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Antipsychotics are first-line treatments for schizophrenia, yet many patients show inadequate response. Clozapine, the gold standard for treatment-resistant schizophrenia, remains underutilised due to safety and monitoring concerns.
Aims
To evaluate the adverse effects of clozapine in schizophrenia through a meta-analysis of randomised controlled trials (RCTs).
Method
We systematically searched MEDLINE, CENTRAL, Embase, PsycINFO, ClinicalTrials.gov and WHO ICTRP up to 10 October 2024 for RCTs comparing clozapine (as either monotherapy or combination therapy) with other antipsychotics. We assessed 37 distinct adverse outcomes. Risk ratios were calculated for dichotomous outcomes and standardised mean differences for continuous outcomes, with confidence intervals.
Results
A total of 116 RCTs (n = 8431) were included. In 69 monotherapy RCTs (n = 6281), clozapine showed no difference in either mortality (risk ratio 1.01, 95% CI: 0.50, 2.01, prevalence 0.1%) or discontinuation due to adverse effects (risk ratio 1.18, 95% CI: 0.91, 1.53, prevalence 7.2%). Agranulocytosis risk was nearly tripled (risk ratio 2.81, 95% CI: 0.97, 8.12, prevalence 0.7%), although with wide confidence intervals. Clozapine increased the risk of seizures (risk ratio 3.61, 95% CI: 1.80, 7.95, prevalence 3.1%) and orthostatic hypotension/bradycardia/syncope (risk ratio 1.66, 95% CI: 1.00, 2.77, prevalence 11%). No difference was found for myocarditis/cardiomyopathy (risk ratio 0.33, 95% CI: 0.01, 8.13). Clozapine increased the risk of leukopenia, hypersalivation, sedation, tachycardia, hypertension, constipation, nausea/vomiting, fever, flu-like syndrome and headache. In 47 combination RCTs (n = 2150), clozapine combinations were not associated with increased risk of severe adverse effects; no cases of agranulocytosis (21 RCTs, n = 894) or seizures (8 RCTs, n = 313) were reported in trials that explicitly assessed these outcomes.
Conclusions
Life-threatening adverse events remain rare with clozapine. With appropriate monitoring, its safety profile supports broader and potentially earlier use. Future studies should refine monitoring protocols and explore additional indications.
We describe an outbreak of hospital-acquired Legionella pneumonia in a hematology ward; a cold drinking water dispenser was identified as the source. Regular surveillance and provision of appropriate water quality to high-risk patients are critical, and hospitals should be aware of the risks associated with the use of these devices.
This paper examines the life trajectories, social contexts and living conditions of women of uncertain status in post-slavery, colonial-era Tabora, with a focus on those involved in the production and consumption of beer. It thereby searches insights into the aftermath of slavery in this region, particularly for women. It reflects on the persistent social unease surrounding slavery and its aftermath, and on the way it shapes and limits sources, arguing that a focus on post-slavery is nevertheless productive. Set in context, brewers’ life stories provide a vivid illustration of a competitive urban environment, the chances for self-emancipation that it offered, and the concomitant challenges and dangers. They thereby also enable fresh insight into the social history of alcohol and of urban women in colonial Africa. We find evidence of more successful brewing careers than existing studies would predict, but also of very stark vulnerability and persistent quests for safety in family networks. This spread of outcomes highlights the contingent nature of emancipation and the endlessly varied ways in which social constraints and personal motivations combined in individual lives.
Although civil–military relations scholarship has rightly prioritized establishing policies that subordinate the military to civilian political control, there has been less focus on how lawfully elected executives may abuse their military authorities to undermine democracy. However, recent history shows that executives can and have critically shirked their responsibilities as commanders-in-chief. In doing so, they contribute to democratic backsliding. Some executive mismanagement of the military is harmless and routine, but other types of executive mismanagement are dangerous and exceptional. Although executives have the right to be wrong regarding security policy making, they also have a responsibility to be a reasonable commander-in-chief who upholds the nonpartisan character of the military and keeps it within democratic constraints. In this article I build on a principal-agent (P-A) framework of civil–military relations by importing a concept from the P-A literature, “principal shirking,” to establish a new concept, “executive shirking.” This conceptualization lays out a framework for scholars of civil–military relations and democratic backsliding and provides a typology of executive misbehavior based on the degree of potential democratic harm. In doing so, it provides a valuable tool to detect and analyze executive shirking and offers steps to take when executives abuse their military powers.
J.L. Schellenberg’s argument from divine hiddenness partly rests on the claim that non-resistant non-belief exists. In this paper, I take up the question of whether such non-belief is pervasive and argue that it is, in fact, relatively common. To support this claim, I present a novel argument grounded in a distinction between acquisition responsibility and maintenance responsibility. I argue that, for a non-believer to count as resistant in Schellenberg’s sense, they must be acquisition-responsible for their non-belief in God. I further contend that many non-believers lack such responsibility and therefore qualify as non-resistant. This argument has the added benefit of showing that many prominent objections to the existence of non-resistant non-belief are irrelevant or incomplete. Finally, I highlight the broader significance of this conclusion, both for Schellenberg’s argument and in light of recent shifts in the literature towards more evidential approaches.
Liturgies of Empire adopts a deliberately satirical, epistolary voice to examine the after-lives of Anglican imperialism as reconfigured in contemporary neocolonial activity. Some terms and turns of phrase assume an insider’s knowledge, and familiarity with socio-political definitions, the geographical regions and their specific religious registers and discourse would place the reader in a better position to appreciate the North/South epistemic critiques. Whilst the English narrator, recipient and institutional offices in the missive are entirely fictional, all events, statistics, and quotations are factual and have been verified against the sources cited. The memo casts an eye over three postcolonial Anglican dioceses as case studies to examine how the Anglican Realignment revives the spirit of empire through insistence on its monopoly of truth. It traces how conservative evangelical networks, under the banner of biblical warrant and “Global South” identity, reintensify imperial-era logics of propriety and paternalism. Attempting to supplant Canterbury’s more generous ecclesial disposition, these self-proclaimed guardians of truth are grounded in patriarchal authority, marked not by self-scrutiny but fixation on policing gender and sexuality. Theirs is an ecclesiology that cannot abide dissent, ambiguity, or difference, sanctifying conformity as faithfulness and exclusion as orthodoxy.
It has long been challenging to assess local residents’ quality of life, which is affected by numerous natural and man-made amenities. We develop a novel compensating differential model of quality-of-life rankings applicable to developing countries by introducing farm income into the household budget alongside housing and labour market differentials. We apply this model to Indonesia using detailed household data from the Indonesian Family Life Survey for two different time periods and combining estimates of agricultural, off-farm labour and housing market differentials. We find heterogeneous amenity impacts across the agricultural and off-farm labour sectors. We use our model to show how significant changes in rankings across time are consistent with contemporaneous internal migration patterns in Indonesia. These rankings yield important information for policymakers on expected changes in migration and can be used to help inform public investment.
Wall slip sensitivity and non-sphericity and orientation effects are investigated for a moving no-slip solid body immersed in a fluid above a plane slip wall with a Navier slip. The wall–particle interactions are examined for the body motion in a quiescent fluid (resistance problem) or when freely suspended in a prescribed ‘linear’ or quadratic ambient shear flow. This is achieved, assuming Stokes flows, by using a boundary method which reduces the task to the treatment of six boundary-integral equations on the body surface. For a wall slip length $\lambda$ small compared with the wall–particle gap $d$ a ‘recipe’ connecting, at $O((\lambda /d)^2),$ the results for the slip wall and another no-slip wall with gap $d+\lambda$ is established. A numerical analysis is performed for a family of inclined non-spheroidal ellipsoids, having the volume of a sphere with radius $a,$ to quantity the particle behaviour sensitivity to the normalised wall slip length $\overline {\lambda }=\lambda /a,$ the normalised wall–particle gap ${\overline {d}}=d/a$ and the particle shape and orientation (here one angle $\beta ).$ The friction coefficients for the resistance problem exhibit quite different behaviours versus the particle shape and $({\overline {d}}, \overline {\lambda },\beta ).$ Some coefficients increase in magnitude with the wall slip. The migration of the freely suspended particle can also strongly depend on $({\overline {d}}, \overline {\lambda },\beta )$ and in a non-trivial way. For sufficiently small $\overline {d}$ a non-spherical particle can move faster than in the absence of a wall for a large enough wall slip for the ambient ‘linear’ shear flow and whatever the wall slip for the ambient quadratic shear flow.
I aim at dissolving Saul Kripke’s dogmatism paradox by defending the idea that, with respect to any particular proposition p known by a subject A, it is not irrational for A to ignore all evidence against p. Here my defence of the dogmatic attitude depends on the crucial assumption – and this is an assumption made by Kripke himself in the setting of the paradox – that A wishes above all else to avoid gaining a false belief or losing a true one. An appendix briefly examines the possibility of a knowledge version of the paradox, as opposed to Kripke’s original true-belief version.
Historians of the Cold War and the nuclear age have largely overlooked the existence of tabletop role-playing games (TTRPGs), while films, comics, novels, and television programmes that tackled the challenging imaginary, yet all-too-possible, wastes of a post-nuclear landscape have been abundantly analysed. As cultural products and tools through which to imagine other worlds, TTRPGs offer powerful insights into how, where, and why certain groups thought about the spectre of the nuclear age and how they dealt with this threat by gaming within make-believe postapocalyptic worlds. This article draws together several threads in its analysis of the American-designed and -produced Twilight: 2000 TTRPG’s historical significance. Through analysing Twilight: 2000 as a case study of how a TTRPG functions as a specific nuclear-cultural object in its own right, the article also locates this game as a part of a wider-reaching dystopian fantasy rooted in the massive everyday reality of atomic annihilation. Likewise, the game, its mechanics, setting, and artwork are analysed here as part of a distinctive Cold War culture that permitted participants to derive pleasure and affirmation from fictional “adventures” in the postapocalyptic environment.
Haritalodes derogata (Fabricius) (Lepidoptera: Crambidae), commonly known as the cotton leaf roller, is an important polyphagous pest that causes damage to various agricultural and forest plants, especially those of the Malvaceae family, but also to crops such as cotton, cashew, bamboo, oats, and jute. While microbial control agents are known for their efficacy and environmental friendliness, there are few studies demonstrating their effect on H. derogata. The aim of this study was to evaluate the bioefficacy of microbial agents from different pathogen groups against this pest. To this end, we investigated the insecticidal potential of fifteen indigenous microbial isolates from our entomopathogen collection. These included five Bacillus thuringiensis strains (Bn1, MnD, Mm2, Xd3, Lyd8), five entomopathogenic fungi (Metarhizium flavoviride As2, M. anisopliae KTU-51 and Beauveria bassiana Pa4, Pa5, Hp5), and five baculoviruses (HycuGV-Hc1, LdMNPV-T2, AcMNPV, DapuNPV-T1, SeMNPV-U), applied at concentrations of 1.8 × 109 cfu/mL, 1 × 107 conidia/mL, and 1 × 107 PIB/mL, respectively, against H. derogata larvae under laboratory conditions. Among these, B. thuringiensis subsp. kurstaki Bn1, B. bassiana Pa4, Hyphantria cunea granulovirus (HycuGV-Hc1), and Spodoptera exigua nucleopolyhedrovirus (SeMNPV-U) showed strong insecticidal activity and were selected for virulence assays, each achieving 100% mortality in third instar larvae. The median lethal concentrations (LC50) were determined to be 7.1 × 104 cfu/mL, 3.3 × 103 conidia/mL, 1.2 × 103 PIB/mL, and 1 × 103 PIB/mL, respectively. These results indicate that indigenous microbial agents are a promising environmentally friendly alternative to chemical pesticides in the control of H. derogata.
This article analyses how forms of private cooperation between East and West were reshaped during the late Cold War and beyond. It does so by studying an elitist East–West club, called the International Vienna Council, which brings together leaders of multinational companies and leaders of the planned economy. While the permeability of the iron curtain has been well documented, little is known about the evolution of East–West circulation patterns during that time or the role played by economic elites. The International Vienna Council, initially a forum for ‘parallel diplomacy’, gradually became a platform for concrete business cooperation. The club’s activities continued after 1989, but it struggled with the transition from an East–West club to an interest group within the European Union. These dynamics shed light on the gradual autonomy of a private East–West cooperation group and its contribution to defining a pan-European economic space since the 1970s.
The Pósa–Seymour conjecture determines the minimum degree threshold for forcing the $k$th power of a Hamilton cycle in a graph. After numerous partial results, Komlós, Sárközy, and Szemerédi proved the conjecture for sufficiently large graphs. In this paper, we focus on the analogous problem for digraphs and for oriented graphs. We asymptotically determine the minimum total degree threshold for forcing the square of a Hamilton cycle in a digraph. We also give a conjecture on the corresponding threshold for $k$th powers of a Hamilton cycle more generally. For oriented graphs, we provide a minimum semi-degree condition that forces the $k$th power of a Hamilton cycle; although this minimum semi-degree condition is not tight, it does provide the correct order of magnitude of the threshold. Turán-type problems for oriented graphs are also discussed.
This study was undertaken to investigate the molecular detection of biofilm-producing Staphylococcus aureus (S. aureus) from goat mastitis. An overall 384 milk samples were initially screened for subclinical mastitis (SCM) followed by molecular characterization of S. aureus isolates. The biofilm formation was assessed using Congo Red agar (CRA), a microtiter plate and the presence of the icaA gene. The results revealed a molecular prevalence of 53.24% (115/216) for pathogenic S. aureus in milk samples of goats. The phenotypic prevalence of biofilm production by CRA and microtitre methods was recorded to be 38.26% (44/115) and 26.96% (31/115) respectively, while the molecularly confirmed biofilm-forming S. aureus through polymerase chain reaction targeting icaA gene was 58.26% (67/115). The phylogenetic analysis of icaA gene revealed high identity between sequences of study isolates and the isolates of other neighbouring countries. The antibiogram profiling of pathogenic S. aureus showed increased resistance to cefoxitin and oxytetracycline followed by gentamicin. Out of 115, 45.22% (52/115) were declared as multiple drug resistant with multiple antibiotic resistance index greater than 0.2. The study concluded that biofilm-producing S. aureus strains are considered to be a common cause of SCM in dairy goats of Pakistan and biofilm formation is associated with multidrug resistance of study isolates.