Repetitive negative thinking as a unique transdiagnostic risk factor for suicidal ideation.

Repetitive negative thinking (RNT) is a transdiagnostic symptom observed across mood and anxiety disorders and is characterized by frequent, distressing thoughts that are perceived as uncontrollable. Specific forms of RNT have been linked to increased suicide risk. However, most work examining links between RNT and suicide has been conducted within specific disorders and subtypes of RNT (e.g., rumination in individuals with depression). The present study aimed to investigate associations between transdiagnostic RNT and suicidal ideation. We hypothesized RNT would be associated with suicide risk beyond disorder-specific clinical symptoms. Fifty-four participants with mood, anxiety, and/or traumatic stress disorders completed an interview assessing suicidal risk (Columbia-Suicide Severity Rating Scale (C-SSRS)) and self-report questionnaires assessing transdiagnostic RNT, depression, and anxiety. Based on C-SSRS, we divided participants into high or low suicide risk groups. We analyzed the relationship between suicidal risk group and RNT and found that RNT was uniquely associated with suicidal risk group, controlling for depression and anxiety severity. Our results suggest including assessments of RNT may have clinical utility for understanding the degree of suicide risk in individuals and point to the potential utility of including clinical interventions to target this symptom for those at high risk of suicide.

Comparing pain intensity rating scales in acute postoperative pain: boundary values and category disagreements.

Pain intensity assessment scales are important in evaluating postoperative pain and guiding management. Different scales can be used for patients to self-report their pain, but research determining cut points between mild, moderate and severe pain has been limited to studies with < 1500 patients. We examined 13,017 simultaneous acute postoperative pain ratings from 913 patients taken at rest and on activity, between 4 h and 48 h following surgery using both a verbal rating scale (no, mild, moderate or severe pain) and 0-100 mm visual analogue scale. We determined the best cut points on the visual analogue scale between mild and moderate pain as 35 mm, and moderate and severe pain as 80 mm. These remained consistent for pain at rest and on activity, and over time. We also explored the presence of category disagreements, defined as patients verbally describing no or mild pain scored above the mild/moderate cut point on the visual analogue scale, and patients verbally describing moderate or severe pain scored below the mild/moderate cut point on the visual analogue scale. Using 30 and 60 mm cut points, 1533 observations (12%) showed a category disagreement and using 35 and 80 mm cut points, 1632 (13%) showed a category disagreement. Around 1 in 8 simultaneous pain scores implausibly disagreed, possibly resulting in incorrect pain reporting. The reasons are not known but low rates of literacy and numeracy may be contributing factors. Understanding these disagreements between pain scales is important for pain research and medical practice.

Effectiveness of non-pharmacological interventions for fibromyalgia and quality of review methods: an overview of Cochrane Reviews.

BACKGROUND: Fibromyalgia syndrome (FMS) is defined as chronic widespread pain associated with sleep disorders, cognitive dysfunction, and somatic symptoms present for at least three months and cannot be better explained by another diagnosis. OBJECTIVES: To examine efficacy and safety of non-pharmacological interventions for FMS in adults reported in Cochrane Reviews, and reporting quality of reviews. METHODS: Systematic reviews of randomised controlled trials (RCTs) of non-pharmacological interventions for FMS were identified from the Cochrane Database of Systematic Reviews (CDSR 2022, Issue 3 and CDSR 2023 Issue 6). Methodological quality was assessed using the AMSTAR-2 tool and a set of methodological criteria critical for analgesic effects. The primary efficacy outcomes of interest were clinically relevant pain relief, improvement in health-related quality of life (HRQoL), acceptability, safety, and reduction of mobility difficulties as reported by study participants. No pooled analyses were planned. We assumed a clinically relevant improvement was a minimal clinically important difference (MCID) between interventions and controls of 15%, or a SMD of more than 0.2, or a MD of more than 0.5, on a 0 to 10 scale. RESULTS: Ten Cochrane reviews were eligible, reporting 181 randomized or quasi- randomized trials (11,917 participants, average trial size 66 participants). The reviews examined exercise training, acupuncture, transcutaneous electrical nerve stimulation, and psychological therapies. One review was rated moderate according to AMSTAR 2, seven were rated low and two were rated critically low. All reviews met most of the additional methodological quality criteria. All reviews included studies with patient-reported outcomes for pain. We found low certainty evidence of clinically relevant positive effects of aerobic and mixed exercise training and for cognitive behavioural therapies (CBTs) at reducing mobility difficulties and for mixed exercise training and CBTs for improving HRQoL at the end of the intervention. Number needed to treat for an additional beneficial outcome (NNTB) values for a MCID of 15% ranged between 4 and 9. We found low certainty evidence that was clinically relevant for mixed exercise and CBTs for reducing mobility difficulties at an average follow up of 24 weeks. We found low certainty evidence of clinically relevant positive effects of mixed exercise on HRQoL at an average follow up of 24 weeks. NNTB values for a MCID of 15% ranged from 5 to 11. The certainty of evidence of the acceptability (measured by dropouts) of the different non-pharmacological interventions ranged from very low to moderate and the dropout rate for any reason did not differ across the interventions or the controls, except for biofeedback and movement therapies. All the systematic reviews stated that the reporting of adverse events was inconsistent in the studies analysed (very low certainty evidence). AUTHORS' CONCLUSIONS: There is low certainty evidence of clinically relevant reduction of mobility difficulties and of improvement of HRQoL among individuals with FMS by aerobic and mixed exercise training and by CBTs at the end of the intervention. There is low certainty evidence that CBTs and mixed exercise training reduces mobility difficulties post-treatment and that mixed exercise training improves HRQoL at follow-up by clinically meaningful scores.

Trends in firearm production and firearm deaths in U.S. youth.

INTRODUCTION: Firearms are now the leading cause of death for U.S. children and teens ages 0-19. The U.S. Department of Justice Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) reported data in 2022 on firearm production, for specific firearm types and calibers. We hypothesized there would be a correlation between firearm production and firearm deaths and nonfatal injuries in youth. METHODS: All firearm deaths and nonfatal injury rates for youth ages 0-19 were extracted from the Centers for Disease Control and Prevention from 2001 to 2020. Firearm production from 2001 to 2020 was extracted from the 2022 ATF Firearms in Commerce Report for overall firearm production, production by weapon type and pistol caliber. Relationships between firearm death and injury and firearm production were evaluated using correlational analyses. RESULTS: Firearm death and nonfatal injury rates for youth increased from 2001 to 2020 by 48.2% and 69.2%, respectively, and firearm production increased 265% overall and 1298% for 9 mm pistols. There was no correlation between total firearm manufacturing and total firearm deaths or nonfatal injury rates from 2001 to 2020 (all r < 0.28). Pistol caliber (25 and 9 mm) was associated with total firearm deaths and nonfatal injuries (all r > 0.55). CONCLUSION: While total firearm manufacturing was not related to firearm deaths and injuries, except suicides, there were strong relationships between 9 mm pistol production and firearm deaths and injuries in youth. Firearm injuries are preventable; we must invest in stronger information systems that track details of firearms linked with deaths and injuries.

Isolation, characterization, and experimental infection of Streptococcus gallolyticus subspecies pasteurianus from commercial turkeys with acute septicemia: a pilot study.

Streptococcus gallolyticus (SG) is a Gram-positive cocci found as commensal gut flora in animals and humans. SG has emerged as a cause of disease in young poults between 1 and 3 wk of age. SG is associated with septicemia resulting in acute mortality with no premonitory signs in turkeys. Three SG isolates were obtained from clinical field cases of acute septicemia of commercial turkeys and used in three independent experiments. In Experiment 1, embryos were inoculated 25 d of embryogenesis with varying concentrations of SG1, SG2, or SG3. In Experiment 2, day of hatch, poults were inoculated with varying concentrations using different routes of administration of SG1, SG2, or SG3. In Experiment 3, day of hatch, poults were inoculated with only isolate SG1 using different paths. Poults were randomly selected for necropsy on d 8 and d 15 and sampled to collect spleen, heart, and liver for SG on d 21, the remaining poults were necropsied and cultured. Samples were plated on Columbia nalidixic acid and colistin agar (CNA) (40°C, 18-24 h). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) confirmed suspect colonies. Data were analyzed using the chi-square test of independence, testing all possible combinations to determine significance (P < 0.05). Weight data were subjected to ANOVA using JMP with significance (P < 0.05). No differences were found in BW or BWG on d 0, 8, 15, or 22. Splenomegaly, focal heart necrosis, and pericarditis were observed in all groups in experiments 1 through 3. In Experiment 3, only airsacculitis was observed in a negative control in separate isolation (P > 0.05). On d 21 of Experiment 3, increased (P < 0.05) recovery of SG from spleens were observed in co-housed negative controls, as well as poults challenged by oral gavage (P > 0.05 for d 7 and d 14). These results confirm numerous previous studies indicating that SG subsp. pasteurianus is a primary infectious microorganism that causes septicemia in young poults.

Alcohol and drug use severity are independently associated with antiretroviral adherence in the current treatment era.

Substance use in people with HIV (PWH) negatively impacts antiretroviral therapy (ART) adherence. However, less is known about this in the current treatment era and the impact of specific substances or severity of substance use. We examined the associations of alcohol, marijuana, and illicit drug use (methamphetamine/crystal, cocaine/crack, illicit opioids/heroin) and their severity of use with adherence using multivariable linear regression in adult PWH in care between 2016 and 2020 at 8 sites across the US. PWH completed assessments of alcohol use severity (AUDIT-C), drug use severity (modified ASSIST), and ART adherence (visual analogue scale). Among 9400 PWH, 16% reported current hazardous alcohol use, 31% current marijuana use, and 15% current use of ≥1 illicit drugs. In multivariable analysis, current methamphetamine/crystal use, particularly common among men who had sex with men, was associated with 10.1% lower mean ART adherence (p < 0.001) and 2.6% lower adherence per 5-point higher severity of use (ASSIST score) (p < 0.001). Current and more severe use of alcohol, marijuana, and other illicit drugs were also associated with lower adherence in a dose-dependent manner. In the current HIV treatment era, individualized substance use treatment, especially for methamphetamine/crystal, and ART adherence should be prioritized.

Trials We Cannot Trust: Investigating Their Impact on Systematic Reviews and Clinical Guidelines in Spinal Pain.

We previously conducted an exploration of the trustworthiness of a group of clinical trials of cognitive-behavioral therapy and exercise in spinal pain. We identified multiple concerns in 8 trials, judging them untrustworthy. In this study, we systematically explored the impact of these trials ("index trials") on results, conclusions, and recommendations of systematic reviews and clinical practice guidelines (CPGs). We conducted forward citation tracking using Google Scholar and the citationchaser tool, searched the Guidelines International Network library and National Institute of Health and Care Excellence archive to June 2022 to identify systematic reviews and CPGs. We explored how index trials impacted their findings. Where reviews presented meta-analyses, we extracted or conducted sensitivity analyses for the outcomes of pain and disability, to explore how the exclusion of index trials affected effect estimates. We developed and applied an 'Impact Index' to categorize the extent to which index studies impacted their results. We included 32 unique reviews and 10 CPGs. None directly raised concerns regarding the veracity of the trials. Across meta-analyses (55 comparisons), the removal of index trials reduced effect sizes by a median of 58% (Inter Quartlie Range (IQR) 40-74). 85% of comparisons were classified as highly, 3% as moderately, and 11% as minimally impacted. Nine out of 10 reviews conducting narrative synthesis drew positive conclusions regarding the intervention tested. Nine out of 10 CPGs made positive recommendations for the intervention(s) evaluated. This cohort of trials, with concerns regarding trustworthiness, has substantially impacted the results of systematic reviews and guideline recommendations. PERSPECTIVE: We found that a group of trials of CBT for spinal pain with concerns relating to their trustworthiness has had substantial impacts on the analyses and conclusions of systematic reviews and clinical practice guidelines. This highlights the need for a greater focus on the trustworthiness of studies in evidence appraisal. PRE-REGISTRATION: Our protocol was preregistered on the Open Science Framework: https://osf.io/m92ax/.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

BACKGROUND: Pain is a common symptom in people with cancer; 30% to 50% of people with cancer will experience moderate-to-severe pain. This can have a major negative impact on their quality of life. Opioid (morphine-like) medications are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. Pain is not sufficiently relieved by opioid medications in 10% to 15% of people with cancer. In people with insufficient relief of cancer pain, new analgesics are needed to effectively and safely supplement or replace opioids. OBJECTIVES: To evaluate the benefits and harms of cannabis-based medicines, including medical cannabis, for treating pain and other symptoms in adults with cancer compared to placebo or any other established analgesic for cancer pain. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 26 January 2023. SELECTION CRITERIA: We selected double-blind randomised, controlled trials (RCT) of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment for cancer pain in adults, with any treatment duration and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The primary outcomes were 1. proportions of participants reporting no worse than mild pain; 2. Patient Global Impression of Change (PGIC) of much improved or very much improved and 3. withdrawals due to adverse events. Secondary outcomes were 4. number of participants who reported pain relief of 30% or greater and overall opioid use reduced or stable; 5. number of participants who reported pain relief of 30% or greater, or 50% or greater; 6. pain intensity; 7. sleep problems; 8. depression and anxiety; 9. daily maintenance and breakthrough opioid dosage; 10. dropouts due to lack of efficacy; 11. all central nervous system adverse events. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified 14 studies involving 1823 participants. No study assessed the proportions of participants reporting no worse than mild pain on treatment by 14 days after start of treatment. We found five RCTs assessing oromucosal nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD)) or THC alone involving 1539 participants with moderate or severe pain despite opioid therapy. The double-blind periods of the RCTs ranged between two and five weeks. Four studies with a parallel design and 1333 participants were available for meta-analysis. There was moderate-certainty evidence that there was no clinically relevant benefit for proportions of PGIC much or very much improved (risk difference (RD) 0.06, 95% confidence interval (CI) 0.01 to 0.12; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 8 to 100). There was moderate-certainty evidence for no clinically relevant difference in the proportion of withdrawals due to adverse events (RD 0.04, 95% CI 0 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 16 to endless). There was moderate-certainty evidence for no difference between nabiximols or THC and placebo in the frequency of serious adverse events (RD 0.02, 95% CI -0.03 to 0.07). There was moderate-certainty evidence that nabiximols and THC used as add-on treatment for opioid-refractory cancer pain did not differ from placebo in reducing mean pain intensity (standardised mean difference (SMD) -0.19, 95% CI -0.40 to 0.02). There was low-certainty evidence that a synthetic THC analogue (nabilone) delivered over eight weeks was not superior to placebo in reducing pain associated with chemotherapy or radiochemotherapy in people with head and neck cancer and non-small cell lung cancer (2 studies, 89 participants, qualitative analysis). Analyses of tolerability and safety were not possible for these studies. There was low-certainty evidence that synthetic THC analogues were superior to placebo (SMD -0.98, 95% CI -1.36 to -0.60), but not superior to low-dose codeine (SMD 0.03, 95% CI -0.25 to 0.32; 5 single-dose trials; 126 participants) in reducing moderate-to-severe cancer pain after cessation of previous analgesic treatment for three to four and a half hours (2 single-dose trials; 66 participants). Analyses of tolerability and safety were not possible for these studies. There was low-certainty evidence that CBD oil did not add value to specialist palliative care alone in the reduction of pain intensity in people with advanced cancer. There was no difference in the number of dropouts due to adverse events and serious adverse events (1 study, 144 participants, qualitative analysis). We found no studies using herbal cannabis. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that oromucosal nabiximols and THC are ineffective in relieving moderate-to-severe opioid-refractory cancer pain. There is low-certainty evidence that nabilone is ineffective in reducing pain associated with (radio-) chemotherapy in people with head and neck cancer and non-small cell lung cancer. There is low-certainty evidence that a single dose of synthetic THC analogues is not superior to a single low-dose morphine equivalent in reducing moderate-to-severe cancer pain. There is low-certainty evidence that CBD does not add value to specialist palliative care alone in the reduction of pain in people with advanced cancer.

ANTECEDENTES: El dolor es un síntoma común en las personas con cáncer; entre el 30% y el 50% de las personas con cáncer experimentarán dolor de moderado a intenso. Esto puede tener un gran impacto negativo en su calidad de vida. Los fármacos opiáceos (similares a la morfina) se utilizan habitualmente para tratar el dolor por cáncer moderado o intenso, y se recomiendan para este propósito en la escala de tratamiento del dolor de la Organización Mundial de la Salud (OMS). El dolor no se alivia lo suficiente con los medicamentos opiáceos en el 10% al 15% de las personas con cáncer. En las personas con un alivio insuficiente del dolor por cáncer, se necesitan nuevos analgésicos que complementen o sustituyan de forma eficaz y segura a los opiáceos. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de los medicamentos con cannabis, incluido el cannabis medicinal, para tratar el dolor y otros síntomas en adultos con cáncer en comparación con placebo o cualquier otro analgésico establecido para el dolor por cáncer. MÉTODOS DE BÚSQUEDA: Se utilizaron los métodos exhaustivos estándar de búsqueda de Cochrane. La última fecha de búsqueda fue el 26 de enero de 2023. CRITERIOS DE SELECCIÓN: Se seleccionaron los ensayos controlados aleatorizados (ECA) doble ciego de cannabis medicinal, medicamentos derivados de plantas y sintéticos con cannabis versus placebo o cualquier otro tratamiento activo para el dolor por cáncer en adultos, con cualquier duración del tratamiento y al menos 10 participantes por grupo de tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los métodos estándar de Cochrane. Los desenlaces principales fueron los siguientes: 1. proporción de participantes que declararon dolor leve; 2. Patient Global Impression of Change (PGIC) de mucha o muchísima mejoría y 3. retiros debido a eventos adversos. Los desenlaces secundarios fueron 4. número de participantes que declararon un alivio del dolor del 30% o superior y un consumo general de opiáceos reducido o estable; 5. número de participantes que declararon un alivio del dolor del 30% o superior, o del 50% o superior; 6. intensidad del dolor; 7. problemas de sueño; 8. depresión y ansiedad; 9. dosis diaria de opiáceos de mantenimiento y de inicio; 10. abandonos por falta de eficacia; 11. todos los eventos adversos del sistema nervioso central. Se utilizó el método GRADE para evaluar la calidad de la evidencia de cada desenlace. RESULTADOS PRINCIPALES: Se identificaron 14 estudios con 1823 participantes. Ningún estudio evaluó las proporciones de participantes que declararon un dolor no peor que leve a los 14 días de inicio del tratamiento. Se encontraron cinco ECA que evaluaron nabiximoles oromucosos (tetrahidrocannabinol [THC] y cannabidiol [CBD]) o THC solo, con 1539 participantes con dolor moderado o intenso a pesar del tratamiento con opiáceos. Los periodos doble ciego de los ECA variaron entre dos y cinco semanas. Para el metanálisis se dispuso de cuatro estudios con un diseño paralelo y 1333 participantes. Hubo evidencia de certeza moderada de que no hubo efectos beneficiosos clínicamente relevantes en las proporciones de PGIC de mucha o muchísima mejoría (diferencia de riesgos [DR] 0,06; intervalo de confianza [IC] del 95%: 0,01 a 0,12; número necesario a tratar para lograr un resultado beneficioso adicional [NNTB] 16; IC del 95%: 8 a 100). Hubo evidencia de certeza moderada de que no hubo diferencias clínicamente relevantes en la proporción de retiros debido a eventos adversos (DR 0,04; IC del 95%: 0 a 0,08; número necesario a tratar para lograr un desenlace perjudicial adicional [NNTD] 25; IC del 95%: 16 a infinito). Hubo evidencia de certeza moderada de que no hubo diferencias entre nabiximols o THC y placebo en la frecuencia de eventos adversos graves (DR 0,02; IC del 95%: ­0,03 a 0,07). Hubo evidencia de certeza moderada de que los nabiximoles y el THC utilizados como tratamiento complementario para el dolor por cáncer refractario a los opiáceos no difirieron del placebo en cuanto a la reducción de la intensidad media del dolor (diferencia de medias estandarizada [DME] ­0,19; IC del 95%: ­0,40 a 0,02). Hubo evidencia de certeza baja de que un análogo sintético del THC (nabilona) administrado durante ocho semanas no fue superior a placebo para reducir el dolor asociado con la quimioterapia o la radioquimioterapia en personas con cáncer de cabeza y cuello y cáncer de pulmón de células no pequeñas (dos estudios, 89 participantes, análisis cualitativo). En estos estudios no fue posible realizar análisis de tolerabilidad y seguridad. Hubo evidencia de certeza baja de que los análogos sintéticos del THC fueron superiores a placebo (DME ­0,98; IC del 95%: ­1,36 a ­0,60), pero no superiores a la codeína en dosis bajas (DME 0,03; IC del 95%: ­0,25 a 0,32; cinco ensayos de dosis única; 126 participantes) en cuanto a la reducción del dolor moderado a intenso por cáncer después de la interrupción del tratamiento analgésico previo durante tres a cuatro horas y media (dos ensayos de dosis única; 66 participantes). En estos estudios no fue posible realizar análisis de tolerabilidad y seguridad. Hubo evidencia de certeza baja de que el aceite de CBD no agregó valor a los cuidados paliativos especializados solos en la reducción de la intensidad del dolor en personas con cáncer avanzado. No hubo diferencias en el número de abandonos debido a eventos adversos ni eventos adversos graves (un estudio, 144 participantes, análisis cualitativo). No se encontraron estudios que utilizaran la planta de cannabis. CONCLUSIONES DE LOS AUTORES: Existe evidencia de certeza moderada de que los nabiximoles y el THC por vía oromucosa no son efectivos para aliviar el dolor de moderado a intenso por cáncer refractario a los opiáceos. Hay evidencia de certeza baja de que la nabilona no es efectiva para reducir el dolor asociado con la radio­quimioterapia en personas con cáncer de cabeza y cuello y cáncer de pulmón de células no pequeñas. Hay evidencia de certeza baja de que una dosis única de análogos sintéticos del THC no es superior a una dosis única baja equivalente de morfina para reducir el dolor moderado a intenso por cáncer. Hay evidencia de certeza baja de que el CBD no aporta valor a los cuidados paliativos especializados solos en la reducción del dolor en personas con cáncer avanzado.

Characteristics of retracted publications related to pain research: a systematic review.

ABSTRACT: Retraction is a mechanism for correcting the scientific record and alerts readers when a study contains unreliable or flawed data. Such data may arise from error or research misconduct. Studies examining the landscape of retracted publications provide insight into the extent of unreliable data and its effect on a medical discipline. We aimed to explore the extent and characteristics of retracted publications in pain research. We searched the EMBASE, PubMed, CINAHL, PsycINFO, and Retraction Watch databases to December 31, 2022. We included retracted articles that (1) investigated mechanisms of painful conditions, (2) tested treatments that aimed to reduce pain, or (3) measured pain as an outcome. Descriptive statistics were used to summarise the included data. We included 389 pain articles published between 1993 and 2022 and retracted between 1996 and 2022. There was a significant upward trend in the number of retracted pain articles over time. Sixty-six percent of articles were retracted for reasons relating to misconduct. The median (interquartile range) time from article publication to retraction was 2 years (0.7-4.3). The time to retraction differed by reason for retraction, with data problems, comprising data falsification, duplication, and plagiarism, resulting in the longest interval (3 [1.2-5.2] years). Further investigations of retracted pain articles, including exploration of their fate postretraction, are necessary to determine the impact of unreliable data on pain research.

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm.  DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain.  Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.

A porcine bladder model of pre-clinical urodynamics demonstrates increased afferent nerve activity during filling.

INTRODUCTION AND OBJECTIVES: Urodynamics are the accepted gold standard for the evaluation of multiple forms of voiding dysfunction. However, the tests are expensive, invasive, poorly reproducible, and often prone to artifacts. Therefore, there is a pressing need to develop next-generation urodynamics. The purpose of this study was to develop a novel ex vivo porcine bladder urodynamics model with afferent pelvic nerve signaling that can be used as a preclinical surrogate for bladder sensation. METHODS: Porcine bladders including the ureters and vascular supply were harvested from local abattoirs using an established protocol in both male and female animals. Ex vivo bladder perfusion was performed using physiologic MOPS (3-(N-morpholino) propanesulfonic acid) buffer solution. The pelvic nerve adjacent to the bladder was grasped with micro-hook electrodes and electroneurogram (ENG) signals recorded at 20 kHz. Bladders were filled with saline at a nonphysiologic rate (100 mL/min) to a volume of 1 L using standard urodynamics equipment to simultaneously record intravesical pressure. ENG amplitude was calculated as the area under the curve for each minute, and ENG firing rate was calculated as number of spikes (above baseline threshold) per minute. At the conclusion of the experiment, representative nerve samples were removed and processed for nerve histology by a pathologist (hematoxylin and eosin and S100 stains). RESULTS: A total of 10 pig bladders were used, and nerve histology confirmed the presence of nerve in all adequately processed samples. Vesical pressure, ENG firing rate, and ENG amplitude all increased as a function of filling. During filling tertiles (low fill: min 1-3, med fill: min 4-6, and high fill: min 7-10), normalized pressures were 0.22 ± 0.04, 0.38 ± 0.05, and 0.72 ± 0.07 (cmH2O). Similarly, normalized ENG firing rates were 0.08 ± 0.03, 0.31 ± 0.06, and 0.43 ± 0.04 spikes/minute, respectively, and normalized nerve amplitudes were 0.11 ± 0.06, 0.39 ± 0.06, and 0.56 ± 0.14) µV, respectively. Strong relationships between average normalized pressure values and averaged normalized ENG firing rate (r2 = 0.66) and average normalized ENG amplitude (r2 = 0.8) were identified. CONCLUSIONS: The ex vivo perfused porcine bladder can be used as a preclinical model for the development of next-generation urodynamics technologies. Importantly, the model includes a reproducible method to measure afferent nerve activity that directly correlates with intravesical pressure during filling and could potentially be used as a surrogate measure of bladder sensation.

Fruit and vegetable consumption as a preventative strategy for non-communicable diseases.

A high intake of fruit and vegetables (FV) has consistently been associated with a reduced risk of a number of non-communicable diseases. This evidence base is largely from prospective cohort studies, with meta-analyses demonstrating an association between increased FV intake and reduced risk of both CHD and stroke, although the evidence is less certain for cancer and diabetes. Controlled intervention trials examining either clinical or intermediate risk factor endpoints are more scarce. Therefore, evidence that FV consumption reduces the risk of disease is so far largely confined to observational epidemiology, which is hampered by some methodological uncertainties. Although increased FV intake is promoted across all dietary guidelines, national surveys confirm that dietary intakes are suboptimal and are not increasing over time. A range of barriers to increasing FV intake exist, including economic, physical and behavioural barriers that must be considered when exploring potential opportunities to change this, considering the feasibility of different approaches to encourage increased FV consumption. Such interventions must include consideration of context, for example, challenges and uncertainties which exist with the whole food system.

Investigating the veracity of a sample of divergent published trial data in spinal pain.

ABSTRACT: Evidence-based medicine is replete with studies assessing quality and bias, but few evaluating research integrity or trustworthiness. A recent Cochrane review of psychological interventions for chronic pain identified trials with a shared lead author with highly divergent results. We sought to systematically identify all similar trials from this author to explore their risk of bias, governance procedures, and trustworthiness. We searched OVID MEDLINE, EMBASE, CENTRAL, and PEDro from 2010 to December 22, 2021 for trials. We contacted the authors requesting details of trial registration, ethical approval, protocol, and access to the trial data for verification. We used the Cochrane risk-of-bias tool and the Cochrane Pregnancy and Childbirth group's Trustworthiness Screening Tool to guide systematic exploration of trustworthiness. Ten trials were included: 9 compared cognitive behavioural therapy and physical exercise to usual care, exercise alone, or physiotherapy and 1 compared 2 brief cognitive behavioural therapy programmes. Eight trials reported results divergent from the evidence base. Assessment of risk of bias and participant characteristics identified no substantial concerns. Responses from the lead author did not satisfactorily explain this divergence. Trustworthiness screening identified concerns about research governance, data plausibility at baseline, the results, and apparent data duplication. We discuss the findings within the context of methods for establishing the trustworthiness of research findings generally. Important concerns regarding the trustworthiness of these trials reduce our confidence in them. They should probably not be used to inform the results and conclusions of systematic reviews, in clinical training, policy documents, or any relevant instruction regarding adult chronic pain management.

Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis.

ABSTRACT: Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy-as second- or third-line treatment-in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.

Prevalence and correlates of stocking up on drugs during the COVID-19 pandemic: Data from the C3PNO Consortium.

BACKGROUND: Data from the COVID-19 pandemic describes increases in drug use and related harms, especially fatal overdose. However, evidence is needed to better understand the pathways from pandemic-related factors to substance use behaviours. Thus, we investigated stockpiling drugs among people who use drugs (PWUD) in five cities in the United States and Canada. METHODS: We used data from two waves of interviews among participants in nine prospective cohorts to estimate the prevalence and correlates of stockpiling drugs in the previous month. Longitudinal correlates were identified using bivariate and multivariate generalized linear mixed-effects modeling analyses. RESULTS: From May 2020 to February 2021, we recruited 1873 individuals who completed 2242 interviews, of whom 217 (11.6%) reported stockpiling drugs in the last month at baseline. In the multivariate model, stockpiling drugs was significantly and positively associated with reporting being greatly impacted by COVID-19 (Adjusted Odds Ratio [AOR]= 1.21, 95% CI: 1.09-1.45), and at least daily use of methamphetamine (AOR = 4.67, 95% CI: 2.75-7.94) in the past month. CONCLUSIONS: We observed that approximately one-in-ten participants reported stocking up on drugs during the COVID-19 pandemic. This behaviour was associated with important drug-related risk factors including high-intensity methamphetamine use. While these correlations need further inquiry, it is possible that addressing the impact of COVID-19 on vulnerable PWUD could help limit drug stockpiling, which may lower rates of high-intensity stimulant use.

Bayesian estimation of sensitivity and specificity of a milk pregnancy-associated glycoprotein ELISA test for pregnancy diagnosis between 23 and 27 days after insemination in Holstein dairy cows.

Pregnancy diagnosis using pregnancy-associated glycoprotein (PAG) ELISA technology in blood or milk samples is validated from 28 d after insemination in dairy cows. The objective of this study was to estimate the sensitivity (Se) and specificity (Sp) of a commercial milk PAG-based ELISA in Holstein dairy cows between 23 and 27 d after insemination. Milk samples (n = 268) from 257 Holstein dairy cows 23 to 27 d after AI were submitted for PAG ELISA testing. Pregnancy status was confirmed by either a second milk PAG ELISA test conducted between 28 and 50 d after insemination (n = 200) or transrectal ultrasonography performed between 28 and 59 d after insemination (n = 68). A Bayesian latent class model was used to compare the paired results from the test at 23 to 27 d after AI test to the reference test. The latent class model typically used for comparing 2 or more imperfect tests was extended to include the possibility of pregnancy loss between the 23 to 27 d test and the reference test. Informative priors for the probability of pregnancy loss, and for the Se and Sp of the PAG and ultrasonography reference tests were obtained from the scientific literature. Estimated median Se and Sp of the PAG ELISA test conducted between 23 and 27 d after AI were 0.98 (95% credible interval 0.93 to 1.0) and 0.98 (0.89 to 1.0), respectively, when using a standardized corrected optical density threshold of 0.15. Although the accuracy of the test under investigation was excellent, more data will be needed to confirm the optimal diagnostic cut point for PAG in milk for early pregnancy diagnosis in this time window. The optimal timing of pregnancy diagnosis will depend on herd-specific logistics and the action to be taken to re-inseminate nonpregnant cows.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.