Use of antipsychotic drugs and cholinesterase inhibitors and risk of falls and fractures: self-controlled case series

Objective To evaluate the association between the use of antipsychotic drugs and cholinesterase inhibitors and the risk of falls and fractures in elderly patients with major neurocognitive disorders. Design Self-controlled case series. Setting Taiwan’s National Health Insurance Database. Participants 15 278 adults, aged ≥65, with newly prescribed antipsychotic drugs and cholinesterase inhibitors, who had an incident fall or fracture between 2006 and 2017. Prescription records of cholinesterase inhibitors confirmed the diagnosis of major neurocognitive disorders; all use of cholinesterase inhibitors was reviewed by experts. Main outcome measures Conditional Poisson regression was used to derive incidence rate ratios and 95% confidence intervals for evaluating the risk of falls and fractures for different treatment periods: use of cholinesterase inhibitors alone, antipsychotic drugs alone, and a combination of cholinesterase inhibitors and antipsychotic drugs, compared with the non-treatment period in the same individual. A 14 day pretreatment period was defined before starting the study drugs because of concerns about confounding by indication. Results The incidence of falls and fractures per 100 person years was 8.30 (95% confidence interval 8.14 to 8.46) for the non-treatment period, 52.35 (48.46 to 56.47) for the pretreatment period, and 10.55 (9.98 to 11.14), 10.34 (9.80 to 10.89), and 9.41 (8.98 to 9.86) for use of a combination of cholinesterase inhibitors and antipsychotic drugs, antipsychotic drugs alone, and cholinesterase inhibitors alone, respectively. Compared with the non-treatment period, the highest risk of falls and fractures was during the pretreatment period (adjusted incidence rate ratio 6.17, 95% confidence interval 5.69 to 6.69), followed by treatment with the combination of cholinesterase inhibitors and antipsychotic drugs (1.35, 1.26 to 1.45), antipsychotic drugs alone (1.33, 1.24 to 1.43), and cholinesterase inhibitors alone (1.17, 1.10 to 1.24). Conclusions The incidence of falls and fractures was high in the pretreatment period, suggesting that factors other than the study drugs, such as underlying diseases, should be taken into consideration when evaluating the association between the risk of falls and fractures and use of cholinesterase inhibitors and antipsychotic drugs. The treatment periods were also associated with a higher risk of falls and fractures compared with the non-treatment period, although the magnitude was much lower than during the pretreatment period. Strategies for prevention and close monitoring of the risk of falls are still necessary until patients regain a more stable physical and mental state.

Regulatory Influence of Galanin and GALR1/GALR2 Receptors on Inflamed Uterus Contractility in Pigs

Uterine inflammation is a very common and serious pathology in domestic animals, the development and progression of which often result from disturbed myometrial contractility. We investigated the effect of inflammation on the protein expression of galanin (GAL) receptor subtypes (GALR)1 and GALR2 in myometrium and their role in the contractile amplitude and frequency of an inflamed gilt uterus. The gilts of the E. coli and SAL groups received E. coli suspension or saline in their uteri, respectively, and only laparotomy was performed (CON group). Eight days later, the E. coli group developed severe acute endometritis and lowered GALR1 protein expression in the myometrium. Compared to the pretreatment period, GAL (10−7 M) reduced the amplitude and frequency in myometrium and endometrium/myometrium of the CON and SAL groups, the amplitude in both stripes and frequency in endometrium/myometrium of the E. coli group. In this group, myometrial frequency after using GAL increased, and it was higher than in other groups. GALR2 antagonist diminished the decrease in amplitude in myometrium and the frequency in endometrium/myometrium (SAL, E. coli groups) induced by GAL (10−7 M). GALR1/GALR2 antagonist and GAL (10−7 M) reversed the decrease in amplitude and diminished the decrease in frequency in both examined stripes (CON, SAL groups), and diminished the drop in amplitude and abolished the rise in the frequency in the myometrium (E. coli group). In summary, the inflammation reduced GALR1 protein expression in pig myometrium, and GALR1 and GALR2 participated in the contractile regulation of an inflamed uterus.

Low-Dose Acitretin for Secondary Prevention of Keratinocyte Carcinomas in Solid-Organ Transplant Recipients

<b><i>Background:</i></b> Keratinocyte carcinomas, particularly squamous cell carcinoma (SCC), occur more frequently and aggressively in solid-organ transplant recipients (SOTRs) than in the general population. Systemic retinoids are effective in secondary prevention of keratinocyte carcinomas in this population, but their use is limited by adverse effects including a rebound effect in cases of treatment discontinuation. <b><i>Objective:</i></b> Our aim was to determine whether low-dose acitretin is efficient in the secondary prevention of keratinocyte carcinomas in SOTRs. <b><i>Methods:</i></b> This retrospective case-crossover study was conducted at a specialized dermatology clinic for SOTRs in a large transplantation center in 2010–2017. Patients with at least 1 previous keratinocyte carcinoma who were treated with acitretin 10 mg/day for 2 years were included. The main outcome was the difference in the number of new keratinocyte carcinomas diagnosed during treatment compared to during the 2-year pretreatment period. <b><i>Results:</i></b> The cohort included 34 SOTRs. A significant reduction in the mean number of new keratinocyte carcinomas during treatment relative to the pretreatment period was observed (1.7 vs. 3.6, –53% <i>p</i> = 0.002). Similar results were noted on analysis by tumor type, for both SCC and basal cell carcinoma. <b><i>Conclusion:</i></b> This study of SOTRs demonstrated positive results for low-dose acitretin as a chemoprevention of keratinocyte carcinomas in this population.

How to reduce household costs for people with tuberculosis: a longitudinal costing survey in Nepal

The aim of this study was to compare costs and socio-economic impact of tuberculosis (TB) for patients diagnosed through active (ACF) and passive case finding (PCF) in Nepal. A longitudinal costing survey was conducted in four districts of Nepal from April 2018 to October 2019. Costs were collected using the WHO TB Patient Costs Survey at three time points: intensive phase of treatment, continuation phase of treatment and at treatment completion. Direct and indirect costs and socio-economic impact (poverty headcount, employment status and coping strategies) were evaluated throughout the treatment. Prevalence of catastrophic costs was estimated using the WHO threshold. Logistic regression and generalized estimating equation were used to evaluate risk of incurring high costs, catastrophic costs and socio-economic impact of TB over time. A total of 111 ACF and 110 PCF patients were included. ACF patients were more likely to have no education (75% vs 57%, P = 0.006) and informal employment (42% vs 24%, P = 0.005) Compared with the PCF group, ACF patients incurred lower costs during the pretreatment period (mean total cost: US$55 vs US$87, P &lt; 0.001) and during the pretreatment plus treatment periods (mean total direct costs: US$72 vs US$101, P &lt; 0.001). Socio-economic impact was severe for both groups throughout the whole treatment, with 32% of households incurring catastrophic costs. Catastrophic costs were associated with ‘no education’ status [odds ratio = 2.53(95% confidence interval = 1.16–5.50)]. There is a severe and sustained socio-economic impact of TB on affected households in Nepal. The community-based ACF approach mitigated costs and reached the most vulnerable patients. Alongside ACF, social protection policies must be extended to achieve the zero catastrophic costs milestone of the End TB strategy.

Testosterone induces plumage ornamentation followed by enhanced territoriality in a female songbird

We know little of the proximate mechanisms underlying the expression of signaling traits in female vertebrates. Across males, the expression of sexual and competitive traits, including ornamentation and aggressive behavior, is often mediated by testosterone. In the white-shouldered fairywren (Malurus alboscapulatus) of New Guinea, females of different subspecies differ in the presence or absence of white shoulder patches and melanic plumage, whereas males are uniformly ornamented. Previous work has shown that ornamented females circulate more testosterone and exhibit more territorial aggression than do unornamented females. We investigated the degree to which testosterone regulates the expression of ornamental plumage and territorial behavior by implanting free-living unornamented females with testosterone. Every testosterone-treated female produced a male-like cloacal protuberance, and 15 of 20 replaced experimentally plucked brown with white shoulder patch feathers but did not typically produce melanic plumage characteristic of ornamented females. Testosterone treatment did not elevate territorial behavior prior to the production of the plumage ornament or during the active life of the implant. However, females with experimentally induced ornamentation, but exhausted implants, increased the vocal components of territory defense relative to the pretreatment period and also to testosterone-implanted females that did not produce ornamentation. Our results suggest that testosterone induces partial acquisition of the ornamental female plumage phenotype and that ornament expression, rather than testosterone alone, results in elevations of some territorial behaviors.

A new biofeedback approach for the control of awake bruxism and chronic migraine headache: utilization of an awake posterior interocclusal device

ABSTRACT Background: The relationship of bidirectional comorbidity between chronic migraine and pain in the cephalic segment led us to evaluate the improvement in reducing the pain in patients diagnosed with chronic migraine headache and awake bruxism, when undergoing treatment with a partial posterior interocclusal device designed for the management and control of awake bruxism through biofeedback. Methods: Seventy-four patients were evaluated during the following periods: pretreatment, seven, thirty, ninety, one hundred and eighty days, and one year. The evaluation was carried out by measuring the pain in the pretreatment period and pain reduction after awake bruxism treatment, using clinical evaluation and numerical scales for pain. Results: Most of the patients who complained of headache migraine pain, masticatory myofascial pain, temporomandibular joint and neck pain experienced a significant reduction in overall pain, including headaches, between t0 and t30 (p<0.0001). After 30 days of using the device, it was observed that the improvement remained at the same level without any recurrence of pain up to t90. At t180 and t360, it was observed that even with the device withdrawal (at t90) the improvement remained at the same level. Conclusion: The utilization of a posterior interocclusal device designed for the management and control of awake bruxism through biofeedback seems to contribute to the reduction of pain (including migraine headache) in the majority of patients, and, even with the device withdrawal (at t90), the improvement remained at the same level, suggesting the patients succeeded in controlling their awake bruxism and consequently the pains.

Therapeutic Efficacy of a Mixed Formulation of Conventional and PEGylated Liposomes Containing Meglumine Antimoniate, Combined with Allopurinol, in Dogs Naturally Infected with Leishmania infantum

ABSTRACT The treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote a marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP plus Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg of body weight/dose) at 4-day intervals plus allopurinol at 30 mg/kg/12 h per os (p.o.) during 130 days (LCP+Allop); LC plus Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) plus allopurinol during 130 days (LC+Allop); Allop, treated with allopurinol only; and a nontreated control. Parasite loads were evaluated by quantitative PCR in liver, spleen, and bone marrow tissue and by immunohistochemistry in the ear skin, before treatment, just after treatment, and 4 months later. The LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen, and bone marrow 4 months after treatment compared to the pretreatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin in comparison to the control group. On the basis of clinical staging and parasitological evaluations, the LCP formulation exhibited a more favorable therapeutic profile than the LC one, being therefore promising for the treatment of canine visceral leishmaniasis.

Screw-Dislocation-Driven Growth Mode in Two Dimensional GaSe on GaAs(001) Substrates Grown by Molecular Beam Epitaxy

Regardless of the dissimilarity in the crystal symmetry, the two-dimensional GaSe materials grown on GaAs(001) substrates by molecular beam epitaxy reveal a screw-dislocation-driven growth mechanism. The spiral-pyramidal structure of GaSe multi-layers was typically observed with the majority in ε-phase. Comprehensive investigations on temperature-dependent photoluminescence, Raman scattering, and X-ray diffraction indicated that the structure has been suffered an amount of strain, resulted from the screw-dislocation-driven growth mechanism as well as the stacking disorders between monolayer at the boundaries of the GaSe nanoflakes. In addition, Raman spectra under various wavelength laser excitations explored that the common ε-phase of 2D GaSe grown directly on GaAs can be transformed into the β-phase by introducing a Se-pretreatment period at the initial growth process. This work provides an understanding of molecular beam epitaxy growth of 2D materials on three-dimensional substrates and paves the way to realize future electronic and optoelectronic heterogeneous integrated technology as well as second harmonic generation applications.

Tumor growth rate as an early indicator of the efficacy of anti-PD-1 immunotherapy in advanced melanoma.

e21050 Background: As immunotherapeutics take longer time to show clinical efficacy compared with chemotherapy and targeted therapy, it is critical to select patients with low tumor growth rate (TGR) prior immunotherapy as to get sufficient time for immunotherapeutics to play functions. However, which threshold of TGR before immunotherapy may be associated with good outcome remains unknown. Methods: Medical records from patients with advanced refractory melanoma prospectively treated in clinical trials (NCT02836795 and NCT03013101) of anti-PD-1 antibody toripalimab were analyzed. TGR was computed during the pretreatment period (reference) and the treatment period (treatment). Associations between TGR and objective response at the first evaluation, progression free survival (PFS), overall survival (OS) were computed. Results: We analyzed a total of 142 patients enrolled in these two clinical trials. Excluded for no measurable lesions in pretreatment period or incomplete imaging data through the pretreatment/treatment periods, a total of 90 patients could be explored for the relationship of TGR and the efficacy of anti-PD-1 antibody. TGR and hyperprogression were defined as Champiat S. used to make. The distribution of TGR is as follows: median 63.7 (range: -51~720). A total of 15 (16.7%), 41 (45.6%), 34 (37.8%) and 0 patients exhibited PR, SD, PD, CR, respectively. An association between lower TGR (TGR ≤55) and objective response was observed (P≤0.001). Among evaluable patients at week 8, 83.9% (13+34/56) and 26.5% (2+7/34) showed PR/SD from baseline tumor measurements for the group of TGR≤55 and TGR > 55, respectively. Median PFS was 5.5 0.9m in the group of TGR≤55 compared 1.8 0.4m in the group of TGR > 55 (P≤0.001). Median OS was not reached in the group of TGR≤55 group and was 15.9 1.8m in the group of TGR > 55 (p = 0·02). Two patients were confirmed pseudoprogression in the follow-up. The TGR of these two patients was lower than 55. Five patients experienced hyperprogression. The TGR of each patient was 9, 12, 54, 56, 78, respectively. Conclusions: Melanoma patients with TGR≤55 prior anti-PD-1 antibody therapy are more likely to benefit from this regimen. However, it could not predict patients who may develop hyperprogression after anti-PD-1 antibody therapy. Clinical trial information: NCT02836795 and NCT03013101.