The relationship between police contacts for drug use-related crime and future arrests, incarceration, and overdoses: a retrospective observational study highlighting the need to break the vicious cycle.

BACKGROUND: Individuals with substance use disorder often encounter law enforcement due to drug use-related criminal activity. Traditional policing approaches may not be effective for reducing recidivism and improving outcomes in this population. Here, we describe the impact of traditional policing approach to drug use-related crime on future recidivism, incarceration, and overdoses. METHODS: Using a local Police Department (PD) database, we identified individuals with a police contact with probable cause to arrest for a drug use-related crime ("index contact"), including for an opioid-related overdose, between September 1, 2015, and August 31, 2016 (Group 1, N = 52). Data on police contacts, arrests, and incarceration 12 months before and after the index contact were extracted and compared using Fisher's exact or Wilcoxon signed-rank tests. County-level data on fatal overdoses and estimates of time spent by PD officers in index contact-related responses were also collected. To determine whether crime-related outcomes changed over time, we identified a second group (Group 2, N = 263) whose index contact occurred between September 1, 2017, and August 31, 2020, and extracted data on police contacts, arrests, and incarceration during the 12 months prior to their index contact. Pre-index contact data between Groups 1 and 2 were compared with Fisher's exact or Mann-Whitney U tests. RESULTS: Comparison of data during 12 months before and 12 months after the index contact showed Group 1 increased their total number of overdose-related police contacts (6 versus 18; p = 0.024), incarceration rate (51.9% versus 84.6%; p = 0.001), and average incarceration duration per person (16.2 [SD = 38.6] to 50 days [SD = 72]; p < 0.001). In the six years following the index contact, 9.6% sustained a fatal opioid-related overdose. For Group 1, an average of 4.7 officers were involved, devoting an average total of 7.2 h per index contact. Comparison of pre-index contact data between Groups 1 and 2 showed similar rates of overdose-related police contacts and arrests. CONCLUSIONS: The results indicated that the traditional policing approach to drug use-related crime did not reduce arrests or incarceration and was associated with a risk of future overdose fatalities. Alternative law enforcement-led strategies, e.g., pre-arrest diversion-to-treatment programs, are urgently needed.

Breast tuberculosis in East London: A 13-year retrospective observational study.

SETTING: Breast tuberculosis (TB) is rare in Western Europe, and its diagnosis may be delayed through lack of awareness of presenting features. Our institution serves a large East London population with a high incidence of TB. OBJECTIVE: To characterize presenting features and avoidable diagnostic delay in breast TB patients. DESIGN: We conducted a 13-year retrospective study of breast TB patients treated at our institution including demographic, clinical, microbiology, and pathology data. RESULTS: Forty-seven cases were included; 44 (94%) were female, with a median age of 33 years (IQR 28.5-39.5). The main presenting feature was a breast lump in 41 cases (87%); which were predominantly solitary unilateral lesions (25, 61%) and frequently located in the upper outer quadrant (28, 68%). Where performed, Mycobacterium tuberculosis was cultured in 15/36 (42%) cases. Granulomata were present on biopsy or aspirate in 21 (47%) and 17 (36%) cases, respectively. The median duration between symptom onset and treatment was 20 weeks (IQR 15-30). Forty-six (98%) completed treatment successfully and one relapsed. CONCLUSION: A high index of suspicion for TB is required for individuals presenting with breast symptoms from countries where TB is endemic. Development of standardized pathways may improve detection and management of breast TB may reduce diagnostic delay.

Critical role of mTOR, PPARγ and PPARδ signaling in regulating early pregnancy decidual function, embryo viability and feto-placental growth.

STUDY QUESTION: What are the consequences of inhibiting mTOR, the mechanistic target of rapamycin (mTOR), and the peroxisome proliferator activated receptor gamma (PPARγ) and PPARδ pathways in the early post-implantation period on decidual function, embryo viability and feto-placental growth in the rat? SUMMARY ANSWER: mTOR inhibition from Days 7 to 9 of pregnancy in rats caused decidual PPARγ and PPARδ upregulation on Day 9 of pregnancy and resulted in embryo resorption by Day 14 of pregnancy. PPARγ and PPARδ inhibition differentially affected decidual mTOR signaling and levels of target proteins relevant to lipid histotrophic nutrition and led to reduced feto-placental weights on Day 14 of pregnancy. WHAT IS KNOWN ALREADY: Although mTOR, PPARγ and PPARδ are nutrient sensors important during implantation, the role of these signaling pathways in decidual function and how they interact in the early post-implantation period are unknown. Perilipin 2 (PLIN2) and fatty acid binding protein 4 (FABP4), two adipogenic proteins involved in lipid histotrophic nutrition, are targets of mTOR and PPAR signaling pathways in a variety of tissues. STUDY DESIGN, SIZE, DURATION: Rapamycin (mTOR inhibitor, 0.75 mg/kg, sc), T0070907 (PPARγ inhibitor, 0.001 mg/kg, sc), GSK0660 (PPARδ inhibitor, 0.1 mg/kg, sc) or vehicle was injected daily to pregnant rats from Days 7 to 9 of pregnancy and the studies were performed on Day 9 of pregnancy (n = 7 per group) or Day 14 of pregnancy (n = 7 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: On Day 9 of pregnancy, rat decidua were collected and prepared for western blot and immunohistochemical studies. On Day 14 of pregnancy, the resorption rate, number of viable fetuses, crown-rump length and placental and decidual weights were determined. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibition of mTOR in the early post-implantation period led to a reduction in FABP4 protein levels, an increase in PLIN2 levels and an upregulation of PPARγ and PPARδ in 9-day-pregnant rat decidua. Most embryos were viable on Day 9 of pregnancy but had resorbed by Day 14 of pregnancy. This denotes a key function of mTOR in the post-implantation period and suggests that activation of PPAR signaling was insufficient to compensate for impaired nutritional/survival signaling induced by mTOR inhibition. Inhibition of PPARγ signaling resulted in decreased decidual PLIN2 and FABP4 protein expression as well as in inhibition of decidual mTOR signaling in Day 9 of pregnancy. This treatment also reduced feto-placental growth on Day 14 of pregnancy, revealing the relevance of PPARγ signaling in sustaining post-implantation growth. Moreover, following inhibition of PPARδ, PLIN2 levels were decreased and mTOR complex 1 and 2 signaling was altered in decidua on Day 9 of pregnancy. On Day 14 of pregnancy, PPARδ inhibition caused reduced feto-placental weight, increased decidual weight and increased resorption rate, suggesting a key role of PPARδ in sustaining post-implantation development. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: This is an in vivo animal study and the relevance of the results for humans remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The early post-implantation period is a critical window of development and changes in the intrauterine environment may cause embryo resorption and lead to placental and fetal growth restriction. mTOR, PPARγ and PPARδ signaling are decidual nutrient sensors with extensive cross-talk that regulates adipogenic proteins involved in histotrophic nutrition and important for embryo viability and early placental and fetal development and growth. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina (PICT 2014-411 and PICT 2015-0130), and by the International Cooperation (Grants CONICET-NIH-2014 and CONICET-NIH-2017) to A.J. and T.J. The authors have no conflicts of interest.

Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis.

RESEARCH QUESTION: Can maternal treatments with idebenone, a structural analogue of coenzyme Q10, prevent alterations on markers of proinflammatory-prooxidant processes, on the expression of genes involved in mitochondrial biogenesis and function, and on the apoptotic rate in embryos from mild diabetic rats? DESIGN: A mild diabetic rat model was induced by neonatal-streptozotocin administration (90 mg/kg subcutaneously). Female diabetic rats and controls were mated with healthy males. From day 1 of pregnancy, control and diabetic rats were orally treated with idebenone (100 mg/kg daily). On day 10.5 of gestation, the embryos were explanted and prepared for immunohistochemical studies, for the evaluation of gene expression by reverse transcription polymerase chain reaction and for TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end-labelling assay analysis. RESULTS: Embryos from mild diabetic rats showed increased levels of nitrated proteins, 4-hydroxynonenal and matrix metalloproteinase 9, which were prevented by idebenone administration. We also found a decreased embryonic expression of cytochrome c oxidase and reduced mRNA levels of peroxisome proliferator activated receptor-γ coactivator-1-α and nuclear respiratory factor-1, both of which were prevented by idebenone administration to the diabetic pregnant rats. Embryos from mild diabetic rats also showed an increased apoptotic rate, which was diminished by idebenone treatment. CONCLUSION: Maternal idebenone treatment ameliorates altered parameters related to the prooxidant-proinflammatory environment found in embryos from mild diabetic rats, suggesting a putative treatment to prevent diabetes-induced embryo alterations.

IGF2 stimulates fetal growth in a sex- and organ-dependent manner.

BackgroundInsulin-like growth factor 2 (IGF2) is a key determinant of fetal growth, and the altered expression of IGF2 is implicated in fetal growth disorders and maternal metabolic derangements including gestational diabetes. Here we studied how increased levels of IGF2 in late pregnancy affect fetal growth.MethodsWe employed a rat model of repeated intrafetal IGF2 administration in late pregnancy, i.e., during GD19-GD21, and measured the consequences on fetal organ weight and expression of insulin/IGF-axis components.ResultsIGF2 treatment tended to increase fetal weight, but only weight increase of the fetal stomach reached significance (+33±9%; P<0.01). Sex-dependent data analysis revealed a sexual dimorphism of IGF2 action. In male fetuses, IGF2 administration significantly increased fetal weight (+13±3%; P<0.05) and weight of fetal stomach (+42±10%; P<0.01), intestine (+26±5%; P<0.05), liver (+13±4%; P<0.05), and pancreas (+25±8%; P<0.05). Weights of heart, lungs, and kidneys were unchanged. In female fetuses, IGF2 increased only stomach weight (+26±9%; P<0.05). Furthermore, gene expression of insulin/IGF axis in the heart, lungs, liver, and stomach was more sensitive toward IGF2 treatment in male than in female fetuses.ConclusionData suggest that elevated circulating IGF2 in late pregnancy predominantly stimulates organ growth of the digestive system, and male fetuses are more susceptible toward the IGF2 effects than female fetuses.

Tuberculous tales: an East London experience.

Tuberculous meningitis presents a diagnostic and therapeutic challenge, and considering its long history and increasing global incidence, the evidence base for its treatment is relatively scanty. Many UK neurologists will have little first-hand experience of this deadly condition, and if faced with a patient with possible tuberculous meningitis will find decision making less than straightforward. In parts of East London (UK) the rates of tuberculosis and tuberculous meningitis are among the highest in Western Europe, and so the neurologists and respiratory physicians at the Royal London Hospital have encountered many such patients over the years. We have found experience to be a valuable teacher and so would like to share five cases that illustrate the complexities of diagnosis and management of the disease, and complications of its treatment.

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428) versus 85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, p<0.0001, respectively) and on success rates (59.7% versus 77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients.

Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6-9)versus 5 (4-6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49-156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.

Diabetes-associated changes in the fetal insulin/insulin-like growth factor system are organ specific in rats.

BACKGROUND: Diabetes in pregnancy affects fetal growth and development. The insulin/insulin-like growth factors (IGF) system comprising insulin, IGF, their receptors, and binding proteins, has been implicated in fetal growth regulation. This study tested the hypothesis that maternal diabetes alters the fetal insulin/IGF system in a tissue-specific manner. METHODS: Wistar rats were rendered diabetic by neonatal administration of streptozotocin and mated with control rats. At day 21 of gestation, the weights of fetuses, placentas, and fetal organs (heart, lung, liver, stomach, intestine, and pancreas) were determined. Maternal and fetal plasma concentrations of insulin, IGF1, and IGF2 were measured by ELISA, and expression of IGF1, IGF2, IGF1R, IGF2R, IR, IGFBP1, BP2, and BP3 in placenta and fetal organs by qPCR. RESULTS: The well-known increase in fetal growth in this model of mild diabetes is accompanied by elevated insulin and IGF1 levels and alterations of the insulin/IGF system in the fetus and the placenta. These alterations were organ and gene specific. The insulin/IGF system was generally upregulated, especially in the fetal heart, while it was downregulated in fetal lung. CONCLUSION: In our model of mild diabetes, the effect of maternal diabetes on fetal weight and fetal insulin/IGF system expression is organ specific with highly sensitive organs such as lung and heart, and organs that were less affected, such as stomach.

Impact of diet-induced maternal obesity on the reproductive capacity of F1 female offspring and the early development of the second generation.

The aim of this study was to examine the impact of maternal obesity on the reproductive capacity of the female offspring (F1) and on the early development of the second generation (F2). To this end, rats were fed either standard (SD) or cafeteria (CD) diet. CD rats and their offspring were divided into 2 groups: rats with 18% and ≥25% overweight (CD18 and CD25, respectively) and offspring from CD18 and CD25 rats (OCD18 and OCD25, respectively). Both OCD groups achieved greater weight gain than controls, without changes in the serum levels of glucose, cholesterol or triglycerides. However, they showed increased gonadal cholesterol concentration and fat content compared to controls. Female OCD groups showed a slight prolongation of the estrous cycle and different pattern of changes in the weight gain during pregnancy. The OCD25 group displayed an increased fertility index and preimplantation losses, and changes in some fetal measurements. Some OCD25 dams gave birth to a larger litter of pups and displayed a lower viability index and lactation rate than controls. OCD25 dams also showed an increase in estradiol and a decrease in testosterone and anti-Müllerian hormone. OCD25 rats showed increased mRNA levels of steroidogenenic enzymes. The offspring from OCD25 females (F2OCD25 offspring) showed early vaginal opening and higher ovulation rate in females, and lower ano-genital distances in males, compared to controls. In conclusion, these results reflect that maternal obesity impacts on the reproductive health of successive generations, probably as a result of epigenetic changes in different systems, including germ cells.

Intestinal alterations and mild glucose homeostasis impairments in the offspring born to overweight rats.

The gut plays a crucial role in metabolism by regulating the passage of nutrients, water and microbial-derived substances to the portal circulation. Additionally, it produces incretins, such as glucose-insulinotropic releasing peptide (GIP) and glucagon-like derived peptide 1 (GLP1, encoded by gcg gene) in response to nutrient uptake. We aimed to investigate whether offspring from overweight rats develop anomalies in the barrier function and incretin transcription. We observed pro-inflammatory related changes along with a reduction in Claudin-3 levels resulting in increased gut-permeability in fetuses and offspring from overweight rats. Importantly, we found decreased gip mRNA levels in both fetuses and offspring from overweight rats. Differently, gcg mRNA levels were upregulated in fetuses, downregulated in female offspring and unchanged in male offspring from overweight rats. When cultured with high glucose, intestinal explants showed an increase in gip and gcg mRNA levels in control offspring. In contrast, offspring from overweight rats did not exhibit any response in gip mRNA levels. Additionally, while females showed no response, male offspring from overweight rats did exhibit an upregulation in gcg mRNA levels. Furthermore, female and male offspring from overweight rats showed sex-dependent anomalies when orally challenged with a glucose overload, returning to baseline glucose levels after 120 min. These results open new research questions about the role of the adverse maternal metabolic condition in the programming of impairments in glucose homeostasis, enteroendocrine function and gut barrier function in the offspring from overweight mothers and highlight the importance of a perinatal maternal healthy metabolism.

Law enforcement-led, pre-arrest diversion-to-treatment may reduce crime recidivism, incarceration, and overdose deaths: Program evaluation outcomes.

INTRODUCTION: Substance use disorder (SUD), overdose, and drug use-related crime continue to increase in the U.S. Pre-arrest diversion-to-treatment programs may decrease crime recidivism and overdose deaths. We assessed the impact of a community-wide diversion-to-treatment initiative on crime, incarceration, and overdose. METHODS: This article reports on the prospective evaluation of a law enforcement-led, pre-arrest diversion-to-treatment program on crime, incarceration, and overdose deaths compared between participants who did not engage (non-engaged; n = 103), engaged but did not complete (non-completers; n = 60) and completed (completers; n = 100) the program. Participants included 263 adults apprehended by police officers for low-level, drug use-related crimes between September 1, 2017 and August 31, 2020. The program offered eligible persons participation in a six-month program consisting of a clinical assessment, referral to addiction treatment services based on each individual's needs, connection to recovery peer support, and treatment engagement monitoring. Completers had their initial criminal charges 'voided,' while non-engaged and non-Completer participants had their original charges filed with local prosecutors. The project collected participant-level data on arrests and incarceration within 12 months before and 12 months after program enrollment and data on fatal overdose within 12 months after program enrollment. Logistic regression predicted outcomes using baseline demographics (sex, age, race, housing status) and pre-index crime arrest and incarceration indices as covariates. RESULTS: After accounting for baseline demographics and pre-enrollment arrest/incarceration history, logistic regression models found that the non-engaged and the non-Completer groups were more likely than completers to be arrested (odds ratios [ORs]: 3.9 [95 % CI, 2.0-7.7] and 3.6 [95 % CI, 1.7-7.5], respectively) and incarcerated (ORs: 10.3 [95 % CI, 5.0-20.8] and 21.0 [95 % CI, 7.9-55.7], respectively) during the 12-month follow-up. Rates of overdose deaths during the 12-month follow-up were greatest in non-engaged (6/103, 5.8 %) and non-Completer (2/60, 3.3 %) groups; completers had the lowest rate (2/100, 2.0 %), with all deaths occurring after completion of the six-month treatment/monitoring program. CONCLUSIONS: Collaboration between law enforcement, clinicians, researchers, and the broader community to divert adults who commit a low-level, drug use-related crime from criminal prosecution to addiction treatment may effectively reduce crime recidivism, incarceration, and overdose deaths.

Recreational nitrous oxide and thrombotic events: a case series.

Background: The study aimed to elucidate the prevalence of nitrous oxide (N2O) usage in patients with unexplained venous thromboembolism (VTE), highlighting the potential association with hyperhomocysteinaemia (HHcy). Methods: We conducted a retrospective study at the Royal London Hospital, examining cases of N2O-related VTE from March to August 2023. Among 50 patients identified, four (8%) had recent unprovoked VTE. Patient data were collected based on N2O ambulatory emergency care pathway admissions. Results: Among the 50 patients identified, four (8%) had recent or concurrent VTE. Three were male (75%), with an ethnic distribution of 50% Asian or Asian British and 50% Black or Black British. Patients were distributed across quintiles of the index of multiple deprivation. All had actual or functional vitamin B12 deficiency. Discussion: The association between N2O use and VTE requires further investigation, though a plausible mechanism involving HHcy has been proposed. Clinicians should be vigilant for VTE in N2O users, especially those presenting with unexplained symptoms. VTE prophylaxis may be worth considering, particularly if continued exposure to nitrous oxide is anticipated. Conclusion: N2O misuse may increase the risk of VTE, warranting attention from healthcare providers. Further research is needed to elucidate this association and inform preventive strategies. Public awareness about the risks of N2O remains essential.

Maternal overweight induced by a diet with high content of saturated fat activates placental mTOR and eIF2alpha signaling and increases fetal growth in rats.

The mammalian target of rapamycin (mTOR) and the eukaryotic initiation factor 2 (eIF2) signaling pathways control protein synthesis in response to nutrient availability. Moreover, mTOR is a positive regulator of placental nutrient transport and is involved in the regulation of fetal growth. We hypothesized that maternal overweight, induced by a diet with high saturated fat content, i) up-regulates placental mTOR activity and nutrient transport, resulting in fetal overgrowth; ii) inhibits phosphorylation of eIF2 at its alpha subunit (eIF2alpha); and iii) leads to placental inflammation. Albino Wistar female rats were fed a control or high-saturated-fat (HF) diet for 7 wk before mating and during pregnancy. At gestational day 21, the HF diet significantly increased maternal and fetal triglyceride, leptin, and insulin (but not glucose) levels and maternal and fetal weights, and placental weights trended to increase. Phosphorylated 4EBP1 (T37/46 and S65) was significantly higher, and phosphorylated rpS6 (S235/236) tended to increase, in the placentas of dams fed an HF diet, indicating an activation of mTOR complex 1 (mTORC1). Phosphorylation of AMPK and eIF2alpha was reduced in the HF diet group compared to the control. The expression and activity of placental nutrient transporters and lipoprotein lipase (LPL), as well as the activation of inflammatory pathways, were not altered by the maternal diet. We conclude that maternal overweight induced by an HF diet stimulates mTORC1 activity and decreases eIF2alpha phosphorylation in rat placentas. We speculate that these changes may up-regulate protein synthesis and contribute to placental and fetal overgrowth.

Paternal diabetes programs sex-dependent placental alterations and fetal overgrowth.

The aim of this study was to evaluate the paternal programming of sex-dependent alterations in fetoplacental growth and placental lipid metabolism regulated by peroxisome proliferator-activated receptor (PPAR) target genes in F1 diabetic males born from F0 pregestational diabetic rats. F1 control and diabetic male rats were mated with control female rats. On day 21 of gestation, F2 male and female fetoplacental growth, placental lipid levels, and protein and mRNA levels of genes involved in lipid metabolism and transport were evaluated. Fetal but not placental weight was increased in the diabetic group. Triglyceride, cholesterol and free fatty acid levels were increased in placentas of male fetuses from the diabetic group. The mRNA levels of Pparα and Pparγ coactivator 1α (Pgc-1α) were increased only in placentas of male fetuses from the diabetic group. Protein levels of PPARα and PGC-1α were decreased only in placentas of male fetuses from the diabetic group. No differences were found in Pparγ mRNA and protein levels in placentas from the diabetic group. The mRNA levels of genes involved in lipid synthesis showed no differences between groups, whereas the mRNA levels of genes involved in lipid oxidation and transport were increased only in placentas of male fetuses from the diabetic group. In conclusion, paternal diabetes programs fetal overgrowth and sex-dependent effects on the regulation of lipid metabolism in the placenta, where only placentas of male fetuses show an increase in lipid accumulation and mRNA expression of enzymes involved in lipid oxidation and transport pathways.

Activation of the nuclear receptor PPARα regulates lipid metabolism in foetal liver from diabetic rats: implications in diabetes-induced foetal overgrowth.

BACKGROUND: peroxisome proliferator-activated receptor α (PPARα) is a crucial regulator of liver lipid metabolism. As maternal diabetes impairs foetal lipid metabolism and growth, we aimed to determine whether PPARα activation regulates lipid metabolism in the foetal liver from diabetic rats as well as foetal weight and foetal liver weight. METHODS: diabetes was induced by neonatal streptozotocin administration (90 mg/kg). For ex vivo studies, livers from 21-day-old foetuses from control and diabetic rats were explanted and incubated in the presence of PPARα agonists (clofibrate and leukotriene B(4) ) for further evaluation of lipid levels (by thin layer chromatography and densitometry), de novo lipid synthesis (by (14) C-acetate incorporation) and lipid peroxidation (by thiobarbituric reactive substances evaluation). For in vivo studies, foetuses were injected through the uterine wall with leukotriene B(4) on days 19, 20 and 21 of gestation. On day 21 of gestation, foetal liver concentrations of lipids and lipoperoxides were evaluated. RESULTS: foetuses from diabetic rats showed increased body weight and liver weight, as well as accumulation of triglycerides and cholesteryl esters, increased de novo lipid synthesis and lipid peroxidation in the liver when compared to controls. Ex vivo studies showed that PPARα ligands reduced both the concentrations and synthesis of the lipid species studied and lipid peroxidation in the foetal liver from diabetic rats. In vivo experiments showed that leukotriene B(4) reduced the concentrations of triglycerides, cholesteryl esters and phospholipids, as well as lipid peroxidation, foetal weight and foetal liver weight in diabetic rats. CONCLUSIONS: PPARα activation regulates the impaired foetal liver lipid metabolism, prevents hepatomegaly and reduces foetal overgrowth induced by maternal diabetes.

Breathlessness and cough in the acute setting.

The symptom of breathlessness is well recognized as part of the presentation of a wide range of medical conditions. It can be a manifestation of a life-threatening emergency. In acute medical settings, the priority is to quickly recognize patients who are critically unwell and require emergency treatment. For these patients, rapid initial assessment and immediate treatment are essential. However, once symptoms have stabilized or in less acute settings, a more thorough assessment is required. Cough is a common respiratory symptom, often part of a symptom complex, which is troublesome for the patient. It is important to recognize worrying associated features to prompt further investigation. In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection emerged from a zoonotic source, resulting in many cases of infection, hospitalizations and deaths, and has since spread in a pandemic across every continent. A substantial percentage of patients with COVID-19 develop an acute respiratory illness requiring hospital care. Cough and acute breathlessness are two of the most prevalent symptoms in this infection; any patient presenting to an acute setting should currently be assumed to have this infection and immediately tested with a viral swab from the upper airway to guide management.

Classification of Opioid Usage Through Semi-Supervised Learning for Total Joint Replacement Patients.

Opioid misuse and overdose have become a public health hazard and caused drug addiction and death in the United States due to rapid increase in prescribed and non-prescribed opioid usage. The misuse and overdose are highly related to opioid over-prescription for chronic and acute pain treatment, where a one-size-fits-all prescription plan is often adopted but can lead to substantial leftovers for patients who only consume a few. To reduce over-prescription and opioid overdose, each patient's opioid usage pattern should be taken into account. As opioids are often prescribed for patients after total joint replacement surgeries, this study introduces a machine learning model to predict each patient's opioid usage level in the first 2 weeks after discharge. Specifically, the electronic health records, patient prescription history, and consumption survey data are collected to investigate the level of short-term opioid usage after joint replacement surgeries. However, there are a considerable number of answers missing in the surveys, which degrades data quality. To overcome this difficulty, a semi-supervised learning model that assigns pseudo labels via Bayesian regression is proposed. Using this model, the missing survey answers of opioids amount taken by the patients are predicted first. Then, based on the prediction, pseudo labels are assigned to those patients to improve classification performance. Extensive experiments indicate that such a semi-supervised learning model has shown a better performance in the resulting patients classification. It is expected that by using such a model the providers can adjust the amount of prescribed opioids to meet each patient's actual need, which can benefit the management of opioid prescription and pain intervention.