomes and reoperation rates after laparoscopic sacrocolpopexy (LSC). We examined 119 patients undergoing LSC for symptomatic pelvic organ prolapse (POP). The primary outcomes were subjective failure and anatomical failure at 2 years; a score ≥ 2 on question 3 of the PFDI-20 was considered to indicate subjective failure. POP-Q stage 2 or higher in any compartment was considered to indicate anatomical failure. Secondary outcomes were reoperations for POP recurrence, mesh-related complications, and stress urinary incontinence (SUI). The rates of subjective failure and anatomical failure were 4.2% (n = 5) and 9.2% (n = 11), respectively. Reoperations were needed in 13.4% (n = 16) of patients, including SUI with tape procedure in 7.5% (n = 9), POP recurrence in 4.2% (n = 5), and mesh-related complications in 1.6% (n = 2). The subjective failure rate at 2 years after LSC was acceptably low.Impact StatementWhat is already known on this subject? Laparoscopic sacrocolpopexy (LSC) has clinical efficacy equivalent to open sacrocolpopexy, and there is evidence that LSC involves less blood loss and shorter length of hospital stay. However, there is still insufficient evidence to assess medium-term outcomes after LSC in Japan.What the results of this study revealed? The findings of this study showed excellent medium-term rates of subjective failure (4.2%) and anatomical failure (8.4%) after LSC. We demonstrated that patients with persistent postoperative vaginal bulge (subjective failure) also had no improvement in postoperative urinary and colorectal symptoms. Our cohort had low rates of reoperation (13.4%) after LSC. The most common reoperations were for stress urinary incontinence (SUI) (7.5%), followed by pelvic organ prolapse (POP) recurrence (4.2%) and mesh-related complications (1.6%).What are the implications of these findings in clinical practice and/or further research? This study showed that LSC is a safe and effective treatment for POP. Comparative evaluation of anatomical outcomes and the patient's condition is required to understand the extent to which LSC positively impacts a woman's pelvic floor-related quality of life.

Lack of hepatocarcinogenicity of 2,2'-[1,2-ethanediylbis(oxymethylene)]bis-oxirane, 3-hydroxy-2-naphthoic acid, and acetoacetanilide in a medium-term rat liver bioassay.

The carcinogenicity of 2,2'-[1,2-ethanediylbis(oxymethylene)]bis-oxirane (ethylene glycol diglycidyl ether; EGDE), 3-hydroxy-2-naphthoic acid (HNA), and acetoacetanilide (AAA) was investigated using a medium-term rat liver bioassay for an occupational safety assessment. F344 male rats were administered a single intraperitoneal injection of diethylnitrosamine (200 mg/kg body weight (bw)/day) and then starting 2 weeks later, they received EGDE at 6, 20, and 60 mg/kg bw/day, HNA at 20, 60, and 200 mg/kg bw/day, or AAA at 60, 200, and 600 mg/kg bw/day by oral gavage for 6 weeks. The animals in the positive control group received phenobarbital sodium solution (PB, 25 mg/kg bw/day) by oral gavage and those in the negative control group received a vehicle (water/corn oil) during the administration period of test substances in this model. All animals were subjected to two-thirds partial hepatectomy at week 3 and euthanized at week 8. Neither the number nor the area of hepatocellular foci positive for glutathione S-transferase placental form (GST-P) increased in any of the EGDE, HNA, or AAA treated groups. However, the number and area of GST-P-positive foci significantly increased in the positive control group treated with PB. The results indicate that EGDE, HNA, and AAA lack hepatocarcinogenicity in rats.

Aristolochic acid I promoted clonal expansion but did not induce hepatocellular carcinoma in adult rats.

Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P+) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P+ foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg-1 · d-1, 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P+ foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg-1· d-1, 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P+ foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg-1· d-1) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC.

Effectiveness of local exercise therapy versus spinal manual therapy in patients with patellofemoral pain syndrome: medium term follow-up results of a randomized controlled trial.

BACKGROUND: Increasing evidence has shown benefits of spinal manipulations in patients with patellofemoral pain syndrome (PFPS). There is scarcity regarding medium term effects of spinal manual therapy on outcome measures in PFPS patients. Therefore, the aim of the present study was to compare the effectiveness of local exercise therapy and spinal manual therapy for knee pain, function and maximum voluntary peak force (MVPF) velocity of the quadriceps in PFPS patients. METHODS: Forty-three patients with PFPS were randomly assigned to a local exercise or spinal manual therapy group. The local exercise group received six sessions (one session per week) of supervised training of the knee-and hip muscles with mobilization of the patellofemoral joint. The spinal manual therapy group received six interventions (one intervention per week) of high velocity low thrust manipulations at the thoracolumbar region, sacroiliac joint, and/or hip. All patients were also asked to do home exercises. Maximum, minimum and current pain were measured using the visual analogue scale. Function was assessed with the anterior knee pain scale (AKPS) and MPFV was recorded using a Biodex System 3 dynamometer. Patients were assessed before intervention, after 6 weeks of intervention and after 6 weeks of follow-up. Between-group differences at assessments were analysed by way of analysis of covariance with Bonferroni correction. RESULTS: Pain and functionality improved more following spinal manipulative therapy than local exercise therapy. After 6 weeks of intervention the between-group difference (local versus spinal) for maximal pain was 23.4 mm [95% CI: 9.3, 37.6; effect size (ES): 1.04] and - 12.4 [95% CI: - 20.2, - 4.7; ES: 1.00] for the AKPS. At 6 weeks of follow-up the between-group difference for maximal pain was 18.7 mm [95% CI: 1.4, 36.0; ES: 0.68] and - 11.5 [95% CI: - 19.9, - 3.3; ES: - 0.87] for the AKPS. CONCLUSIONS: This study suggests that spinal manual therapy is more effective than local exercise therapy in improving pain and function in patients with PFPS in the medium term. We suggest for future research to investigate whether combining local exercise therapy and spinal manual therapy is more effective than either single intervention on its own. This clinical trial study was approved by the Medical Ethics Committee METC Z under registration number NL57207.096. and registered retrospectively in ClinicalTrials.gov PRS with registration ID number NCT04748692 on the 10th of February 2021.

Foramen magnum decompression in adults with Chiari type 1 malformation: use of intraoperative ultrasound to guide extent of surgery.

BACKGROUND: Foramen magnum decompression (FMD) is an established technique for patients with Chiari-1 malformation. However, the extent of decompressive surgery is controversial, in particular whether dural opening is undertaken. OBJECTIVE: In this study, we report outcomes with our technique utilising intraoperative ultrasound (iOU) findings. Decision to proceed for further decompression was based on CSF flow around foramen magnum and visualisation of tip of tonsils. METHODS: Review of adults with CM-1 undergoing FMD 2013-2018. Patients underwent a suboccipital craniectomy ± partial C1 superior laminectomy ± duraplasty in a stepwise manner. Favourable iOU findings of CSF flow around the foramen magnum and pulsation of the tonsillar tips were sought at each step. Post-operative outcomes were assessed using the Chicago Chiari Outcome Score (CCOS). RESULTS: Fifty-seven patients were included. The mean age was 47 years (range 18-77 years). There was a strong female preponderance (48 females to nine males). The mean follow-up was 3.2 years (range 1-5 years). Surgery included: suboccipital craniectomy (52/57, 91%), plus partial C1 superior laminectomy (2/57, 4%), and plus duraplasty (3/57, 6%). Redo surgery was undertaken in 7/57 patients (12%). At final follow-up, 56/57 (98%) patients achieved a good (CCOS 13-16) or satisfactory (CCOS 9-12) outcome based on COSS. CONCLUSIONS: A patient centred approach to surgery utilising findings from iOU can achieve favourable outcomes. Dural opening is not routinely required.

Additive Ensemble Neural Network with Constrained Weighted Quantile Loss for Probabilistic Electric-Load Forecasting.

This work proposes a quantile regression neural network based on a novel constrained weighted quantile loss (CWQLoss) and its application to probabilistic short and medium-term electric-load forecasting of special interest for smart grids operations. The method allows any point forecast neural network based on a multivariate multi-output regression model to be expanded to become a quantile regression model. CWQLoss extends the pinball loss to more than one quantile by creating a weighted average for all predictions in the forecast window and across all quantiles. The pinball loss for each quantile is evaluated separately. The proposed method imposes additional constraints on the quantile values and their associated weights. It is shown that these restrictions are important to have a stable and efficient model. Quantile weights are learned end-to-end by gradient descent along with the network weights. The proposed model achieves two objectives: (a) produce probabilistic (quantile and interval) forecasts with an associated probability for the predicted target values. (b) generate point forecasts by adopting the forecast for the median (0.5 quantiles). We provide specific metrics for point and probabilistic forecasts to evaluate the results considering both objectives. A comprehensive comparison is performed between a selection of classic and advanced forecasting models with the proposed quantile forecasting model. We consider different scenarios for the duration of the forecast window (1 h, 1-day, 1-week, and 1-month), with the proposed model achieving the best results in almost all scenarios. Additionally, we show that the proposed method obtains the best results when an additive ensemble neural network is used as the base model. The experimental results are drawn from real loads of a medium-sized city in Spain.

COVID-19 and fiscal space for health system in Pakistan: It is time for a policy decision.

Most developing countries with weak economies and low GDPs strive to invest an optimal amount of budget to health sector. Compounding on this state of affairs is their inherent inefficiency to spend even that meager amount on the welfare of the patients, improving service delivery, motivating their workforce and making their health systems responsive to the needs of the people they serve. With weak fiscal base and inelasticity in budget spending, when these countries face a catastrophe like COVID-19, there is a whole situation of havoc and lack of finances emerges as the biggest issue in such crises. Pakistan has been no exception to this kind of situation. Government funds allocated to other public sector development schemes are diverted to deal with the health emergency. Hence, the result is an overall socioeconomic shock that a country has to face. Amid such crises, other international commitments also face a state of uncertainty. With the changing disease patterns all over the world, the public financial management system for health sector needs to be revisited to devise a more sustainable and resilient mechanism not only to absorb shocks like COVID-19 but also to meet the international health commitments.

Towards Modified Entropy Mutual Information Feature Selection to Forecast Medium-Term Load Using a Deep Learning Model in Smart Homes.

Over the last decades, load forecasting is used by power companies to balance energy demand and supply. Among the several load forecasting methods, medium-term load forecasting is necessary for grid's maintenance planning, settings of electricity prices, and harmonizing energy sharing arrangement. The forecasting of the month ahead electrical loads provides the information required for the interchange of energy among power companies. For accurate load forecasting, this paper proposes a model for medium-term load forecasting that uses hourly electrical load and temperature data to predict month ahead hourly electrical loads. For data preprocessing, modified entropy mutual information-based feature selection is used. It eliminates the redundancy and irrelevancy of features from the data. We employ the conditional restricted Boltzmann machine (CRBM) for the load forecasting. A meta-heuristic optimization algorithm Jaya is used to improve the CRBM's accuracy rate and convergence. In addition, the consumers' dynamic consumption behaviors are also investigated using a discrete-time Markov chain and an adaptive k-means is used to group their behaviors into clusters. We evaluated the proposed model using GEFCom2012 US utility dataset. Simulation results confirm that the proposed model achieves better accuracy, fast convergence, and low execution time as compared to other existing models in the literature.